Re: 장신구, 벨트, 지퍼 알레르기 원인은? 주로 니켈 알레르기..

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Int J Environ Res Public Health. 2020 Feb; 17(3): 679.

Published online 2020 Jan 21. doi: 10.3390/ijerph17030679

PMCID: PMC7037090

PMID: 31973020

Nickel: Human Health and Environmental Toxicology

Giuseppe Genchi,1 Alessia Carocci,2,* Graziantonio Lauria,1 Maria Stefania Sinicropi,1,* and Alessia Catalano2

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Abstract

Nickel is a transition element extensively distributed in the environment, air, water, and soil. It may derive from natural sources and anthropogenic activity. Although nickel is ubiquitous in the environment, its functional role as a trace element for animals and human beings has not been yet recognized. Environmental pollution from nickel may be due to industry, the use of liquid and solid fuels, as well as municipal and industrial waste. Nickel contact can cause a variety of side effects on human health, such as allergy, cardiovascular and kidney diseases, lung fibrosis, lung and nasal cancer. Although the molecular mechanisms of nickel-induced toxicity are not yet clear, mitochondrial dysfunctions and oxidative stress are thought to have a primary and crucial role in the toxicity of this metal. Recently, researchers, trying to characterize the capability of nickel to induce cancer, have found out that epigenetic alterations induced by nickel exposure can perturb the genome. The purpose of this review is to describe the chemical features of nickel in human beings and the mechanisms of its toxicity. Furthermore, the attention is focused on strategies to remove nickel from the environment, such as phytoremediation and phytomining.

니켈은 

환경, 공기, 물, 토양에 광범위하게 분포하는 

전이 원소입니다. 

니켈은 

자연적인 공급원과 

인위적인 활동에서 파생될 수 있습니다. 

니켈은 

환경에 어디에나 존재하지만 

동물과 인간을 위한 미량 원소로서의 기능적 역할은 아직 밝혀지지 않았습니다. 

니켈로 인한 환경 오염은 

산업, 액체 및 고체 연료의 사용, 

도시 및 산업 폐기물로 인해 발생할 수 있습니다. 

니켈 접촉은 

알레르기, 심혈관 및 신장 질환, 폐 섬유증, 폐암 및 비강암과 같은 

인체 건강에 다양한 부작용을 일으킬 수 있습니다. 

니켈로 인한 독성의 분자 메커니즘은 

아직 명확하지 않지만, 

미토콘드리아 기능 장애와 

산화 스트레스가 

이 금속의 독성에 주요하고 중요한 역할을 하는 것으로 생각됩니다. 

최근 니켈이 

암을 유발하는 능력을 특성화하려는 연구자들은 

니켈 노출로 인한 후성 유전학적 변화가 게놈을 교란할 수 있다는 사실을 발견했습니다. 

이 리뷰의 목적은 

인간에게 니켈의 화학적 특징과 

독성 메커니즘을 설명하는 것입니다. 

또한 식물 정화 및 피

토마이닝과 같은 환경에서 

니켈을 제거하기 위한 전략에 초점을 맞추고 있습니다.

Keywords: nickel, nickel toxicity, nickel allergy, epigenetics, apoptosis, nickel phytoremediation

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1. Introduction

Nickel is a hard, ductile, silvery-white transition metal; it is the 28th element in the periodic table. It may exist in several oxidative states (from −1 to +4); nevertheless, the +2 oxidation state (Ni2+) is the most widespread in the environment and biological systems [1]. Nickel belongs to the ferromagnetic elements, and it is naturally present in the Earth crust usually in combination with oxygen and sulfur as oxides and sulfides. In combination with other elements, nickel may be present in the soil, meteorites and emitted from volcanoes. About eight billion tons of nickel are in the sea. Thanks to its unique physical and chemical properties, nickel is used in modern metallurgies in a broad variety of metallurgical processes, such as alloy production, electroplating, in the production of nickel-cadmium batteries and as a catalyst in chemical and food industry. The high spread of products containing this metal unavoidably leads to pollution of the environment by nickel and its secondary products at all stages of manufacturing, recycling and disposal. Even though no existing evidence denotes the nutritional value of Ni in humans, it has been recognized as an essential nutrient for some microorganisms, plants, and animal species [2]. Enzymes or cofactors containing nickel are not known in higher organisms, but nickel-based enzymes are well known in the Archaea, bacteria, algae, primitive eukaryotes and plants [3,4,5,6,7]. Nickel is essential in proper growth and development of the plants and has vital roles in a wide range of morphological and physiological functions, such as germination seeds and productivity. However, at high levels nickel alters the metabolic activities of the plants inhibiting enzymatic activity, photosynthetic electron transport and chlorophyll biosynthesis [8]. At the present time, several nickel enzymes have been ascertained, including urease, methyl-coenzyme M reductase, CO-dehydrogenase, Ni-superoxide dismutase, glyoxalase, acireductone dioxygenase, lactate racemase, prolyl cis-trans isomerase and [NiFe] hydrogenase [9,10]. Furthermore, other nickel-dependent enzymes, such as glycerol-1-phosphate dehydrogenase from Bacillus subtilis and quercitinase from Streptomyces sp. FLA are known [11,12]. Nickel enzymes implicate the use and/or production of gases (CO, CO2, CH4, H2, NH3 and O2) which play important roles in the global carbon, nitrogen and oxygen cycles [5,13]. The catalytic center of nickel-dependent enzymes is typically coordinated by histidine and cysteine residues with the contributions from aspartate and glutamate [3].

Depending on the dose and length of exposure, as an immunotoxic and carcinogen agent, Ni can cause a variety of health effects, such as contact dermatitis, cardiovascular disease, asthma, lung fibrosis, and respiratory tract cancer [14]. Inhalation exposure in occupational contexts is a main route for nickel-induced toxicity in the respiratory tract, in the lung, and immune system. Inhalation exposure may also affect non-occupationally exposed individuals, mainly those who handle stainless steel and nickel-plated articles, with a high preval‎ence of allergic contact dermatitis [15,16]. However, the exposure of human beings mainly concerns oral ingestion through water and food as nickel may be a contaminant in drinking water and/or food (Table 1) [17]. Although the molecular mechanisms of nickel-induced neurotoxicity are not yet clear, an important role is due to oxidative stress and mitochondrial dysfunctions. Nickel-induced mitochondrial damage can occur, due to impairment of mitochondrial membrane potential, reduction of mitochondrial ATP concentration and destruction of mitochondrial DNA. According to Song and collaborators [2], the use of antioxidant molecules, such as L-carnitine, taurine and melatonin, molecules that stimulate and amplify antioxidant enzyme activity, can prevent nickel-induced neurotoxicity and carcinogenicity [18,19]. Mitochondrial dysfunctions can interfere with electron respiratory chain and can increase ROS. These three antioxidants, synthesized from all mammals, play significant roles in neurotransmission, detoxification and mitochondrial energy homeostasis, reducing oxidative stress and ROS production [20].

니켈은 

단단하고 연성이 있는 

은백색의 전이 금속으로 주기율표에서 28번째 원소입니다. 

니켈은 

여러 가지 산화 상태(-1에서 +4까지)로 존재할 수 있지만, 

+2 산화 상태(Ni2+)가 

환경과 생물학적 시스템에서 가장 널리 퍼져 있습니다[1]. 

니켈은 

강자성 원소에 속하며 

일반적으로 지각에 산소와 황과 결합하여 

산화물 및 황화물로 자연적으로 존재합니다. 

니켈은 

다른 원소와 함께 

토양, 운석에 존재하거나 화산에서 방출될 수 있습니다. 

약 80억 톤의 니켈이 바다에 존재합니다. 

독특한 물리적, 화학적 특성 덕분에 니켈은 

합금 생산, 전기 도금, 니켈-카드뮴 배터리 생산, 

화학 및 식품 산업의 촉매제와 같은 

다양한 야금 공정에서 현대 야금에 사용됩니다. 

이 금속이 포함된 제품이 널리 보급되면 

제조, 재활용 및 폐기의 모든 단계에서 

니켈과 그 2차 생성물에 의한 환경 오염이 불가피하게 발생합니다. 

인간에게 니켈의 영양학적 가치를 나타내는 기존 증거는 없지만 

일부 미생물, 식물 및 동물 종의 필수 영양소로 인식되고 있습니다[2]. 

니켈을 포함하는 효소 또는 보조 인자는 

고등 생물에서는 알려져 있지 않지만 

고세균, 박테리아, 조류, 원시 진핵생물 및 식물에서는 

니켈 기반 효소가 잘 알려져 있습니다 [3,4,5,6,7]. 

니켈은 

식물의 적절한 성장과 발달에 필수적이며 

발아 종자 및 생산성과 같은 광범위한 형태적 및 생리적 기능에 중요한 역할을 합니다. 

그러나 

높은 수준의 니켈은 

식물의 대사 활동을 변화시켜 

효소 활동, 광합성 전자 수송 및 엽록소 생합성을 억제합니다 [8]. 

현재 우레아제, 메틸-코엔자임 M 환원 효소, CO- 탈수소 효소, 

Ni- 슈퍼 옥사이드 디스 뮤 타제, 글리 옥살 라제, 아 시레 악톤 디 옥시 다제, 젖산 라세 마제, 프롤릴 시스-트랜스 이성질체 효소 및 [NiFe] 수소화 효소를 포함한 여러 니켈 효소가 확인되었습니다 [9,10]. 

또한, 바실러스 서브틸리스의 글리세롤-1-포스페이트 탈수소효소 및 스트렙토마이세스 FLA의 케르시티나아제와 같은 다른 니켈 의존성 효소가 알려져 있습니다[11,12]. 니켈 효소는 지구 탄소, 질소 및 산소 순환에서 중요한 역할을 하는 가스(CO, CO2, CH4, H2, NH3 및 O2)의 사용 및/또는 생산과 관련이 있습니다[5,13]. 니켈 의존성 효소의 촉매 중심은 일반적으로 히스티딘과 시스테인 잔기에 의해 조정되며 아스파르트산염과 글루타메이트가 기여합니다[3].

노출량과 노출 기간에 따라 

면역 독성 및 발암 물질인 Ni는 

접촉성 피부염, 

심혈관 질환, 

천식, 

폐 섬유증, 

호흡기 암 등 다양한 건강 영향을 유발할 수 있습니다[14]. 

직업적 맥락에서의 흡입 노출은 

호흡기, 폐, 면역계에서 

니켈로 인한 독성이 발생하는 주요 경로입니다. 

흡입 노출은 

주로 스테인리스 스틸 및 

니켈 도금 제품을 취급하는 

비직업적 노출자에게도 영향을 미칠 수 있으며, 

알레르기성 접촉 피부염의 

유병률이 높습니다[15,16]. 

그러나 

니켈은 

식수 및/또는 식품의 오염 물질일 수 있으므로 

인간의 노출은 주로 

물과 식품을 통한 경구 섭취와 관련이 있습니다(표 1)[17]. 

니켈로 인한 신경 독성의 분자 메커니즘은 

아직 명확하지 않지만, 

산화 스트레스와 미토콘드리아 기능 장애가 중요한 역할을 합니다. 

니켈에 의한 미토콘드리아 손상은 

미토콘드리아 막 전위의 손상, 

미토콘드리아 ATP 농도의 감소 및 

미토콘드리아 DNA의 파괴로 인해 발생할 수 있습니다. 

송과 협력자들에 따르면[2], 

항산화 효소 활성을 자극하고 증폭하는 분자인 

L- 카르니틴, 

타우린 및 

멜라토닌과 같은 항산화 분자를 사용하면 

니켈로 인한 신경 독성 및 발암 성을 예방할 수 있습니다 [18,19]. 

미토콘드리아 기능 장애는 

전자 호흡 사슬을 방해하고 

ROS를 증가시킬 수 있습니다. 

모든 포유류에서 합성되는 이 세 가지 항산화제는 

신경 전달, 

해독 및 미토콘드리아 에너지 항상성 유지에 중요한 역할을 하며 

산화 스트레스와 ROS 생성을 감소시킵니다 [20].

Table 1

Nickel-containing foods and items and nickel toxic effects.

Nickel Containing Foods	Hazelnuts; cocoa and dark chocolate; fruits (almonds, dates, figs, pineapple, plums, raspberries); grains (bran, buckwheat, millet, whole grain bread, oats, brown rice, sesame seeds, sunflower seeds); seafood (shrimps, mussels, oysters, crab, salmon); vegetables (beans, savoy cabbage, leeks, lettuce, lentils, peas, spinach, cabbage), tea from drinks dispensers; soya and soya products; peanuts; licorice; baking powder.
Nickel Containing Items	Inexpensive jewelry; cosmetics; keys; cell phones; eyeglass frames; paper clips; orthodontic braces; stainless steel articles; nickel plated articles; clothing fasteners (zippers, snap buttons, belt buckles); electrical equipment; armaments; alloy; metallurgical and food processing industries; pigments; catalysts.
Nickel Toxic Effects	Contact dermatitis; headaches; gastrointestinal manifestations; respiratory manifestations; lung fibrosis; cardiovascular diseases; lung cancer; nasal cancer; epigenetic effects.

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2. Chemical Form, Properties and Sources of Nickel Compounds

Nickel (Ni; atomic number 28, atomic weight 58.6934; density 8908 kg/m3; melting point 1455 °C; boiling point 2913 °C; electronic configuration [Ar] 3d84s2) belongs to group 10 of periodic table along with iron, cobalt, palladium, platinum and five other elements. Nickel is the 24th most abundant element in the Earth’s crust, and it is the 5th most abundant element regarding weight after iron, oxygen, magnesium and silicon. Most nickel on Earth is inaccessible because it is placed in the planet iron-nickel alloy molten outer core, 10% of which is represented by nickel and that lies above Earth solid inner core and below the mantel. In nature, nickel is found in combination with antimony, arsenic, and sulfur; elemental nickel is a silver-white solid metal with high thermal and electrical conductivity. Nickel exists in +2 (Ni2+) oxidation state; other valences (+3 and +4) may be found, even if they are less frequent. Nickel is a naturally occurring element that exists in diverse mineral forms [21]. It is resistant to air, water and alkali corrosion, but it is readily soluble at pH < 6.5 in dilute oxidizing acids. Nickel salts of strong acids (chloride, nitrate and sulphate) and organic salts are easily water-soluble, whereas, nickel salts of weak inorganic acids, nickel sulfides and nickel oxides are poorly water-soluble [22]. Compounds of great commercial importance are nickel chloride, carbonate, nitrate, sulphate, acetate, hydroxide and oxide.

Nickel and nickel compounds have many industrial and commercial uses thanks to the chemical properties, gloss and low price. Nickel is used in a wide range of application because of its peculiar combination of outstanding physicochemical properties. It is resistant to very high temperatures, corrosion and oxidation; in addition, it is very ductile, it alloys readily and is fully recyclable. Nickel is used in inexpensive jewelry, keys, paper clips, clothing fasteners (such as zippers, snap buttons and belt buckles), stainless steel household utensils, electrical equipment, armaments, coins, alloy, metallurgical and food processing industries, pigments and catalysts [23,24]. Nickel Raney (in powder or in granular form) is a catalyst employed in reduction reactions, such as the hydrogenation of unsaturated compounds. Nickel alloys are present in solders, surgical steel instruments (5–20% Ni), white gold (10–15% Ni), German silver (10–15%Ni), and sterling silver [22]. Nickel compounds are used in electroplating [25], electroforming and production of nickel-cadmium batteries and electronic equipment. Nickel alloys, such as stainless steel, are largely used in the production of tools, machinery, armaments, aerospace equipment, coins, inexpensive jewelry, medical prostheses and orthodontic materials [26]. Nickel is extensively distributed in the environment as it derives from the anthropogenic activity and natural sources. Nickel released from anthropogenic sources is emitted as oxides, sulfides, soluble compounds, and to a lesser content, as metallic nickel [16]. The greatest presence of nickel compounds in air derives from the combustion of fossil fuels. Direct leaching from rocks and sediments produces high concentrations of nickel in water, where it is present in divalent nickel form, as well as suspended insoluble particles.

Natural sources of atmospheric nickel include wind-blown dust, derived from weathering of rocks and soils, forest fires and volcano activities. The presence of nickel in the air also derives from the combustion of coal, diesel oil and fuel oil, and the incineration of waste and sewage [27]. Other environmental sources of nickel include stainless steel kitchen utensils, inexpensive jewelry and tobacco smoking. It has been demonstrated that each cigarette contains a nickel amount of 1.1 to 3.1 μg; nickel in tobacco smoke may be present as nickel carbonyl, which is extremely hazardous to human health [23]. Another source of nickel exposure in the human population is through dietary exposure; in fact, some vegetables (spinach, asparagus, carrots, broccoli and green beans, tomato), cocoa, chocolate and nuts contain high amounts of this toxic metal [28,29]. Nickel is also involuntarily added to the diet through food processing using stainless steel equipment or through hand to mouth contact [30].

Occupational exposure of several million workers worldwide has given rise to high levels of nickel in blood, urine and body tissues, especially in lung. In this case, workers are exposed to fumes and dusts containing nickel and its compounds; thus, inhalation may be considered the main route of uptake. It is also noted that kitchen kettles may release nickel into drinking water when it is boiled in kettles with nickel-plated elements. Finally, nickel nanoparticles (NiNPs) are among the most widely used nanomaterials, which are employed in many fields, such as catalysts, magnetic materials, biological medicines, conductive pastes and additive to lubricant [31,32,33].

니켈(Ni, 원자 번호 28, 원자량 58.6934, 밀도 8908kg/m3, 녹는점 1455°C, 끓는점 2913°C, 전자 구성 [Ar] 3d84s2)은 

철, 코발트, 팔라듐, 백금 및 기타 다섯 원소와 함께 

주기율표의 10족에 속하는 원소입니다. 

니켈은 

지각에서 24번째로 풍부한 원소이며, 

무게 기준으로 철, 산소, 마그네슘, 규소 다음으로 

5번째로 풍부한 원소입니다. 

지구상의 니켈은 

대부분 철-니켈 합금으로 용융된 외핵에 존재하며, 

그 중 10%가 니켈로 구성되어 있고 

지구의 단단한 내핵 위와 맨틀 아래에 있기 때문에 접근이 불가능합니다. 

자연에서 니켈은 

안티몬, 비소, 황과 함께 발견되며 

원소 니켈은 열 및 전기 전도도가 높은 은백색의 고체 금속입니다. 

니켈은 +2(Ni2+) 산화 상태로 존재하며, 

다른 원자가(+3 및 +4)는 빈도는 적지만 존재할 수 있습니다. 

니켈은 다양한 광물 형태로 존재하는 자연 발생 원소입니다[21]. 

니켈은 

공기, 물, 알칼리 부식에 강하지만 

묽은 산화성 산에서는 pH 6.5 미만에서 쉽게 용해됩니다. 

강산(염화물, 질산염 및 황산염)과 유기염의 니켈 염은 

쉽게 수용성이지만, 

약 무기산, 황화 니켈 및 산화 니켈의 니켈 염은 수용성이 낮습니다[22]. 

상업적으로 매우 중요한 화합물은 

염화 니켈, 탄산염, 질산염, 황산염, 아세테이트, 수산화물 및 산화물입니다.

니켈과 니켈 화합물은 화학적 특성, 광택 및 저렴한 가격 덕분에 많은 산업 및 상업적 용도로 사용됩니다. 니켈은 뛰어난 물리화학적 특성의 독특한 조합으로 인해 다양한 용도로 사용됩니다. 매우 높은 온도, 부식 및 산화에 강하며, 연성이 뛰어나고 쉽게 합금되며 완전히 재활용할 수 있습니다. 

니켈은 

저렴한 보석, 

열쇠, 

종이 클립, 

의류 패스너(지퍼, 스냅 버튼, 벨트 버클 등), 

스테인리스 스틸 가정용품, 

전기 장비, 무기, 동전, 합금, 야금 및 식품 가공 산업, 

안료 및 촉매에 사용됩니다[23,24]. 

니켈 레이니(분말 또는 과립 형태)는 불포화 화합물의 수소화와 같은 환원 반응에 사용되는 촉매입니다. 니켈 합금은 땜납, 수술용 강철 기구(5-20% Ni), 화이트 골드(10-15% Ni), 독일은(10-15%Ni) 및 스털링 실버에 존재합니다[22]. 니켈 화합물은 전기 도금[25], 니켈-카드뮴 배터리 및 전자 장비의 전기 성형 및 생산에 사용됩니다. 스테인리스강과 같은 니켈 합금은 주로 공구, 기계, 병기, 항공 우주 장비, 동전, 저렴한 보석, 의료 보철 및 교정 재료의 생산에 사용됩니다[26]. 니켈은 인위적인 활동과 천연 자원에서 유래하기 때문에 환경에 광범위하게 분포되어 있습니다. 인위적 배출원에서 방출되는 니켈은 산화물, 황화물, 용해성 화합물, 그리고 그보다 적은 함량의 금속 니켈로 방출됩니다 [16]. 대기 중 니켈 화합물의 가장 큰 존재는 화석 연료의 연소로부터 비롯됩니다. 암석과 퇴적물에서 직접 침출되면 물에 고농도의 니켈이 생성되며, 이 니켈은 2가 니켈 형태와 부유 불용성 입자 형태로 존재합니다.

대기 중 니켈의 자연적 공급원에는 암석과 토양의 풍화, 산불 및 화산 활동으로 인해 발생하는 바람에 날리는 먼지가 포함됩니다. 대기 중 니켈의 존재는 석탄, 디젤유 및 연료유의 연소, 폐기물 및 하수 소각에서도 발생합니다[27]. 니켈의 다른 환경 오염원으로는 스테인리스 스틸 주방 용품, 값싼 장신구, 흡연 등이 있습니다. 

각 담배에는 1.1 ~ 3.1 μg의 니켈이 포함되어 있으며, 

담배 연기 속의 니켈은 

인체 건강에 매우 위험한 니켈 카보닐로 존재할 수 있습니다 [23]. 

실제로 일

부 채소(시금치, 아스파라거스, 당근, 브로콜리 및 녹두, 토마토), 

코코아, 초콜릿 및 견과류에는 

이 독성 금속이 다량 함유되어 있습니다[28,29]. 

니켈은 또한 

스테인리스 스틸 장비를 사용한 

식품 가공이나 손에서 입으로의 접촉을 통해 

무의식적으로 식단에 추가됩니다[30].

전 세계 수백만 명의 근로자가 직업적으로 

니켈에 노출되어 

혈액, 소변, 신체 조직, 특히 폐에서 높은 수준의 니켈이 검출되고 있습니다. 

이 경우 근로자는 

니켈과 그 화합물이 포함된 연기와 분진에 노출되므로 

흡입이 주요 섭취 경로로 간주될 수 있습니다. 

또한 니켈이 도금된 주전자에서 물을 끓일 때 

니켈이 식수로 방출될 수 있다는 사실도 

알려져 있습니다. 

마지막으로 

니켈 나노 입자(NiNP)는 

촉매, 자성 물질, 생물학적 의약품, 전도성 페이스트 및 윤활유 첨가제 등 

여러 분야에서 사용되는 가장 널리 사용되는 나노 물질 중 하나입니다[31,32,33].

3. Nickel Toxicity and Carcinogenicity

In order of nickel abundance in the Earth crust, humans are constantly exposed to nickel. Due to its abundance, natural nickel deficiency does not easily occur; moreover, a nickel-deficient diet is difficult to maintain because of its abundance in food [28]. Human exposure to highly nickel-polluted environments may cause a variety of pathological effects [34,35]. Accumulation of nickel and nickel compounds in the body through chronic exposure may be responsible for a variety of adverse effects on the health of human beings, such as lung fibrosis, kidney and cardiovascular diseases and cancer of the respiratory tract [36,37]. High incidence of nasal and lung cancer in workers exposed to nickel and nickel compounds was observed [37,38,39,40,41,42]. A small fraction of nickel is dermally absorbed, and Ni2+ ions and nickel particles penetrate the skin at sweat ducts and hair follicles. Moreover, dermal absorption of this metal is affected by solubilizing agents, such as detergents, and clothes and gloves that behave as a barrier to the skin.

Nickel nanoparticles are associated with reproductive toxicity. Kong et al. [31] exposed female rats by oral gavage to nickel nanoparticles, selecting indicators like reactive oxygen species (ROS), oxidant and antioxidant enzymes, and cell apoptosis-related factors. Nickel nanoparticles decreased the activity of superoxide dismutase (SOD) and catalase (CAT) significantly, and increased the levels of ROS, malondialdehyde (MDA, lipid peroxidation marker) and nitric oxide (NO), in comparison with control groups. Moreover, the authors showed mitochondrial swelling and disappearance of cristae of mitochondrial ovaries in the nickel nanoparticles exposure groups. The mRNA expressions of caspases (cysteine proteases), and the expressions of Cyt C, Bax and Bid proteins on the ovaries significantly increased, while the expressions of B-cell lymphoma-2 (Bcl-2) protein were drastically decreased. Exposure of workers to industrial and research laboratories could be a cause for concern during the production and handling of nickel nanoparticles. Among other causes, even high temperature processes, such as welding, can generate nanoparticles. The results of many in vivo and in vitro researches suggest that nickel and nickel oxide nanoparticles are responsible for lung toxicity, inflammation, oxidative stress and apoptosis [43,44,45].

IARC (The International Agency for Research on Cancer) classified soluble and insoluble nickel compounds as Group 1 (carcinogen to humans), and nickel and alloys as Group 2B (possibly carcinogenic to humans) [46]. The toxic and carcinogenic effects of nickel are related to the way of assumption into the organism. Potential toxicity of nickel and nickel compounds is dependent on their physico-chemical characteristics, as well as the amount, duration of contact and route of exposure. Nickel can enter the body via inhalation, ingestion with food and dermal absorption [47]; however, the route for this element to enter cells is determined by its chemical form. The riskiest route of exposure to nickel is by inhalation [48]. The absorption of nickel particles deposed in the alveolar, tracheobronchial and nasopharyngeal regions of the respiratory system depends on various factors, first of all on the diameter of the inhaled particles, and therefore, the solubility, the quantity deposited, ventilation rate and retention rates [49]. Only particles with a diameter fewer than 100 μm can be inhaled to settle along the respiratory tract. Particles with a diameter of less than 4 μm are deposited in the lower alveolar region of the respiratory system; particles deposited in the tracheobronchial region are between 4 and 10 μm in size, and finally, particles with a diameter between 10 and 100 μm are deposited in the nasopharyngeal region [50]. Water-soluble nickel compounds are absorbed by lungs and removed by the kidneys. They can cause nose and sinuses irritation and may also lead to losing the sense of smell and to the nasal septum perforation. Insoluble nickel compounds remain in the lungs for a longer time, and they are the forms of nickel responsible for cancer. Epidemiological studies have demonstrated increased mortality from lung cancer and from cancer of nasal cavities in nickel refinery workers, because of their chronical exposition to nickel-containing dusts and fumes [37]. Insoluble nickel sulfide (Ni2S3) is a carcinogen agent for the respiratory tract: When it is inhaled, particles of nickel sulfide accommodate themselves in the lungs of human beings, where they remain in contact with epithelial cells. These nickel particles are removed by macrophages in the digestive tract. Under high exposure to nickel, the macrophage activity of removal could be perturbed, and Ni2S3 particles may be taken into epithelial cells by endocytosis. In this way, nickel particles are delivered to the nucleus of lung epithelial cells, causing a heritable change in chromosomes, inducing lesions of both double- and single-stranded DNA in cultured human cells (Raji and HeLa cells) [51].

Chen and co-authors, in their study, propose that the enzyme iron- and 2-oxoglutarate-dependent dioxygenases are an important target that mediates the toxicity and carcinogenicity of nickel. The structural motif of this dioxygenase family is a triad of 2-histidine-1-carboxylate that coordinates the Fe2+ ion in the catalytic site. According to their hypothesis, two different classes of enzymes in this iron- and 2-oxoglutarate-dependent dioxygenase family, including JMJD1A histone demethylase and DNA repair enzyme ABH2, are all sensitive to inhibition of nickel ions. Their studies with X-ray spectroscopy suggest that nickel is the cause of both JMJD1A and ABH2 inhibition because it replaces iron in their catalytic sites [52,53].

In literature, metallopeptidase with Zn2+, Cu2+ and Co2+ at the active site and sensitive to nickel are known. The Trypanosoma cruzi metallocarboxylase (Tcmcp-1) is the causative agent of the tropical parasitic American trypanosomiasis Chagas disease. This Zn-carboxypeptidase cleaves the C-terminal aminoacid residue from peptides and proteins and lost 54% of its activity upon treatment with 10 μM Ni2+. In the active center of this enzyme, there are two histidines and one glutamate residues to bind Zn2+ ion. The enzyme nitrous oxide reductase from Rhodobacter sphaeroides f. sp. denitrificans catalyzes the reduction of nitrate or nitrite to N2 gas under anaerobic conditions. This enzyme contains 4 Cu2+, 2 Zn2+ and 1 Ni2+ atoms per enzyme. Zn and Ni ions cause at 100 μM concentrations reductions in the activity of 100% and 60%, respectively. Hydrogenobyrinic acid a,c-diamide is the substrate of cobaltochelatase, that in Pseudomonas denitrificans (Gram-negative aerobic bacterium) catalyzes cobalt insertion in the corrin ring during the biosynthesis of coenzyme B12. Cobaltochelatase is a complex enzyme composed of two different components of Mr 140,000 and 450,000. Each component is inactive by itself, but cobaltochelatase activity is reconstituted upon mixing the two different components. This enzyme is ATP-dependent, and its activity is blocked by nickel [54].

It is known that nickel inhibits many enzymes that do not need metal cations to carry out the catalysis. This inhibition takes place when the nickel binds to particular amino acids in the active site of the enzyme, such as cysteine, histidine, glutamate and lysine, blocking the catalytic activity, or binds to secondary sites of the enzyme influencing allosterically its activity. However, in most cases, the inhibition mechanism is not known.

ATP: Cob (I) alamin adenosyltransferase from Salmonella enterica catalyzes the final step in the conversion of vitamin B12 to coenzyme B12, namely, the adenylation of cobalamin/vitamin B12 to adenosylcobalamin/coenzyme B12. This enzyme, that contains iron in its active site, is inhibited upon exposure to 100 μM Ni2+, losing about 50% of its activity. At nickel concentration higher than 100 μM, the activity of this enzyme did not decrease below 50%. This result suggests that nickel binds to an allosteric site, rather than displacing iron from the catalytic center [55,56,57].

Nickel at a concentration as low as 100 nM inhibits the activity of the enzyme N-carbamoyl D-amino acid amidohydrolase from Agrobacterium radiobacter. This enzyme, which has the triad of Cys/Glu/Lys amino acids in the active site, as well as three histidines, is important for the production of the β-lactam antibiotic. [58].

Schaeffer and co-authors have shown that the treatment of the pyroglutamyl peptidase I (PPI) enzyme from Leishmania major to 100 μM Ni2+ causes the loss of 48–50% of its activity. This enzyme, which belongs to the cysteine peptidase family, hydrolyzes the N-terminal L-pyroglutamate residues that play an important role in protein metabolism and defense against antibiotic peptides. The Leishmania major PPI active site catalytic triad of Glu101, Cys210, and His234 [59].

지각에 니켈이 풍부한 순서대로 인간은 니켈에 지속적으로 노출됩니다. 

니켈은 풍부하기 때문에 

자연적인 니켈 결핍은 쉽게 발생하지 않으며, 

또한 식품에 풍부하기 때문에 

니켈 결핍 식단을 유지하기가 어렵습니다 [28]. 

인간이 

니켈 오염이 심한 환경에 노출되면 

다양한 병리적 영향을 미칠 수 있습니다 [34,35]. 

만성 노출을 통한 니켈 및 니켈 화합물의 체내 축적은 

폐 섬유화, 신장 및 심혈관 질환, 호흡기 암 등 

인체의 건강에 다양한 악영향을 미칠 수 있습니다 [36,37]. 

니켈 및 니켈 화합물에 노출된 근로자의 

비강암 및 폐암 발병률이 높은 것으로 관찰되었습니다[37,38,39,40,41,42]. 

니켈의 일부는 

피부로 흡수되며, 

Ni2+ 이온과 니켈 입자는 

땀샘과 모낭에서 피부를 통해 침투합니다. 

또한 이 금속의 피부 흡수는 

세제와 같은 용해제, 

피부 장벽 역할을 하는 옷과 장갑에 의해 영향을 받습니다.

니켈 나노 입자는 생식 독성과 관련이 있습니다. Kong 등[31]은 암컷 쥐를 경구로 니켈 나노 입자에 노출시켜 활성 산소 종(ROS), 산화 및 항산화 효소, 세포 사멸 관련 인자와 같은 지표를 선택했습니다. 니켈 나노 입자는 대조군에 비해 슈퍼옥사이드 디스뮤타아제(SOD)와 카탈라아제(CAT)의 활성을 현저히 감소시키고 ROS, 말론다이알데히드(MDA, 지질 과산화 표지자), 산화질소(NO) 수치를 증가시켰습니다. 또한 니켈 나노입자 노출 그룹에서 미토콘드리아가 부풀어 오르고 미토콘드리아 난소의 크리스테가 사라지는 것을 확인했습니다. 난소에서 카스파제(시스테인 프로테아제)의 mRNA 발현과 Cyt C, Bax 및 Bid 단백질의 발현은 유의하게 증가한 반면, B세포 림프종-2(Bcl-2) 단백질의 발현은 급격히 감소했습니다. 산업 및 연구 실험실에서 니켈 나노 입자를 생산하고 취급하는 과정에서 근로자의 노출이 우려되는 원인이 될 수 있습니다. 다른 원인 중에서도 용접과 같은 고온 공정에서도 나노 입자가 생성될 수 있습니다. 많은 생체 내 및 시험관 내 연구 결과에 따르면 니켈 및 니켈 산화물 나노 입자는 폐 독성, 염증, 산화 스트레스 및 세포 사멸을 유발하는 것으로 나타났습니다 [43,44,45].

IARC(국제 암 연구 기관)는 용해성 및 불용성 니켈 화합물을 그룹 1(인체 발암 물질)로, 니켈 및 합금을 그룹 2B(인체 발암 가능 물질)로 분류했습니다[46]. 니켈의 독성 및 발암성 영향은 유기체에 대한 가정 방식과 관련이 있습니다. 니켈 및 니켈 화합물의 잠재적 독성은 물리화학적 특성뿐만 아니라 노출량, 접촉 시간 및 노출 경로에 따라 달라집니다. 니켈은 흡입, 음식물 섭취, 피부 흡수[47]를 통해 체내로 유입될 수 있지만, 이 원소가 세포로 유입되는 경로는 화학적 형태에 따라 결정됩니다. 니켈에 노출되는 가장 위험한 경로는 흡입입니다[48]. 호흡기의 폐포, 기관지 및 비인두 영역에 침착 된 니켈 입자의 흡수는 다양한 요인, 우선 흡입 된 입자의 직경, 따라서 용해도, 침착 된 양, 환기 속도 및 유지율에 따라 달라집니다 [49]. 직경이 100μm 미만인 입자만 흡입하여 호흡기를 따라 침전시킬 수 있습니다. 직경 4μm 미만의 입자는 호흡기의 하부 폐포 영역에 침착되고, 기관지 영역에 침착된 입자는 4~10μm 크기이며, 마지막으로 비인두 영역에 직경 10~100μm의 입자가 침착됩니다 [50]. 수용성 니켈 화합물은 폐에 흡수되어 신장에서 제거됩니다. 코와 부비동에 자극을 유발할 수 있으며 후각 상실과 비중격 천공으로 이어질 수도 있습니다. 불용성 니켈 화합물은 폐에 더 오랫동안 남아 있으며 암을 유발하는 니켈의 형태입니다. 역학 연구에 따르면 니켈 정제소 근로자의 경우 니켈 함유 분진 및 연기에 만성적으로 노출되어 폐암과 비강암으로 인한 사망률이 증가하는 것으로 나타났습니다[37]. 불용성 황화 니켈(Ni2S3)은 호흡기 발암 물질로, 흡입 시 황화 니켈 입자가 사람의 폐에 자리 잡아 상피 세포와 접촉하게 됩니다. 이러한 니켈 입자는 소화관의 대식세포에 의해 제거됩니다. 니켈에 많이 노출되면 대식세포의 제거 활동이 교란되어 Ni2S3 입자가 세포 내 침입에 의해 상피 세포로 흡수될 수 있습니다. 이러한 방식으로 니켈 입자는 폐 상피 세포의 핵으로 전달되어 염색체에 유전성 변화를 일으켜 배양 된 인간 세포 (Raji 및 HeLa 세포)에서 이중 가닥 및 단일 가닥 DNA의 병변을 유도합니다 [51].

Chen과 공동 저자들은 연구에서 철 및 2-옥소글루타레이트 의존성 디옥시게나제 효소가 니켈의 독성과 발암성을 매개하는 중요한 표적이라고 제안합니다. 이 디옥시게나제 계열의 구조적 모티브는 촉매 부위에서 Fe2+ 이온을 조정하는 2-히스티딘-1-카복실레이트의 삼합체입니다. 연구팀의 가설에 따르면, 이 철 및 2-옥소글루타레이트 의존성 디옥시게나제 계열의 두 가지 다른 종류의 효소, 즉 JMJD1A 히스톤 탈메틸화 효소 및 DNA 복구 효소 ABH2는 모두 니켈 이온의 억제에 민감합니다. X-선 분광법을 사용한 연구에 따르면 니켈은 촉매 부위에서 철을 대체하기 때문에 JMJD1A와 ABH2 저해의 원인이라고 합니다[52,53].

문헌에 따르면 활성 부위에 Zn2+, Cu2+ 및 Co2+가 있고 니켈에 민감한 메탈로펩티다아제가 알려져 있습니다. 트리파노소마 크루지 메탈로카복실라제(Tcmcp-1)는 열대 기생충인 미국 트리파노소마증 샤가스병의 원인 물질입니다. 이 Zn-카복시펩티다제는 펩타이드와 단백질에서 C-말단 아미노산 잔기를 절단하며 10μM Ni2+로 처리하면 54%의 활성을 잃습니다. 이 효소의 활성 중심에는 두 개의 히스티딘과 하나의 글루타메이트 잔기가 있어 Zn2+ 이온과 결합합니다. 아산화질소 환원 효소는 혐기성 조건에서 질산염 또는 아질산염을 N2 가스로 환원하는 것을 촉매하는 Rhodobacter sphaeroides f. sp. denitrificans의 효소입니다. 이 효소는 효소당 4개의 Cu2+, 2개의 Zn2+, 1개의 Ni2+ 원자를 포함합니다. Zn과 Ni 이온은 100μM 농도에서 각각 100%와 60%의 활성 감소를 유발합니다. 수소오비린산 a,c-다이아미드는 코발토헬라타제의 기질로, 슈도모나스 데니트리피칸스(그람 음성 호기성 박테리아)에서 코엔자임 B12의 생합성 과정에서 코린 고리 내 코발트 삽입을 촉매하는 효소입니다. 코발토켈라타제는 14만 개와 45만 개의 서로 다른 두 가지 성분으로 구성된 복합 효소입니다. 각 성분은 그 자체로는 비활성이지만 두 가지 성분을 혼합하면 코발토켈라타제 활성이 재구성됩니다. 이 효소는 ATP 의존적이며 니켈에 의해 활성이 차단됩니다 [54].

니켈은 촉매 작용을 수행하는 데 금속 양이온이 필요하지 않은 많은 효소를 억제하는 것으로 알려져 있습니다. 이러한 저해는 니켈이 시스테인, 히스티딘, 글루타메이트 및 라이신과 같은 효소의 활성 부위에 있는 특정 아미노산에 결합하여 촉매 활성을 차단하거나 효소의 이차 부위에 결합하여 이차적으로 효소의 활성에 영향을 미칠 때 일어납니다. 그러나 대부분의 경우 억제 메커니즘은 알려져 있지 않습니다.

ATP: 살모넬라 엔테리카의 코브(I) 알라민 아데노실 트랜스퍼라제는 비타민 B12가 코엔자임 B12로 전환되는 마지막 단계, 즉 코발라민/비타민 B12의 아데닐화를 아데노실코발라민/코엔자임 B12로 전환하는 촉매 작용을 합니다. 활성 부위에 철을 포함하는 이 효소는 100μM Ni2+에 노출되면 억제되어 약 50%의 활성을 잃습니다. 100μM 이상의 니켈 농도에서는 이 효소의 활성이 50% 이하로 감소하지 않았습니다. 이 결과는 니켈이 촉매 중심에서 철을 대체하는 것이 아니라 알로스테릭 부위에 결합한다는 것을 시사합니다[55,56,57].

100nm 농도의 니켈은 아그로박테리움 라디오박터에서 N-카바모일 D-아미노산 아미도하이드롤라제 효소의 활성을 억제합니다. 이 효소는 활성 부위에 세 개의 히스티딘뿐만 아니라 세 개의 Cys/Glu/Lys 아미노산 트리아드를 가지고 있으며 β-락탐 항생제 생산에 중요합니다. [58].

셰퍼와 공동 저자들은 리쉬마니아 메이저의 파이로글루타밀 펩티다제 I(PPI) 효소를 100μM Ni2+로 처리하면 활성의 48~50%가 손실된다는 것을 보여주었습니다. 시스테인 펩티다제 계열에 속하는 이 효소는 단백질 대사와 항생제 펩타이드에 대한 방어에 중요한 역할을 하는 N-말단 L-피로글루타메이트 잔기를 가수분해하는 효소입니다. 리슈마니아의 주요 PPI 활성 부위 촉매 트리아드는 Glu101, Cys210, His234입니다[59].

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4. Nickel Allergy

Metals, such as gold, silver, nickel, titanium, chromium and copper, are ubiquitous in our environment and are widely used in costume jewelry, coins, mobile phone and orthodontic materials [28,60,61,62]. The orthodontic patients are exposed to a considerable amount of nickel, cobalt, titanium and other metals deriving from alloys. The microbiologic and aqueous oral environment combined with pH of saliva, intake of drinks, food and mouthwashes facilitate corrosion resulting in the release of ions from orthodontic appliances into oral tissues and saliva of patients. These ions released from orthodontic appliances cause contact dermatitis, hypersensitivity, cytotoxicity and DNA damage [63,64,65]. Among these metals, nickel is the most frequent cause of metal allergy. Clinically, nickel allergy sometimes occurs when nickel-containing items are in direct and prolonged contact with the skin, leading to corrosion of nickel by sweat, releasing nickel ions to be absorbed through the skin and initiating an allergenic effect. Once sensitized, individuals can develop contact dermatitis, lichen planus, dyshidrotic eczema, labial desquamation, angular chelitis, periodontitis, stomatitis with mild to severe erythema, loss of taste and numbness [66]. A particular problem is due to the use of nickel for coinage [67,68], such as the European one and two euro coins [69,70]. The EU Nickel Directive in agreement with European Chemical Agency (ECHA) poses limits on the amount of nickel that may be released from jewelry and other products destined to come to direct and prolonged contact with the skin. These limits are known as migration limits—(a) 0.2 µg/cm2/week for post assemblies which are inserted into pierced ears and other pierced parts of the human body; (b) 0.5 µg/cm2/week for other products intended to come into direct and prolonged contact with the skin. The quantitative test for nickel ion release is the European Standard EN1811, which consists of placing an object in an artificial sweat solution for one week, then nickel release is measured by atomic absorption spectroscopy or any other technique as inductively coupled plasma mass spectrometry (ICP-MS). Wear and corrosion can be simulated by a method known as EN 12472.

By the early 1930–1935 observations of nickel dermatitis produced by objects in everyday use were reported by Rothman and Preininger about the use of coins, by McAlester AW and McAlester AWJr (1931) about the use of spectacle frames and by Du Bois about the use of wrist watch [71,72,73,74].

Literature dates indicate that women are more prone to dermatitis than men. In fact, approximately 13–18% of females and 3–6% of males are allergic to nickel [75], and this may be due to greater contact with nickel-containing items, such as jewelry, buttons, certain shampoos and detergents, and pigments [76]. According to dermatologists, the frequency of nickel allergy is still increasing, and it can be explained by the fashionable piercing, and nickel-containing devices used in medicine like coronary stents and endo prosthesis [38]. Nickel is also a component of many orthodontic materials, as a nickel-titanium alloy with a concentration of about 50%. It is also present in stainless steel in archwires and brackets, with a concentration of approximately 8%. It is also present in surgical stainless steel instruments (10–20% concentration without release nickel at a rate of more than 0.2 µg/cm2/week). If symptoms are present with a nickel hypersensitivity diagnosis, the nickel-titanium apparatus possibly present should be removed and replaced with a stainless steel device and preferably with a titanium-molybdenum alloy, which does not contain nickel [77]. Saliva, some foods and oral hygiene products containing fluoride potentially corrode and solubilize nickel in the alloys, releasing nickel ions onto the oral mucosa [78].

Approximately 10–15% of the population in the Earth suffers from nickel allergy, and many are unable to wear jewelry or handle coins and other objects that contain nickel. Many agents have been developed to reduce the penetration of nickel through the skin, but few formulations are safe and effective. In 2011, Vemula and co-authors showed that the penetration of nickel ions into the skin could be prevented, by applying a thin layer of glycerin containing nanoparticles of calcium carbonate or calcium phosphate either in vitro on an isolated piece of pig skin or in vivo on the skin of mice. The nanoparticles may capture nickel ions by cation exchange, and remain on the surface of the skin, allowing them to be removed by simple washing with water. Therefore, the use of nanoparticles with diameters smaller than 500 nm in topical creams may be effective in limiting the exposure to metal ions that can cause skin irritation [79].

Prevention strategies could reduce the awareness of persons that suffer from allergic contact dermatitis. In a clinical immunology review, it is hypothesized that prevention of exposure to nickel could diminish the number of those that are sensitive to nickel by one-quarter to one-third. Therefore, the identification of sources of nickel is vital to understanding the nickel sensitization processes. Food items like chocolate and many other products, such as zippers, buttons, cell phones, orthodontic braces and eyeglass frames may contain nickel. For example, objects with sentimental value (heirlooms, wedding rings) could be treated with an enamel or rhodium plating [80].

Moreover, nickel-containing cobalt and titanium alloys have become ubiquitous in the manufacturing of neurovascular medical devices. In fact, aneurysm clips, endovascular devices and stents containing varying proportions of nickel (14–35%) are used in treatments of cerebral aneurysms [81]. Allergic reactions to nickel have been implicated in complications related to coronary stents, including migraine headaches, fever, dyspnea, dermatitis and pericarditis [82].

Nickel released from various alloys is a potent allergen or hapten that can trigger skin inflammation. Nickel penetrates the skin and activates epithelial cells, producing cytokines or chemokines. The reaction involves the activation of antigen-presenting cells and T cells in complex immune responses. Activated antigen-presenting cells migrate to the lymph nodes where nickel present the allergen or hapten to naive CD4+ T cells. Following the re-exposure to the same allergen or hapten, these T cells become stimulated and duplicate themselves. Subsequently, they enter in the bloodstream and produce visible signs of hypersensitivity 48–72 h after allergen exposure. After repeated exposures to nickel, the clones of T-cells reach “threshold” value, and the skin develops a rash that can manifest as acute, subacute, or chronic eczema-like skin patches. The skin reaction can take place at the site of contact, or sometimes diffuse to the rest of the body. Cutaneous exposure can cause localized erythematous, pruritic, vesicular, and scaly patches. Ingestion of food containing nickel or nickel compounds may cause adverse systemic reactions [83]. However, the pathogenesis and mechanisms of the allergic response are highly complex, and the precise mechanisms of nickel allergy remain still not completely clarified [66].

금, 은, 니켈, 티타늄, 크롬, 구리와 같은 금속은 우리 환경에 어디에나 존재하며 의상 장신구, 동전, 휴대폰 및 교정 재료에 널리 사용됩니다[28,60,61,62]. 

치아 교정 환자는 상당한 양의 

니켈, 코발트, 티타늄 및 합금에서 파생된 기타 금속에 노출됩니다. 

미생물학적 및 수성 구강 환경과 타액의 pH, 음료, 음식, 구강청결제의 섭취는 

부식을 촉진하여 교정 장치에서 환자의 구강 조직과 타액으로 이온이 방출됩니다. 

교정 장치에서 방출되는 이러한 이온은 접촉성 피부염, 과민증, 세포 독성 및 DNA 손상을 유발합니다[63,64,65]. 이러한 금속 중 니켈은 금속 알레르기의 가장 흔한 원인입니다. 임상적으로 니켈 알레르기는 니켈 함유 제품이 피부에 직접적으로 장시간 접촉할 때 발생하며, 땀에 의해 니켈이 부식되어 니켈 이온이 방출되어 피부를 통해 흡수되고 알레르기 효과를 유발합니다. 일단 민감해지면 접촉성 피부염, 편평 태선, 다한증성 습진, 음순 박리, 각성 구순염, 치주염, 경증에서 중증 홍반을 동반한 구내염, 미각 상실 및 마비가 발생할 수 있습니다[66]. 특히 유럽 1유로 및 2유로 동전[69,70]과 같은 주화[67,68]에 니켈이 사용되기 때문에 문제가 심각합니다. EU 니켈 지침은 유럽 화학물질청(ECHA)과 합의하여 장신구 및 피부에 직접적으로 장기간 접촉하는 기타 제품에서 방출될 수 있는 니켈의 양에 제한을 두고 있습니다. 이러한 한도는 (a) 피어싱된 귀 및 기타 피어싱된 인체 부위에 삽입되는 포스트 어셈블리의 경우 0.2 µg/cm2/주, (b) 기타 피부와 직접 및 장기간 접촉하는 제품의 경우 0.5 µg/cm2/주로 알려져 있습니다. 니켈 이온 방출에 대한 정량적 테스트는 유럽 표준 EN1811로, 물체를 인공 땀 용액에 1주일 동안 넣은 다음 원자 흡수 분광법 또는 유도 결합 플라즈마 질량 분석법(ICP-MS)으로 니켈 방출을 측정하는 방식으로 이루어집니다. 마모와 부식은 EN 12472로 알려진 방법으로 시뮬레이션할 수 있습니다.

1930-1935년 초에 일상적으로 사용하는 물체에 의해 발생하는 니켈 피부염에 대한 관찰은 Rothman과 Preininger가 동전 사용에 대해, McAlester AW와 McAlester AWJr(1931)가 안경테 사용에 대해, Du Bois가 손목 시계 사용에 대해 보고했습니다[71,72,73,74].

문헌에 따르면 여성이 남성보다 피부염에 더 취약한 것으로 나타났습니다. 실제로 여성의 약 13~18%, 남성의 3~6%가 니켈 알레르기가 있으며[75], 이는 보석, 단추, 특정 샴푸 및 세제, 색소 등 니켈 함유 품목과의 접촉이 더 많기 때문일 수 있습니다[76]. 피부과 전문의에 따르면 니켈 알레르기의 빈도는 여전히 증가하고 있으며, 이는 유행하는 피어싱과 관상동맥 스텐트 및 엔도 보철물과 같은 의학에 사용되는 니켈 함유 장치로 설명할 수 있습니다 [38]. 니켈은 또한 약 50% 농도의 니켈-티타늄 합금으로 많은 교정 재료의 구성 요소입니다. 또한 아치 와이어와 브라켓의 스테인리스 스틸에도 약 8%의 농도로 존재합니다. 또한 수술용 스테인리스 스틸 기구(0.2 µg/cm2/주 이상의 속도로 니켈이 방출되지 않는 10~20% 농도)에도 존재합니다. 니켈 과민증 진단과 함께 증상이 나타나면 니켈-티타늄 기구를 제거하고 스테인리스강 기구로, 가급적 니켈이 포함되지 않은 티타늄-몰리브덴 합금으로 교체해야 합니다[77]. 침, 불소가 함유된 일부 식품 및 구강 위생용품은 합금의 니켈을 부식시키고 용해시켜 구강 점막에 니켈 이온을 방출할 가능성이 있습니다[78].

지구 인구의 약 10~15%가 니켈 알레르기를 앓고 있으며, 많은 사람들이 장신구를 착용하거나 니켈이 포함된 동전 및 기타 물체를 다룰 수 없습니다. 피부를 통한 니켈의 침투를 줄이기 위해 많은 약제가 개발되었지만 안전하고 효과적인 제제는 거의 없습니다. 2011년 베뮬라와 공동 저자들은 탄산칼슘 또는 인산칼슘 나노입자가 함유된 글리세린을 시험관 내에서 분리된 돼지 피부 조각에 바르거나 생체 내에서 쥐의 피부에 얇게 발라 니켈 이온이 피부에 침투하는 것을 방지할 수 있음을 보여주었습니다. 나노 입자는 양이온 교환을 통해 니켈 이온을 포획하고 피부 표면에 남아 있어 물로 간단히 씻어 제거할 수 있습니다. 따라서 국소 크림에 직경이 500nm보다 작은 나노 입자를 사용하면 피부 자극을 유발할 수 있는 금속 이온에 대한 노출을 제한하는 데 효과적일 수 있습니다 [79].

예방 전략은 

알레르기성 접촉 피부염을 앓고 있는 사람들의 인식을 줄일 수 있습니다. 임상 면역학 검토에서 니켈 노출을 예방하면 니켈에 민감한 사람의 수를 1/4에서 1/3까지 줄일 수 있다는 가설이 제기되었습니다. 따라서 니켈의 공급원을 파악하는 것은 니켈 민감화 과정을 이해하는 데 필수적입니다. 초콜릿과 같은 식품과 지퍼, 단추, 휴대폰, 치아 교정기, 안경테 등 다양한 제품에 니켈이 함유되어 있을 수 있습니다. 예를 들어, 가보, 결혼반지 등 정서적 가치가 있는 물건은 에나멜 또는 로듐 도금으로 처리할 수 있습니다[80].

또한 니켈 함유 코발트 및 티타늄 합금은 신경 혈관 의료 기기 제조에 보편화되었습니다. 실제로 다양한 비율의 니켈(14~35%)을 함유한 동맥류 클립, 혈관 내 장치 및 스텐트가 뇌동맥류 치료에 사용됩니다[81]. 니켈에 대한 알레르기 반응은 편두통, 발열, 호흡곤란, 피부염, 심낭염 등 관상동맥 스텐트와 관련된 합병증과 관련이 있는 것으로 알려져 있습니다[82].

다양한 합금에서 방출되는 니켈은 피부 염증을 유발할 수 있는 강력한 알레르겐 또는 합텐입니다. 니켈은 피부에 침투하여 상피 세포를 활성화하여 사이토카인 또는 케모카인을 생성합니다. 이 반응에는 복잡한 면역 반응에서 항원 제시 세포와 T 세포의 활성화가 포함됩니다. 활성화된 항원 제시 세포는 림프절로 이동하여 니켈이 알레르겐을 제시하거나 순진한 CD4+ T 세포와 결합합니다. 동일한 알레르겐이나 합텐에 다시 노출되면 이 T 세포는 자극을 받아 스스로 복제합니다. 그 후, 이들은 혈류로 들어가 알레르기 항원에 노출된 후 48-72시간 후에 눈에 보이는 과민증 징후를 일으킵니다. 니켈에 반복적으로 노출되면 T세포의 클론이 "역치" 값에 도달하고 피부에 급성, 아급성 또는 만성 습진과 같은 피부 패치로 나타날 수 있는 발진이 생깁니다. 피부 반응은 접촉 부위에서 발생하거나 때로는 몸의 다른 부위로 확산될 수 있습니다. 피부에 노출되면 국소적인 홍반성, 가려움증, 수포성, 비늘 모양의 패치가 생길 수 있습니다. 니켈 또는 니켈 화합물이 함유된 식품을 섭취하면 전신 부작용을 일으킬 수 있습니다[83]. 그러나 알레르기 반응의 발병 기전과 메커니즘은 매우 복잡하며 니켈 알레르기의 정확한 메커니즘은 아직 완전히 밝혀지지 않았습니다 [66].

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5. Epigenetic Effects of Nickel

Epigenetics refers to heritable modifications in gene expression‎ that do not involve a change in the nucleotide DNA sequence. The principal molecular mechanisms mediating epigenetic regulation of gene expression‎ are DNA methylation [84], histone modification and microRNA expression‎, each of which alters how genes expressed without altering the underlying DNA sequence. These processes may be influenced by a variety of environmental factors, and their dysregulations are implicated in many diseases states [85,86,87].

DNA covalent methylation involves the covalent addition of a methyl group to the cytosine to form 5-methylcytosine in the presence of the enzyme DNA methyltransferase with SAM (S-adenosylmethionine) as methyl group donor. In mammalian cells, the majority of 5-methylcytosine is located in the contest of CpG (CytosinepGuanine) dinucleotides to form the so-called CpG islands; in mammalian genome, the length of a CpG island is generally between 300 and 3000 base pairs. In mammals, 70–80% of CpG cytosine are methylated [88]. DNA methylation is involved in the regulation of many cellular processes, including chromatin structure and remodeling, genomic imprinting, chromosome stability and gene transcription [89]. Histone modification provides another mechanism of epigenetic regulation. Histones are nuclear proteins that package DNA in nucleosomes, the units of chromatin structure. The N-terminal long tail of H3 and H4 histones [90] are subjected to a variety of post-translational covalent modification reactions, like cytosine and arginine methylation, lysine-acetylation and -citrullination, serine and threonine phosphorylation, ADP-ribosylation, -ubiquitination and -sumoylation that influence chromatin structure and gene expression‎. MicroRNAs are single-stranded RNAs of approximately 21–23 nucleotides in length that are transcribed from DNA, but not translated into proteins. Mature microRNAs are partially complemental to one or more messenger RNA molecules. MicroRNA main function is to down-regulate gene expression‎ by interfering with mRNA functions [91,92].

Nickel ions are able to induce heterochromatinization by binding to DNA-histone complexes and initiating chromatin condensation. Both water-insoluble nickel sulfide (NiS) and water-soluble nickel sulphate (NiSO4) and nickel chloride (NiCl2) are human carcinogens, although insoluble nickel compounds are more potent carcinogens than the soluble ones [93]. Nickel compounds can produce histone hyperphosphorylation (H3S10), hypermethylation (H3K4) and hyperubiquitination (H2A and H2B), inducing epigenetic effect that can act on gene expression‎ [94,95,96]. Their carcinogenic potential is thought to be due to the ability to precipitate epigenetic changes [97]. In a study on reconstituted homogeneous oligonucleosomal arrays in the presence of Mg2+ or Ni2+, Ellen and collaborators observed that nickel condenses chromatin to a greater extent than magnesium, the natural cation present into the cell [98]. Given that chromatin condensation is a necessary step towards heterochromatinization, that is in turn associated with various gene expression‎-repressive changes, Ellen and co-authors concluded that the carcinogenic effect of nickel might be mediated by modulation of chromatin, such as heterochromatinization. The authors speculated that heterochromatinization could be followed by DNA methylation, and the outcome might be cell transformation, tumor progression and oncogenesis, if these silenced chromatin regions contained tumor suppressor or senescence-related genes.

Salnikow and Zhitkovich found in vivo changes in DNA methylation in nickel-induced tumors [99]. Intramuscular injection of nickel sulfide into wild type p53+/− mice induced malignant histiocytomas in all mice and this tumor development was associated with hypermethylation of the tumor suppressor gene p16 in all tumors [100]. Kowara et al. showed that both in vivo and in vitro nickel exposure reduces Fiht protein expression‎ in B200 mouse cell line and in murine sarcomas [101].

Exposure of cells to nickel chloride and nickel sulfide resulted in intracellular nickel accumulation, a loss of acetylation at all four core histones in human lung A549 cells, and an increase of dimethylation of histone H3 lysine 9 (H3K9me2), inducing transgenic silencing [101,102]. Nickel hypermethylation had no effect on histone methyltransferases, but was found to be due to the inhibition of H3K9 demethylase by replacing in the catalytic center the Fe2+ by Ni2+ [53,103,104]. Nickel chloride and nickel sulfide may also induce both histone ubiquitination and phosphorylation in A459 cells [94,96]. Treatment of A459 cells with soluble or insoluble nickel compounds resulted in increased levels of H2A and H2B ubiquitination in a dose- and time-dependent manner, indicating that both soluble and insoluble nickel compounds share similar epigenetic effects in inducing histone ubiquitination.

Karaczyn et al., using isolated bovine histone H2A, as well as different rodent (CHO, Chinese hamster ovary; NRK-52, rat renal tubular epithelium) and human (HPL1D, human lung epithelium) cell lines, showed that nickel binds to the C-terminal TESHHKAKGK sequence of histone H2A and hydrolyzes the E-S peptide bond, resulting in the release of the C-terminal octapeptide SHHKAKGK from histone H2A [105]. The authors speculated that the truncation of histone H2A may alter the chromatin structure and affect gene expression‎, which may be involved in mediating nickel toxicity and carcinogenicity.

Nickel exposure has been associated with DNA hypermethylation and transcriptional repression of tumor suppressor genes in vitro and in vivo. In addition, nickel modulates various and different histone post-translational modifications, such as acetylation, methylation, sumoylation, ubiquitination and ADP-ribosylation, by targeting the enzymes that add or remove the specific marks. In addition, nickel may interfere with microRNA network to degrade mRNA or block protein synthesis [88]. Then, piling evidence suggests that epigenetic modifications working in concert with genetic mechanisms to regulate transcriptional activity are dysregulated in many diseases, including cancer. Aberrant DNA methylation, histone modifications, are key epigenetic mechanisms associated with tumor initiation, cancer progression, and metastasis.

후성유전학은 뉴클레오티드 DNA 염기 서열의 변화를 수반하지 않는 유전자 발현의 유전적 변형을 말합니다. 유전자 발현의 후성유전학적 조절을 매개하는 주요 분자 메커니즘은 DNA 메틸화[84], 히스톤 변형 및 마이크로RNA 발현이며, 각 메커니즘은 기본 DNA 서열을 변경하지 않고 유전자의 발현 방식을 변경합니다. 이러한 과정은 다양한 환경적 요인에 의해 영향을 받을 수 있으며, 이러한 조절 장애는 많은 질병 상태와 관련이 있습니다[85,86,87].

DNA 공유 메틸화는 SAM(S-아데노실메티오닌)을 메틸기 공여체로 하는 효소 DNA 메틸전달효소의 존재 하에 시토신에 메틸기를 공유 결합하여 5-메틸시토신을 형성하는 것을 포함합니다. 포유류 세포에서 대부분의 5-메틸시토신은 CpG(사이토신p구아닌) 디뉴클레오타이드의 경합에 위치하여 소위 CpG 섬을 형성하는데, 포유류 게놈에서 CpG 섬의 길이는 일반적으로 300~3000 염기쌍입니다. 포유류에서는 CpG 시토신의 70~80%가 메틸화되어 있습니다[88]. DNA 메틸화는 염색질 구조 및 리모델링, 게놈 각인, 염색체 안정성 및 유전자 전사를 포함한 많은 세포 과정의 조절에 관여합니다 [89]. 히스톤 변형은 후성유전학적 조절의 또 다른 메커니즘을 제공합니다. 히스톤은 염색질 구조의 단위인 뉴클레오솜에 DNA를 포장하는 핵 단백질입니다. 히스톤은 염색질 구조와 유전자 발현에 영향을 미치는 사이토신 및 아르기닌 메틸화, 라이신 아세틸화 및 -시트룰린화, 세린 및 트레오닌 인산화, ADP-리보실화, -유비퀴틴화 및 -스모일화와 같은 다양한 번역 후 공유 결합 변형 반응에 의해 N-말단 롱테일[90]이 형성됩니다. 마이크로RNA는 DNA에서 전사되지만 단백질로 번역되지는 않는 약 21~23개의 뉴클레오타이드 길이의 단일 가닥 RNA입니다. 성숙한 마이크로RNA는 하나 이상의 메신저 RNA 분자를 부분적으로 보완합니다. 마이크로RNA의 주요 기능은 mRNA 기능을 방해하여 유전자 발현을 하향 조절하는 것입니다[91,92].

니켈 이온은 DNA-히스톤 복합체에 결합하고 염색질 응축을 시작하여 이종 염색질화를 유도할 수 있습니다. 불용성 황화니켈(NiS)과 수용성 황산니켈(NiSO4) 및 염화니켈(NiCl2) 모두 인체 발암 물질이지만 불용성 니켈 화합물은 수용성보다 더 강력한 발암 물질입니다 [93]. 니켈 화합물은 히스톤 과인산화(H3S10), 과메틸화(H3K4) 및 과유비퀴틴화(H2A 및 H2B)를 생성하여 유전자 발현에 작용할 수 있는 후성 유전학적 효과를 유발할 수 있습니다 [94,95,96]. 이들의 발암 가능성은 후성유전학적 변화를 촉진하는 능력 때문인 것으로 생각됩니다 [97]. Mg2+ 또는 Ni2+의 존재 하에서 재구성된 균질 올리고뉴클레오솜 배열에 대한 연구에서 Ellen과 공동 연구자들은 니켈이 세포에 존재하는 천연 양이온인 마그네슘보다 염색질을 더 많이 응축시키는 것을 관찰했습니다[98]. 염색질 응축은 이종 염색질화를 위한 필수 단계이며, 이는 다양한 유전자 발현 억제 변화와 관련이 있다는 점을 고려할 때, 엘렌과 공동 저자들은 니켈의 발암 효과가 이종 염색질화와 같은 염색질 조절을 통해 매개될 수 있다고 결론을 내렸습니다. 저자들은 이종 염색질화에 이어 DNA 메틸화가 뒤따를 수 있으며, 이러한 침묵 염색질 영역에 종양 억제 또는 노화 관련 유전자가 포함되어 있는 경우 세포 변형, 종양 진행 및 종양 발생이 일어날 수 있다고 추측했습니다.

살니코프와 지트코비치는 니켈로 유발된 종양에서 DNA 메틸화의 생체 내 변화를 발견했습니다[99]. 야생형 p53+/- 마우스에 황화 니켈을 근육 주사하면 모든 마우스에서 악성 조직 세포종이 유도되었고, 이러한 종양 발생은 모든 종양에서 종양 억제 유전자 p16의 과메틸화와 관련이 있었습니다 [100]. 코와라 등은 생체 내 및 시험관 내 니켈 노출이 B200 마우스 세포주와 쥐 육종에서 Fiht 단백질 발현을 감소시킨다는 사실을 보여주었습니다[101].

세포를 염화니켈과 황화니켈에 노출시키면 세포 내 니켈 축적, 인간 폐 A549 세포의 네 가지 핵심 히스톤에서 아세틸화 손실, 히스톤 H3 라이신 9(H3K9me2)의 탈메틸화가 증가하여 형질전환 침묵을 유도합니다[101,102]. 니켈 과메틸화는 히스톤 메틸화 전이 효소에는 영향을 미치지 않았지만 촉매 중심에서 Fe2+를 Ni2+로 대체하여 H3K9 탈메틸화 효소를 억제하기 때문인 것으로 밝혀졌습니다 [53,103,104]. 염화 니켈과 황화 니켈은 또한 A459 세포에서 히스톤 유비퀴틴화와 인산화를 모두 유도할 수 있습니다 [94,96]. 용해성 또는 불용성 니켈 화합물로 A459 세포를 처리하면 용량 및 시간 의존적으로 H2A 및 H2B 유비퀴틴화 수준이 증가하여 용해성 및 불용성 니켈 화합물이 모두 히스톤 유비퀴틴화를 유도하는 데 유사한 후성 유전 효과를 공유한다는 것을 나타냅니다.

카라친 외., 은 분리된 소 히스톤 H2A와 다른 설치류(CHO, 중국 햄스터 난소, NRK-52, 쥐 신장 관상피) 및 인간(HPL1D, 인간 폐 상피) 세포주를 사용하여 니켈이 히스톤 H2A의 C-말단 TESHHKAKGK 서열에 결합하고 E-S 펩타이드 결합을 가수분해하여 히스톤 H2A에서 C-말단 옥타펩티드 SHHKAKGK를 방출한다는 것을 보여주었습니다[105]. 저자들은 히스톤 H2A의 절단이 염색질 구조를 변화시키고 유전자 발현에 영향을 미쳐 니켈 독성과 발암성을 매개하는 데 관여할 수 있다고 추측했습니다.

니켈 노출은 시험관 및 생체 내에서 종양 억제 유전자의 DNA 과메틸화 및 전사 억제와 관련이 있습니다. 또한 니켈은 특정 마크를 추가하거나 제거하는 효소를 표적으로 하여 아세틸화, 메틸화, 수모일화, 유비퀴틴화 및 ADP-리보실화와 같은 다양하고 다른 히스톤 번역 후 변형을 조절합니다. 또한 니켈은 마이크로RNA 네트워크를 방해하여 mRNA를 분해하거나 단백질 합성을 차단할 수 있습니다[88]. 그런 다음, 전사 활동을 조절하는 유전적 메커니즘과 함께 작용하는 후성유전적 변형이 암을 포함한 많은 질병에서 조절 장애를 일으킨다는 증거가 쌓이고 있습니다. 비정상적인 DNA 메틸화, 히스톤 변형은 종양 개시, 암 진행 및 전이와 관련된 주요 후성유전학적 메커니즘입니다.

6. Teratogenicity of Nickel Compounds

Teratology studies the congenital malformations, retardation growth and their cause. Particularly in early pregnancy, intrauterine exposure to a toxicant stimulates changes in the embryo and fetus that lead to malformations and stillbirths. The teratogenic agents include rubella virus, protozoal infections. Ionizing radiations, hyperthermia, pharmacological drugs as thalidomide and retinoic acid, corticosteroids, antimalarial and antihypertensive agents, industrial pollutants as toluene and pesticides, heavy metals, such as Hg, Cd and Ni. Even bad mother life behavior like alcohol abuse, cigarettes and narcotics during pregnancy negatively affects the embryo and the fetus. Health problems of the mother, such as diabetes mellitus and rheumatoid arthritis, are added to the list of teratogens. The lack of folate in the diet of pregnant women results in spina bifida in the newborn. Nickel can cross the placenta and has embryo toxic and teratogenic properties.

Sanderman and co-authors [106,107] studied the effects of Ni carbonyl, Ni(CO)4, and nickel sulfide (Ni2S3) administered to pregnant hamsters and female rats. In the first paper, Ni carbonyl was administered to pregnant hamsters on different days of gestation; then the dams were sacrificed on day 15 of gestation, and the fetuses were tested for malformations. Progeny of dams treated with Ni(CO)4 (0.06 mg/L/15 min) on days 4 and 5 of gestation included fetuses with cystic lungs, exencephaly, exencephaly plus fused rib and anophthalmia plus cleft palate. In addition, in the progeny of dams treated with Ni carbonyl on days 6 and 7 of gestation, there were two fetuses with hydronephrosis and one with fused ribs. In the second paper, Sunderman illustrated in three experiments the effects of Ni carbonyl and nickel sulfide on the progeny of Fisher rats. Intravenous injection (11 mg Ni/kg) on day 7 of gestation to pregnant dams caused malformations of fetuses, including anophthalmia, microphthalmia and cystic lungs, and fetal mortality. In the second experiment, male rats were treated by inhalation with Ni carbonyl (0.05 mg Ni/L/15 min) two to six weeks to breeding without impair fertilization rates or reproductive yields. However, administration of organic Ni compound by intravenous injection (22 mg Ni/kg) decreased the number of live pups during the fifth week, due to chromosomal damage during the meiosis of spermatogenesis. In the last experiment, female rats were treated by intrarenal injection with Ni2S3 (30 mg Ni/kg) one week prior to breeding, and the result was an intense erythrocytosis in the dams without cause erythrocytosis in the pups; but instead, pups born from dams treated with Ni3S2 had decreased hematocrits at two weeks postpartum.

Leonard and collaborators [108,109] with their experimental studies have demonstrated that nickel compounds have potent effects of carcinogenicity and teratogenicity. Apart from an increase of prenatal and natal mortality, Ni may cause a different type of malformation in the embryos. It was hypothesized by Leonard et al. that the prenatal nickel effects could partially be due to the changes in mitosis, leading to cellular death.

The study of Saini et al. [110] was conducted to assess the potentially harmful effect of Ni (NiCl2.6 H2O) on the fetuses of Swiss albino mice. Ni (46.125, 92.25, 184.5 mg Ni/kg body weight) was administered orally from days 6 to 13 of gestation period. On day 18 of gestation, dams were sacrificed, and uteri were examined. After the administration of the three different dosages of Ni, Saini noted a lower number of implant sites and placental weight compared to the respective controls. Saini and co-authors after the nickel treatment of mice have noticed different malformations in fetuses, such as for example hydrocephaly, microphthalmia, exophthalmia, club foot and umbilical hernia. In addition, bone malformations have been highlighted like reduced ossification of nasal, frontal, parietal and supraoccipital bones, reduced fuses sternebrae and caudal vertebrae, and absence of carpal, metacarpal, tarsal, metatarsal and phalanges.

The results of these researchers indicate the vulnerability of the rats and mice fetus to nickel during prenatal exposure.

기형학은 선천성 기형, 성장 지연 및 그 원인을 연구합니다. 특히 임신 초기에 자궁 내 독성 물질에 노출되면 배아와 태아의 변화를 자극하여 기형과 사산을 유발할 수 있습니다. 기형 유발 물질에는 풍진 바이러스, 원충 감염이 포함됩니다. 이온화 방사선, 온열요법, 탈리도마이드 및 레티노산, 코르티코스테로이드, 항말라리아제 및 항고혈압제, 톨루엔 및 살충제와 같은 산업 오염 물질, Hg, Cd 및 Ni와 같은 중금속과 같은 약물. 임신 중 알코올 남용, 담배, 마약과 같은 나쁜 산모의 생활 습관도 태아와 태아에게 부정적인 영향을 미칩니다. 당뇨병 및 류마티스 관절염과 같은 어머니의 건강 문제가 기형 유발 물질 목록에 추가됩니다. 임산부의 식단에 엽산이 부족하면 신생아에게 척추 이분증이 발생합니다. 니켈은 태반을 통과 할 수 있으며 배아 독성 및 기형 유발 특성을 가지고 있습니다.

샌더만과 공동 저자[106,107]는 임신한 햄스터와 암컷 쥐에게 투여한 니켈 카보닐, Ni(CO)4, 황화니켈(Ni2S3)의 효과를 연구했습니다. 첫 번째 논문에서는 임신한 햄스터에게 임신 일수에 따라 니카보닐을 투여한 후 임신 15일째에 댐을 희생하고 태아의 기형 여부를 검사했습니다. 임신 4일과 5일째에 Ni(CO)4(0.06 mg/L/15분)로 처리한 댐의 자손에는 낭성 폐, 외뇌증, 외뇌증과 융합된 갈비뼈, 무안검증과 구개열을 가진 태아들이 포함되었습니다. 또한 임신 6일과 7일에 니카보닐로 처리한 댐의 자손에서는 수두증과 융합 늑골을 가진 태아 2명과 융합 늑골을 가진 태아 1명이 있었습니다. 두 번째 논문에서 선더만은 세 가지 실험을 통해 니카보닐과 황화니켈이 피셔 쥐의 자손에 미치는 영향을 설명했습니다. 임신한 댐에 임신 7일째에 정맥 주사(11mg Ni/kg)를 한 결과 무안구증, 소안구증, 낭성 폐 등 태아 기형과 태아 사망률이 발생했습니다. 두 번째 실험에서는 수컷 쥐를 대상으로 수정률이나 번식률에 영향을 주지 않으면서 번식 2~6주 전에 니코닐(0.05mg Ni/L/15분)을 흡입하도록 처리했습니다. 그러나 정맥 주사로 유기 Ni 화합물을 투여(22 mg Ni/kg)하면 정자 형성의 감수분열 과정에서 염색체 손상으로 인해 5주차에 새끼의 수가 감소했습니다. 마지막 실험에서는 번식 1주일 전에 암컷 쥐에게 Ni2S3(30 mg Ni/kg)를 신장 내 주사로 처리한 결과, 새끼에게는 적혈구 증가증이 나타나지 않았지만, 대신 Ni3S2로 처리한 댐에서 태어난 새끼는 산후 2주째에 적혈구가 감소한 것으로 나타났습니다.

Leonard와 공동 연구자[108,109]는 실험 연구를 통해 니켈 화합물이 발암성 및 기형 유발성에 강력한 영향을 미친다는 사실을 입증했습니다. 산전 및 산후 사망률 증가 외에도 니켈은 태아에게 다른 유형의 기형을 유발할 수 있습니다. Leonard 등은 태아기 니켈의 영향이 부분적으로 유사 분열의 변화로 인해 세포 사멸로 이어질 수 있다는 가설을 세웠습니다.

Saini 등[110]의 연구는 스위스 알비노 마우스의 태아에 대한 Ni(NiCl2.6 H2O)의 잠재적 유해 영향을 평가하기 위해 수행되었습니다. 임신 기간 6~13일째에 Ni(46.125, 92.25, 184.5 mg Ni/kg 체중)를 경구 투여했습니다. 임신 18일째에 댐을 희생하고 자궁을 검사했습니다. 세 가지 용량의 Ni를 투여한 결과, 사이니는 각각의 대조군에 비해 이식 부위 수와 태반 무게가 감소한 것을 확인했습니다. 사이니와 공동 저자들은 생쥐에게 니켈을 투여한 후 태아에게 수두증, 소안구증, 외안구증, 만곡족, 제대 탈장 등 다양한 기형이 발생하는 것을 발견했습니다. 또한 비골, 전두골, 두정골, 후두골의 골화 감소, 흉골과 꼬리뼈의 융합 감소, 손목, 중수골, 족골, 중족골, 지골의 부재와 같은 뼈 기형도 주목받고 있습니다.

이러한 연구 결과는 태아기 니켈 노출 시 쥐와 생쥐의 태아가 니켈에 취약하다는 것을 나타냅니다.

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7. Nickel-Induced Apoptosis

Apoptosis is a process of programmed cell death that occurs in all multicellular organisms [111,112], and takes place with biochemical events that lead to characteristic cellular changes that have cell death as the last step. These changes include cell shrinkage, blebbing, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation and global RNA decay [113]. The average adult human loses between 50 and 70 billion cells each day, due to apoptosis.

In contrast to necrosis, which is a form of traumatic cell death that is a consequence of acute cellular injury, apoptosis is a highly regulated and controlled process that confers advantages during an organism lifecycle. Unlike necrosis, apoptosis produces cell fragments called apoptotic bodies that phagocytic cells are able to ingest and quickly remove before the content of the cell can split onto surrounding cells and cause damage to the neighboring cells.

Two principal pathways exist by which cells can undergo apoptotic death, known as the intrinsic (also called mitochondrial pathway) and the extrinsic pathways. The former is activated by intracellular signals generated when cells are stressed and are related to the release of Cyt C from the intermembrane space of mitochondria. The latter is activated by extracellular ligands binding to cell-surface death receptors (TNF, Tumor Necrosis Factor-receptor family), which leads to the production of the death-inducing signaling complex. In the intrinsic pathway, the cell kills itself because of cellular stress, while in the extrinsic pathway, the cell kills itself because of signals received from other cells. Both pathways induce cell death by activating caspases (cysteine proteases) or enzymes that degrade proteins.

Nickel ions allow the release of Cyt c from mitochondria in the cytosol, where Cyt C cleaves procaspase-9 with activation of caspase-9, which in turn activates caspase-3, -6, and -7. These caspases act on PARP, which induces apoptosis. On the cell surface, the Ni ions promote the interaction between Fas (First apoptotic signal) and FasL (Fas Ligand) with the formation of the death-inducing signaling complex, which contains FADD and procaspase-8 and -10 that are activated to caspase-8 and -10. In the cell caspase-8 and -10 cleave and activate the effectors of proteases, such as caspase-3, -6 and -7 that act on PARP, which lead to apoptosis (Figure 1). Moreover, some members of Bcl-2 family of proteins inhibit apoptosis [114]. In addition to its importance as a biological phenomenon, defective apoptotic processes have been involved in a wide variety of diseases. Excessive cell death is responsible for many neurodegenerative diseases, whereas, failure to undergo apoptosis results in autoimmune diseases and uncontrolled cell proliferation, such as cancer.

세포 사멸은 모든 다세포 유기체에서 발생하는 프로그램화된 세포 사멸 과정으로[111,112], 세포 사멸을 마지막 단계로 하는 특징적인 세포 변화로 이어지는 생화학적 사건과 함께 일어납니다. 이러한 변화에는 세포 수축, 블리빙, 핵 단편화, 염색질 응축, 염색체 DNA 단편화 및 전체 RNA 붕괴가 포함됩니다[113]. 평균적으로 성인 인간은 세포 사멸로 인해 매일 500억~700억 개의 세포를 잃습니다.

급성 세포 손상의 결과인 외상성 세포 사멸의 한 형태인 괴사와 달리, 세포 사멸은 고도로 조절되고 통제되는 과정으로 유기체의 수명 주기 동안 이점을 제공합니다. 괴사와 달리 세포 사멸은 세포의 내용물이 주변 세포로 퍼져 주변 세포에 손상을 입히기 전에 포식 세포가 섭취하여 신속하게 제거할 수 있는 세포 조각인 세포 사멸체를 생성합니다.

세포가 세포 사멸을 겪을 수 있는 두 가지 주요 경로는 내재적 경로(미토콘드리아 경로라고도 함)와 외재적 경로로 알려져 있습니다. 전자는 세포가 스트레스를 받을 때 생성되는 세포 내 신호에 의해 활성화되며 미토콘드리아의 막간 공간에서 Cyt C가 방출되는 것과 관련이 있습니다. 후자는 세포 표면 사멸 수용체(TNF, 종양 괴사인자 수용체 계열)에 결합하는 세포 외 리간드에 의해 활성화되어 사멸 유도 신호 복합체의 생성으로 이어집니다. 내재적 경로에서는 세포 스트레스로 인해 세포가 스스로 사멸하는 반면, 외재적 경로에서는 다른 세포로부터 받은 신호로 인해 세포가 스스로 사멸합니다. 두 경로 모두 카스파제(시스테인 프로테아제) 또는 단백질을 분해하는 효소를 활성화하여 세포 사멸을 유도합니다.

니켈 이온은 세포질 내 미토콘드리아에서 Cyt c를 방출하고, Cyt c는 카스파제-9의 활성화로 프로카스파제-9를 절단하여 카스파제-3, -6, -7을 활성화합니다. 이러한 카스파제는 PARP에 작용하여 아포토시스를 유도합니다. 세포 표면에서 Ni 이온은 Fas(최초 세포 사멸 신호)와 FasL(Fas 리간드)의 상호 작용을 촉진하여 세포 사멸 유도 신호 복합체를 형성하고, 이 복합체에는 카스파제-8과 -10으로 활성화되는 FADD와 프로카스파제-8 및 -10이 포함되어 있습니다. 세포에서 카스파제-8과 -10은 PARP에 작용하는 카스파제-3, -6, -7과 같은 프로테아제의 이펙터를 절단하고 활성화하여 세포 사멸을 유도합니다(그림 1). 또한, Bcl-2 계열 단백질의 일부 구성원은 세포 사멸을 억제합니다[114]. 생물학적 현상으로서의 중요성 외에도 세포 사멸 과정의 결함은 다양한 질병에 관여하고 있습니다. 과도한 세포 사멸은 많은 신경 퇴행성 질환의 원인이 되는 반면, 세포 사멸이 일어나지 않으면 자가 면역 질환과 암과 같은 통제되지 않은 세포 증식이 발생합니다.

Figure 1

Ni2+-induced mitochondria-apoptosis and caspase-dependent apoptosis.

Su and co-authors reported that NiSO4 induces DNA damage, apoptosis and oxidative stress in rat testes. This study also explored the effect of protection of grape seed proanthocyanidin extract (GSPE) against nickel toxicity in the testes. The authors treated rats with normal saline, nickel alone (1.25, 2.5, and 5.0 mg/kg/day), and nickel (1.25, 2.5, and 5.0 mg/kg/day) in the presence of GSPE (50 and 100 mg/kg/day). After a period of 30 days treatment, nickel (2.5 and 5.0 concentrations) exhibits reproductive toxicity by decreasing sperm motility, while GSPE enhances sperm motility [115].

Ni2+에 의한 미토콘드리아 세포 자멸사 및 카스파제 의존성 세포 자멸사.

Su와 공동 저자들은 NiSO4가 쥐의 고환에서 DNA 손상, 세포 자멸사 및 산화 스트레스를 유도한다고 보고했습니다. 이 연구는 또한 고환의 니켈 독성에 대한 포도씨 프로안토시아니딘 추출물(GSPE)의 보호 효과를 조사했습니다. 저자들은 쥐를 생리식염수, 니켈 단독(1.25, 2.5, 5.0 mg/kg/일), GSPE(50, 100 mg/kg/일)와 함께 니켈(1.25, 2.5, 5.0 mg/kg/일)로 처리했습니다. 30일 처리 후 니켈(2.5 및 5.0 농도)은 정자 운동성을 감소시켜 생식 독성을 나타내는 반면, GSPE는 정자 운동성을 향상시킵니다[115].

Zou and collaborators reported that nickel sulphate induced apoptosis in rat testicular Leydig cells via activating ROS-dependent mitochondria [116]. The results of the study showed that nickel sulphate induced ROS generation with nucleus deformation and apoptosis in Leydig cells, which were attenuated by ROS inhibitors of NAC (N-acetylcysteine) and TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy). In vitro studies on nickel-induced apoptosis suggested that nickel compounds can promote apoptosis in human epatoma cells [117], keratinocytes [118], human T hybridoma cells [119], human breast cancer (MCF-7 cells), abrogated by antioxidant curcumin [120], human liver cells (HepG2) [121], as well as human neutrophils [122]. Ma and co-authors demonstrated that nickel nanowires induce apoptosis in HeLa cells through ROS generation and that ROS induce HeLa cells apoptosis through mitochondrial membrane damage or activation of cell cycle checkpoints [123].

Pan and co-authors [124] investigated the effect of Ni-smelting fumes on cell viability, mitochondrial damage and apoptosis in NIH/3T3 cells. Treatment with Ni-smelting fumes increased mitochondrial permeability transition pore opening and decreased mitochondrial activity of the complex I (NADH: Ubiquinone oxidoreductase), complex II (succinate dehydrogenase) and complex IV (cytochrome c oxidase) of the mitochondrial respiratory chain. The Ni-smelting fumes downregulated Bcl-2, procaspase-3 and -9, and upregulated caspase-3, and -9. In mammalian cells, Ni-smelting fumes caused significant cytotoxicity, oxidative stress, mitochondrial damage and apoptosis through the intrinsic pathway.

Zou와 공동 연구자들은 황산니켈이 ROS 의존성 미토콘드리아 활성화를 통해 쥐의 고환 레이디그 세포에서 세포 사멸을 유도한다고 보고했습니다[116]. 연구 결과에 따르면 황산니켈은 라이딕 세포에서 핵 변형과 세포 사멸을 동반한 ROS 생성을 유도했으며, 이는 NAC(N-아세틸시스테인) 및 TEMPO(2,2,6,6-테트라메틸-1-피페리디닐록시)의 ROS 억제제에 의해 약화되는 것으로 나타났습니다. 니켈에 의한 세포 사멸에 대한 시험관 내 연구에서는 니켈 화합물이 항산화 커큐민에 의해 제거된 인간 상피세포[117], 각질세포[118], 인간 T 하이브리드종 세포[119], 인간 유방암(MCF-7 세포)[120], 인간 간세포(HepG2)[121] 및 인간 호중구[122]에서 세포 사멸을 촉진할 수 있음을 시사했습니다. Ma와 공동 저자들은 니켈 나노와이어가 ROS 생성을 통해 HeLa 세포의 세포 사멸을 유도하고, ROS가 미토콘드리아 막 손상 또는 세포 주기 체크포인트의 활성화를 통해 HeLa 세포 세포 사멸을 유도한다는 사실을 입증했습니다[123].

Pan과 공동 저자[124]는 NIH/3T3 세포에서 Ni-용융 연기가 세포 생존력, 미토콘드리아 손상 및 세포 사멸에 미치는 영향을 조사했습니다. Ni-용융 연기로 처리하면 미토콘드리아 투과성 전이 기공 개방이 증가하고 미토콘드리아 호흡 사슬의 복합체 I(NADH: 유비퀴논 옥시도환원효소), 복합체 II(숙신산염 탈수소효소) 및 복합체 IV(시토크롬 C 산화효소)의 미토콘드리아 활동이 감소하는 것을 확인할 수 있었습니다. 니켈 제련 연기는 Bcl-2, 프로카스파제-3 및 -9를 하향 조절하고 카스파제-3 및 -9를 상향 조절했습니다. 포유류 세포에서 니켈 제련 연기는 내재적 경로를 통해 상당한 세포 독성, 산화 스트레스, 미토콘드리아 손상 및 세포 사멸을 유발했습니다.

8. Nickel Phytoremediation and Phytomining

Since heavy and transition metals (Hg, Pb, As, Cu, Ni and Cr) are no degradable by microorganisms, they accumulate in the environment (soil, water and air) and subsequently contaminate the food chain, generating a risk to human health. Some heavy and transition metals are carcinogenic, teratogenic and endocrine disruptors; some others cause neurological and neurodegenerative diseases and behavioral changes in human beings [28,60,61,62]. Different physical and chemical methods used for remediation of heavy and transition metal pollution suffer from high cost, alteration of soil properties and disturbance of soil microflora and creation of secondary pollution problems. Phytoremediation is a solar-driven technology that uses plants to clean up soil, air, and water contaminated with hazardous chemicals. It removes pollutants, including toxic and radioactive metals, from the environment by using plants [125]. Phytoremediation is a better solution to pollution, because it is environment-friendly and an aesthetically pleasing with good public acceptance. It is a cost-effective plant-based approach that takes advantage of the ability of plants to concentrate elements and compounds from the environment and to metabolize dangerous molecules in their tissues.

It refers to the natural ability of plants, called hyperaccumulators, to bioaccumulate, degrade or render harmless contaminants in soils, water and air. Plants can be defined as a hyperaccumulator if it can concentrate the pollutants in a minimum percentage which varies according to the pollutant involved (for example, more than 1000 mg/kg of dry weight for nickel, copper, cobalt, chromium or lead; or more than 10,000 mg/kg for zinc or manganese). This capacity for accumulation is due to a hypertolerance or phytotolerance. It is the result of adaptive evolution from the plants to hostile environments over many generations. Contaminants, such as heavy metals, pesticides, solvents, explosives, and crude oil have been eliminated with phytoremediation projects worldwide. Phytoremediation may be applied wherever the soil or static water environment has become polluted or is suffering ongoing chronic pollution.

Techniques of phytoremediation include phytoextraction, phytofiltration, phytostabilization, phytodegradation and phytodesalination. Phytoextraction consists in the contaminants uptake from soil and water by plants roots [126]; phytofiltration is the removal of pollutants from contaminated wastewater by plants [127]; phytostabilization is the use of plants for stabilization of contaminants reducing the mobility of pollutants and preventing they entry in the food chain [128]; phytodegradation is the destruction of organic xenobiotics by plants thanks to enzymes like oxygenase and dehalogenase [129], phytodesalination refers to the use of halophytic plants for removal of sodium chloride from salt-affected soils in order to enable them for supporting normal plant growth [130,131].

The extraction of nickel, cobalt, iron, platinum, palladium and other heavy metals from soil by cropping them with hyper accumulating plants that concentrate these metals in aerial parts of the plants, which are then harvested, dried and smelted, allows to recover the metals in a process known as metal phytomining [132]. There are many Ni hyper accumulators, i.e., plants which accumulate more than 1000 mg Ni/kg of dry weight in their shoots when grown in natural habitats. In late 1948, Minguzzi and Vergnano discovered that Alyssum bertolonii Desv. (Brassicaceae) had an extraordinarily high Ni content of about 10 mg/g [l%] in a dried matter which translated to well over 10% of this element in the ash [133].

In 1976, Jaffrè et al. reported that in New Caledonia an endemic tree (Pycnandra acuminata, first known as Sebertia acuminata) has extraordinary ability to accumulate Ni in its latek of blue-green color, due to the presence of nickel (about 25% of the latek dry weight). New Caledonia is an archipelago with a third of its surface covered by Ni-rich soil of ultramafic rocks. Jaffrè and co-authors consider that the rich New Caledonian flora contains 2145 species adapted to ultramafic soils among which 65 are Ni hyperaccumulators [134].

Analyses of New Caledonia hyperaccumulators revealed that Ni was associated with citrate complex in the Pycnandra acuminata [135,136]. Callahan et al. studies of gas chromatography mass spectrometry revealed the presence of Ni-nicotianamine complexes in most of the New Caledonian species, including Pycnandra acuminata. In addition to citric acid, a methylated aldaric acid (2,4,5-trihydroxy-3-methoxy-1,6-hexan-dioic acid) appears to be one of the most abundant small organic molecules present in the latex; others Ni complexes were detected, as well as malic, itaconic, galacturonic, tartaric and aconitic acids [137].

The experiments of Giordani et al. [138] studied the phytoremediation of soil polluted by nickel using agricultural crops on seven herbaceous crops as burley (Hordeum vulgaris), bean (Phaseolus vulgaris), cabbage (Brassica juncea), ricinus (Ricinus communis), sorghum (Sorghum vulgare), spinach (Spinacea oleracea) and tomato (Solanum lycopersicum). At the end of experiments, leaves, roots, stems, fruits or seeds were separately collected, oven-dried at 100 °C, weighed, milled and analyzed. It was shown that spinach, ricinus and cabbage were able to store nickel in the leaves. The bean, barley and tomato showed a high concentration of nickel in leaves and in stems. The bean was the most efficient in the storage of nickel in fruits or seeds and roots—unlike tomato, sorghum, ricinus and barley, which showed a storage capacity lower than that of a bean. With regard to the removal of nickel, spinach was the most efficient as it contains the highest levels of the metal per gram of dry matter with respect to the other six herbaceous crops [138]. The Ni hyper accumulator Alyssum murale has been developed as a commercial crop for phytoremediation/phytomining Ni from metal-enriched soils [139]. Nickel hypertolerance is often specific. It undergoes vacuolar sequestration via epidermal compartmentalization, whereas, cobalt present in the xylem or leaf apoplasm was excreted from leaves and subsequently sequestered on leaf surfaces as soluble precipitate. Therefore, the specialized biochemical processes linked to Ni hypertolerance in Alyssum murale did not confer hypertolerance to cobalt. Broadhurst and Chaney [140] co-cropped Alyssum murale (Ni hyperaccumulator), Alyssum montanum (Ni non-hyperaccumulator), and ryegrass Lolium perenne in a natural serpentine soil to affect Ni, Cu, Fe and Mn uptake. After four months with standard inorganic treatment, A. murale leaves and stems contained 3600 mg/kg Ni. Moreover, the concentration of Ni and Mn were significantly higher in A. murale respect to A. montanum or L. perenne. Both Alyssum species not accumulated Cu, while L. perenne accumulated only 10 mg/kg Cu. Besides, co-cropping A. murale with L. perenne reduced Fe and Mn concentrations in A. murale [141]. Psychotria douarrei and Geissois pruinosa are other plants called hypernickelophores, which accumulate more than 10,000 mg Ni/kg [141]. Fernando et al., using the colorimetric reagent dimethylglyoxime, indicated high levels of Ni in the leaves of Rinorea niccolifera (Violaceae) [142,143]. Subsequent chemical analyses of the plant tissues revealed foliar nickel concentrations varying from 7168 to 18,388 mg/kg on a dry weight basis. The data are based on six sets of plant tissue samples of Rinorea niccolifera collected from two sites of Luzon Island (Zambales Province, Municipalities of Santa Cruz and Candelaria, Philippines). As this species surpasses the 10,000 mg/kg Ni accumulation level in the leaves, it is regarded as a “hypernickelophore”. The studies of Roccotiello et al. highlight that Mediterranean Alyssoides utriculata leaves are Ni-hyper accumulators (higher than 1.0 g/kg) and can be used for Ni-phytoextraction purposes and for cleaning Ni-contaminated areas [144]. In its second paper, Roccotiello et al. [145] investigated in pot experiments the effect of different Ni concentration (0–500 mg Ni/L) on the physiology of Alyssoides utriculata. The results showed that the concentration of this transient metal is higher in leaves than in roots, and at the higher concentration tested (500 mg Ni/L), A. utriculata accumulates 1.1 g Ni/kg leaves as previously found. Plant water content increases significantly with Ni accumulation without affecting chlorophyll fluorescence parameters. In fact, the photosynthetic efficiency of A. utriculata is stable among Ni treatments (always ≥0.8).

The bioaccumulation and distribution of Ni were also elucidated in three plant species: Phyllanthus balgooyi, Phyllanthus securinegioides (Phyllanthaceae) and Rinorea bengalensis (Violaceae) that occur in Sabah (Malaysia) on the Island of Borneo. This study by Van der Ent et al. showed that Ni is mainly concentrated in the phloem, in roots and stems (up to 16.9% Ni in phloem sap in Phyllanthus balgooyi) in all three species [146]. However, regarding their leaves: In Phyllanthus balgooyi the highest Ni concentration is in the phloem, but in Phyllanthus securinegioides and Rinorea bengalensis in the epidermis and in the spongy mesophyll (Rinorea bengalensis). All three species have a highly distinctive tissue Ni distribution patterns with extreme levels of accumulation in the phloem of the root and stem. The phloem tissues in the main stem of all three species are green, due to the exceptionally high concentration of Ni2+ ions, and appear to act as a ‘sink’ with Ni concentrations reaching up to 2.1% in Rinorea bengalensis and up to 16.9 wt%, in the phloem sap from Phyllanthus balgooyi.

Many strategies have been used for solving the problem of heavy metals pollution in the environment. The bioremediation methods for decreasing the amount of heavy metals in the environment have attracted the attention of many researchers. Plants, bacteria, fungi and algae are usually used for bioremediation of heavy metals [147], and in the literature, there are now many publications of biosorption of nickel, among others Pseudomonas fluorescent [148], Bacillus cereus [149], Saccharomyces cerevisiae [150], and filamentous fungi Trichoderma atroviride strains F6 [151].

In their studies, Abdel-Monem et al. [152] used Bacillus subtilis 117S and Pseudomonas cepacia 120 S to remove Ni from bacterial biomass, sludge, tea and sawdust. The authors of this study have shown that the biosorption capacity of nickel by bacterial biomass was greater than that by sludge, tea and sawdust. Moreover, the nickel removal increased with contact time from 1 to 8 h without increasing until 24 h; biosorption efficiency of nickel also increased with pH changes from 2 to 7 and remained constant thereafter. The maximum sorption efficiency of nickel was obtained at 37 °C, while at 45 °C and 55 °C the nickel biosorption was reduced.

Phytoremediation has the advantage that contaminants may be treated in situ; while the major limitation is that it requires a long-term commitment, since the process is dependent on the plant ability to grow and thrive in an environment that is not always appropriate for normal plant growth.

중금속 및 전이금속(Hg, Pb, As, Cu, Ni, Cr)은 미생물에 의해 분해되지 않기 때문에 환경(토양, 물, 공기)에 축적되어 먹이사슬을 오염시켜 인체 건강에 위험을 초래합니다. 일부 중금속과 전이금속은 발암성, 기형 유발성 및 내분비 교란 물질이며, 다른 일부는 인간에게 신경 및 신경 퇴행성 질환과 행동 변화를 일으킵니다[28,60,61,62]. 중금속 및 전이금속 오염을 정화하기 위해 사용되는 다양한 물리적, 화학적 방법은 높은 비용, 토양 특성 변화, 토양 미생물 교란, 2차 오염 문제 발생 등의 문제를 안고 있습니다. 식물 정화란 식물을 이용해 유해 화학물질로 오염된 토양, 공기, 물을 정화하는 태양광 기반 기술입니다. 식물을 사용하여 독성 및 방사성 금속을 포함한 오염 물질을 환경으로부터 제거합니다[125]. 식물 정화법은 환경 친화적이고 미적으로도 아름다워 대중의 수용성이 높기 때문에 오염에 대한 더 나은 해결책입니다. 이는 식물이 환경의 원소와 화합물을 농축하고 조직에서 위험한 분자를 대사하는 능력을 활용하는 비용 효율적인 식물 기반 접근 방식입니다.

이는 토양, 물, 공기 중의 오염 물질을 생체 축적, 분해 또는 무해하게 만드는 식물의 자연적인 능력, 즉 과축적자라고 불리는 식물의 자연적인 능력을 말합니다. 식물은 오염 물질에 따라 달라지는 최소 비율(예: 니켈, 구리, 코발트, 크롬 또는 납의 경우 건조 중량 1000 mg/kg 이상, 아연 또는 망간의 경우 10,000 mg/kg 이상)로 오염 물질을 농축할 수 있는 경우 과축적자로 정의할 수 있습니다. 이러한 축적 능력은 과민성 또는 식물 내성 때문입니다. 이는 식물이 여러 세대에 걸쳐 적대적인 환경에 적응하며 진화한 결과입니다. 중금속, 살충제, 용제, 폭발물, 원유와 같은 오염 물질은 전 세계적으로 식물 정화 프로젝트를 통해 제거되었습니다. 식물정화는 토양이나 고인 물 환경이 오염되었거나 지속적인 만성 오염을 겪고 있는 모든 곳에 적용될 수 있습니다.

식물 정화 기술에는 식물 추출, 식물 여과, 식물 안정화, 식물 분해, 식물 담수화 등이 있습니다. 식물 추출은 식물의 뿌리가 토양과 물에서 오염 물질을 흡수하는 것[126], 식물 여과는 식물이 오염된 폐수에서 오염 물질을 제거하는 것[127], 식물 안정화는 오염 물질의 이동성을 감소시키고 먹이사슬에 유입되는 것을 방지하는 오염 물질의 안정화를 위해 식물을 사용하는 것[128]으로 구성됩니다; 식물 분해는 산소 분해 효소 및 탈 할로겐화 효소 [129]와 같은 효소 덕분에 식물에 의한 유기 이종 생물체의 파괴이며, 식물 담수화는 정상적인 식물 성장을 지원하기 위해 염분에 영향을받는 토양에서 염화나트륨을 제거하기 위해 호염성 식물을 사용하는 것을 말합니다 [130,131].

니켈, 코발트, 철, 백금, 팔라듐 및 기타 중금속을 식물의 공중 부분에 농축하는 과축적 식물로 작물을 재배하여 토양에서 추출한 다음 수확, 건조 및 제련하는 금속 피토마이닝 [132]이라는 과정을 통해 금속을 회수할 수 있습니다. 자연 서식지에서 자랄 때 새싹에 1000mg 이상의 니켈을 건조 중량으로 축적하는 식물, 즉 니켈 과다 축적 식물도 많이 있습니다. 1948년 말, 밍구찌와 베르그나노는 알리섬 베르톨로니 데스브(Alyssum bertolonii Desv., 브라시케이스과)가 건조된 물질에서 약 10 mg/g [l%]의 매우 높은 Ni 함량을 가지고 있다는 사실을 발견했으며, 이는 재에서 이 원소의 10% 이상으로 해석되었습니다 [133].

1976년 Jaffrè 등은 뉴칼레도니아의 한 고유종 나무(피크난드라 아쿠미나타, 처음에는 세베르티아 아쿠미나타로 알려짐)가 청록색의 라텍에 니켈(라텍 건조 중량의 약 25%)을 축적하는 특별한 능력을 가지고 있다고 보고했습니다. 뉴칼레도니아는 표면의 3분의 1이 니켈이 풍부한 초마철암으로 이루어진 토양으로 덮여 있는 군도입니다. 자프레와 공동 저자들은 뉴칼레도니아의 풍부한 식물상에는 초마철암 토양에 적응한 2145종이 있으며, 이 중 65종이 Ni 고축적 식물이라고 말합니다[134].

뉴칼레도니아의 과축적 식물에 대한 분석 결과, Ni는 피크난드라 아쿠미나타의 구연산염 복합체와 관련이 있는 것으로 밝혀졌습니다 [135,136]. Callahan 등의 가스 크로마토그래피 질량 분석법 연구에서는 피크난드라 아쿠미나타를 포함한 대부분의 뉴칼레도니아 종에서 니니코티아민 복합체가 존재한다는 사실이 밝혀졌습니다. 구연산 외에도 메틸화 된 알다 릭산 (2,4,5- 트리 하이드록시 -3- 메 톡시 -1,6- 헥산 디오 산)은 라텍스에 존재하는 가장 풍부한 작은 유기 분자 중 하나 인 것으로 보이며 다른 Ni 복합체와 말산, 이타 코닉, 갈 락투 론, 타르타르산 및 아코 니트 산 [137]도 검출되었습니다.

Giordani 등[138]의 실험은 7가지 초본 작물인 보리(호르데움 벌가리스), 콩(페이폴루스 벌가리스), 양배추(브라시카 정세아), 율무(리시누스 커뮤니스), 수수(수수 벌가레), 시금치(스피나시아 올라세아) 및 토마토(솔라눔 리코퍼시움)에 농작물을 사용하여 니켈로 오염된 토양의 식물 정화 과정을 연구했습니다. 실험이 끝나면 잎, 뿌리, 줄기, 과일 또는 씨앗을 별도로 수집하여 100°C에서 오븐 건조하고 무게를 측정하고 분쇄하여 분석했습니다. 시금치, 리시누스, 양배추는 잎에 니켈을 저장할 수 있는 것으로 나타났습니다. 콩, 보리, 토마토는 잎과 줄기에 니켈 농도가 높은 것으로 나타났습니다. 콩은 과일이나 씨앗, 뿌리에 니켈을 저장하는 데 가장 효율적이었으며, 토마토, 수수, 율무, 보리는 콩보다 저장 능력이 낮았습니다. 니켈 제거와 관련하여 시금치는 다른 6가지 초본 작물에 비해 건조 물질 그램당 가장 높은 수준의 금속을 함유하고 있어 가장 효율적이었습니다[138]. 금속이 풍부한 토양에서 식물 정화/식물 채광을 위한 상업적 작물로 개발된 니켈 과축적자 알리섬 무랄레(Alyssum murale)가 있습니다[139]. 니켈 과민증은 종종 특이적입니다. 니켈은 표피 구획화를 통해 액포 격리를 거치는 반면, 코발트는 잎에서 배설된 후 잎 표면에 가용성 침전물로 격리됩니다. 따라서 알리섬 무랄레의 Ni 과민증과 관련된 특수한 생화학적 과정은 코발트에 대한 과민증을 부여하지 않았습니다. 브로드허스트와 채니[140]는 천연 사문석 토양에서 알리섬 무랄(Ni 과축적자), 알리섬 몬타넘(Ni 비과축적자), 라이그라스 롤리움 페렌을 함께 재배하여 Ni, Cu, Fe 및 Mn 흡수에 영향을 미쳤습니다. 표준 무기 처리로 4개월이 지난 후, A. 뮤랄레의 잎과 줄기에는 3600㎎/㎏의 Ni가 함유되어 있었습니다. 또한, Ni와 Mn의 농도는 A. murale에서 A. 몬타 눔 또는 L. 페렌에 비해 유의하게 높았습니다. 두 알리섬 종 모두 Cu를 축적하지 않은 반면, L. 페렌은 10 mg/kg Cu만 축적했습니다. 게다가, A. murale과 L. perenne을 함께 자르면 A. murale의 Fe 및 Mn 농도가 감소했습니다 [141]. 사이코트리아 두아레이와 가이소이스 프루이노사는 10,000mg 이상의 니켈을 축적하는 하이퍼니켈로포어라고 불리는 다른 식물입니다 [141]. 페르난도 등은 비색 시약인 디메틸글리옥심을 사용하여 리노레아 니콜리페라(Violaceae)의 잎에서 높은 수준의 Ni가 검출되었다고 밝혔습니다[142,143]. 이후 식물 조직을 화학적으로 분석한 결과, 잎의 니켈 농도는 건조 중량 기준으로 7168~18,388 mg/kg으로 다양했습니다. 이 데이터는 루손 섬의 두 곳(필리핀 잠발레스 주, 산타 크루즈 시, 칸델라리아 시)에서 수집한 리노레아 니콜리페라 식물 조직 샘플 6세트에 기반한 것입니다. 이 종은 잎의 니켈 축적량이 10,000 mg/kg을 초과하기 때문에 '니켈과잉 식물'로 간주됩니다. 로코티엘로 등의 연구에 따르면 지중해 알리소이데스 우트리쿨라타 잎은 니오 하이퍼 축적체(1.0g/kg 이상)로서 니오 식물 추출 목적과 니오 오염 지역 청소에 사용할 수 있다고 합니다[144]. 두 번째 논문에서 Roccotiello 등[145]은 화분 실험을 통해 다양한 Ni 농도(0-500 mg Ni/L)가 알리소이데스 우트리쿨라타의 생리에 미치는 영향을 조사했습니다. 그 결과이 일시적인 금속의 농도는 뿌리보다 잎에서 더 높으며 테스트 된 더 높은 농도 (500mg Ni / L)에서 A. utriculata는 이전에 발견 된대로 1.1g Ni / kg 잎을 축적하는 것으로 나타났습니다. 식물 수분 함량은 엽록소 형광 파라미터에 영향을 미치지 않고 Ni 축적에 따라 크게 증가합니다. 실제로, A. utriculata의 광합성 효율은 Ni 처리 중 안정적입니다(항상 ≥0.8).

세 가지 식물 종에서 Ni의 생체 축적과 분포도 밝혀졌습니다: 보르네오 섬의 사바(말레이시아)에 서식하는 필란투스 발구이, 필란투스 세큐리네지오이데스(Phyllanthaceae), 리노레아 벵갈렌시스(Violaceae). Van der Ent 등의 연구에 따르면 Ni는 세 종 모두에서 주로 식물체, 뿌리 및 줄기에 집중되어 있습니다(Phyllanthus balgooyi의 식물체 수액에 최대 16.9% Ni) [146]. 그러나 잎에 관해서는: Phyllanthus balgooyi에서 Ni 농도가 가장 높은 것은 경엽에 있지만 Phyllanthus securinegioides와 Rinorea bengalensis에서는 표피와 해면질 중 엽록체 (Rinorea bengalensis)에 있습니다. 세 종 모두 매우 독특한 조직 Ni 분포 패턴을 가지고 있으며 뿌리와 줄기의 엽록체에 극도로 축적되어 있습니다. 세 종 모두 주 줄기의 엽록체 조직은 매우 높은 농도의 Ni2+ 이온으로 인해 녹색을 띠며, 리노레아 벵갈렌시스에서는 최대 2.1%, 필란투스 발구이의 엽록체 수액에서는 최대 16.9 wt%에 이르는 Ni 농도로 '싱크' 역할을 하는 것으로 보입니다.

환경의 중금속 오염 문제를 해결하기 위해 많은 전략이 사용되어 왔습니다. 환경 내 중금속의 양을 줄이기 위한 생물학적 정화 방법은 많은 연구자들의 관심을 끌고 있습니다. 식물, 박테리아, 곰팡이 및 조류는 일반적으로 중금속의 생물학적 정화에 사용되며 [147], 문헌에는 니켈의 생체 흡착에 대한 많은 논문이 있으며, 그중에서도 슈도모나스 플루오레시스 [148], 바실러스 세레우스 [149], 사카로마이세스 세레비지애 [150], 사상균 Trichoderma atroviride 균주 F6 [151]에 대한 논문이 많이 발표되어 있습니다.

압델 모넴 등[152]은 박테리아 바이오매스, 슬러지, 차, 톱밥에서 질소를 제거하기 위해 바실러스 서브틸리스 117S와 슈도모나스 세파시아 120 S를 사용한 연구를 수행했습니다. 이 연구의 저자들은 박테리아 바이오매스에 의한 니켈의 생체 흡수 능력이 슬러지, 차, 톱밥에 의한 것보다 더 크다는 것을 보여주었습니다. 또한 니켈 제거는 접촉 시간이 1시간에서 8시간까지 증가하지 않고 24시간까지 증가했으며, 니켈의 생흡착 효율도 2에서 7로 pH 변화에 따라 증가했고 그 이후에는 일정하게 유지되었습니다. 니켈의 최대 흡착 효율은 37°C에서 얻은 반면, 45°C와 55°C에서는 니켈 생체 흡착이 감소했습니다.

식물 정화법은 오염 물질을 현장에서 처리할 수 있다는 장점이 있지만, 정상적인 식물 성장에 항상 적합하지 않은 환경에서 식물이 성장하고 번성하는 능력에 따라 달라지기 때문에 장기적인 노력이 필요하다는 것이 가장 큰 한계입니다.

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9. Conclusions

Nickel is a metal of widespread distribution in the environment. Contact with soluble and insoluble nickel compounds can cause a variety of side effects on human health. Human exposure to Ni may occur through food, water or air. Workers in Ni producing and processing industries are exposed by inhalation, and to a lesser extent, dermal contact. The nervous system is one of the main target organs for Ni toxicity; in fact, it can be accumulated in the brain. Allergy to nickel and metals is caused by the materials used in our daily life; therefore, the chances of triggering the onset of allergic reactions are high. This metal can cause an allergy that manifests as contact dermatitis, headaches, gastrointestinal and respiratory manifestations. The molecular mechanisms of Ni induced neurotoxicity are still not clear, but the researchers think that oxidative stress and mitochondrial dysfunctions have a primary and important role. Mitochondrial damage induced by Ni may occur first as mitochondrial membrane potential damage, then as mitochondrial ATP concentration reduction and finally as mitochondrial DNA destruction. Damage to mitochondrial functions interferes with the mitochondrial transport chain, amplifies ROS and exacerbates oxidative stress.

In the last 25–30 years, researchers, trying to characterize the carcinogenicity, due to nickel, have uncovered that epigenetic alterations induced by nickel exposure, can perturb the epigenome. DNA hypermethylation, histone modification and interference with miRNA network, and finally condensed chromatin structure create an aberrant epigenetic landscape that contributes to nickel-induced gene silencing, tumor initiation and progression. Indeed, nickel is known to cause cancer by an epigenetic mechanism, which appears to involve the substitution of Ni2+ for Fe2+ in non-heme iron dioxygenases that are involved in DNA and histone demethylation. In vitro studies demonstrated that Ni sulphate could promote apoptosis in human epatoma cells, human T hybridoma cells human breast cancer, abrogated by curcumin. Many researchers have shown that nickel binds to amino acidic residues (as Cys, His and or Glu) of several enzymes decreasing their activity. Besides, in several enzymes the inhibitory nickel binds to an allosteric secondary site affecting activity.

Pollution of soil, water, and air, due to heavy metals, is probably the most outstanding outcome of the evolution of our society. The reclamation of soils polluted by heavy metals can be achieved with different techniques and technologies. A possible alternative to technologies is the adoption of a biological method that consists of the use of plants that may uptake and accumulate heavy metals in their tissues. The process of metal absorption and accumulation in the plant tissues is called phytoextraction, and in the case of nickel, the phytoremediation capability, which cost is not excessive, depends on the level of nickel concentration in soil.

In the intrinsic pathway, Ni2+ allows the Cyt C release from the mitochondria to the cytosol. Cyt C cleaves and activates caspase-9, which in turn cleaves and activates caspase-3, -6 and -7. Ni2+ promotes in the extrinsic pathway Fas and FasL interactions, leading to activation of caspase-8 and caspase-10 that activate caspase-3, -6 and -7. Caspase-3, -6 and -7 cleave PARP, which then induces apoptosis.

니켈은 환경에 광범위하게 분포하는 금속입니다. 용해성 및 불용성 니켈 화합물과의 접촉은 인체 건강에 다양한 부작용을 일으킬 수 있습니다. 니켈에 대한 인체 노출은 음식, 물 또는 공기를 통해 발생할 수 있습니다. 니켈 생산 및 가공 산업에 종사하는 근로자는 흡입을 통해 노출되며, 피부 접촉을 통해서도 노출될 수 있습니다. 신경계는 니켈 독성의 주요 표적 기관 중 하나이며, 실제로 뇌에 축적될 수 있습니다. 니켈 및 금속 알레르기는 일상 생활에서 사용되는 물질로 인해 발생하므로 알레르기 반응을 유발할 가능성이 높습니다. 이 금속은 접촉성 피부염, 두통, 위장 및 호흡기 증상으로 나타나는 알레르기를 유발할 수 있습니다. Ni로 인한 신경 독성의 분자 메커니즘은 아직 명확하지 않지만 연구자들은 산화 스트레스와 미토콘드리아 기능 장애가 주요하고 중요한 역할을한다고 생각합니다. Ni에 의해 유도된 미토콘드리아 손상은 먼저 미토콘드리아 막 전위 손상, 미토콘드리아 ATP 농도 감소, 그리고 마지막으로 미토콘드리아 DNA 파괴로 발생할 수 있습니다. 미토콘드리아 기능의 손상은 미토콘드리아 수송 사슬을 방해하고 ROS를 증폭시키며 산화 스트레스를 악화시킵니다.

지난 25~30년 동안 니켈로 인한 발암성을 특성화하려는 연구자들은 니켈 노출로 인한 후성유전학적 변화가 후성유전체를 교란시킬 수 있다는 사실을 밝혀냈습니다. DNA 과메틸화, 히스톤 변형 및 miRNA 네트워크 간섭, 마지막으로 응축된 염색질 구조는 니켈에 의한 유전자 침묵, 종양 개시 및 진행에 기여하는 비정상적인 후성유전학적 환경을 조성합니다. 실제로 니켈은 DNA 및 히스톤 탈메틸화에 관여하는 비헴철 산화 환원 효소에서 Ni2+를 Fe2+로 대체하는 것으로 보이는 후성유전학적 메커니즘에 의해 암을 유발하는 것으로 알려져 있습니다. 시험관 내 연구에 따르면 황산니켈은 커큐민에 의해 제거된 인간 상피종 세포, 인간 T 하이브리드종 세포 인간 유방암에서 세포 사멸을 촉진할 수 있는 것으로 나타났습니다. 많은 연구자들은 니켈이 여러 효소의 아미노산 잔기(Cys, His, 또는 Glu)에 결합하여 효소의 활성을 감소시킨다는 사실을 밝혀냈습니다. 또한 몇몇 효소에서는 억제 니켈이 알로스테릭 이차 부위에 결합하여 활성에 영향을 미칩니다.

중금속으로 인한 토양, 수질, 공기의 오염은 아마도 우리 사회의 진화로 인한 가장 두드러진 결과일 것입니다. 중금속으로 오염된 토양을 재생하는 것은 다양한 기술과 기술을 통해 달성할 수 있습니다. 기술의 가능한 대안은 중금속을 조직에 흡수하고 축적할 수 있는 식물을 사용하는 생물학적 방법을 채택하는 것입니다. 식물 조직에서 금속을 흡수하고 축적하는 과정을 식물 추출이라고 하며, 니켈의 경우 토양 내 니켈 농도 수준에 따라 비용이 과도하지 않은 식물 정화 능력이 달라집니다.

내재적 경로에서 Ni2+는 미토콘드리아에서 사이토솔로 Cyt C가 방출되도록 합니다. Cyt C는 카스파제-9를 절단하여 활성화하고, 카스파제-9는 다시 카스파제-3, -6 및 -7을 절단하여 활성화합니다. Ni2+는 외인성 경로에서 Fas 및 FasL 상호 작용을 촉진하여 카스파제-3, -6 및 -7을 활성화하는 카스파제-8 및 카스파제-10을 활성화합니다. 카스파제-3, -6 및 -7은 PARP를 절단한 다음 아포토시스를 유도합니다.

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Abbreviations

DNA	deoxyribonucleic acid;
RNA	ribonucleic acid;
AMP	adenosine 5′-monophosphate;
ATP	adenosine 5′-triphosphate;
ROS	reactive oxygen species;
SOD	superoxide dismutase;
CAT	catalase;
MDA	malondialdehyde;
NO	nitric oxide;
mRNA	messenger RNA;
Cyt C	Cytochrome C;
BAX	BCL2 Associated X;
BID	BH3 interacting domain death agonist;
Bcl-2	B-cell lymphoma-2;
SAM	S-adenosyl methionine;
Fhit	fragile histidine triad protein;
Fas	first apoptosis signal;
FasL	Fas Ligant;
NAC	N-acetylcysteine;
TEMPO	2,2,6,6-tetramethyl-1-piperidinyloxy.

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Author Contributions

Conceptualization, A.C.; writing-original draft preparation, G.G.; writing-review and editing, A.C.; funding acquisition and supervision, M.S.S.; literature review, G.L. All authors have read and agreed to the published version of the manuscript.

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Funding

This study was funded by Grant from ex 60% MiUR by M.S.S.

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Conflicts of Interest

The authors declare that there is no conflict of interest.

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