Metal-induced toxicity, carcinogenesis, mechanisms and cellular responses

A wide variety of metals have been reported to act as mutagenic and carcinogenic agents in both human and animal studies. The underlying mechanisms are being extensively investigated. Recently, a new sub-discipline of molecular carcinogenesis has surfaced and new techniques and instruments are being developed which allow exploration of the complex biological relationships and signaling pathways involved in response to metal exposure at the molecular level. The 2nd Conference on Molecular Mechanisms of Metal Toxicity and Carcinogenesis was held at NIOSH in Morgantown, West Virginia, Sept. 8-11, 2002. One hundred thirty scientist from sixteen countries presented their novel findings and investigations of metal-induced carcinogenesis. The conference focused on state-of-the-art research and developments in metal toxicity and carcinogenesis. Emphasis was placed on delineating molecular mechanisms involved in free radical effects, cellular uptake, signaling pathways/interaction, dose response, biomarkers, and resistance mechanisms. This article reviews some of the novel information presented at the conference and discusses future avenues of research in this field.     

Heavy metals toxicity in plants: An overview on the role of glutathione and phytochelatins in heavy metal stress tolerance of plants

Plants experience oxidative stress upon exposure to heavy metals that leads to cellular damage. In addition, plants accumulate metal ions that disturb cellular ionic homeostasis. To minimize the detrimental effects of heavy metal exposure and their accumulation, plants have evolved detoxification mechanisms. Such mechanisms are mainly based on chelation and subcellular compartmentalization. Chelation of heavy metals is a ubiquitous detoxification strategy described in wide variety of plants. A principal class of heavy metal chelator known in plants is phytochelatins (PCs), a family of Cys-rich peptides. PCs are synthesized non-translationally from reduced glutathione (GSH) in a transpeptidation reaction catalyzed by the enzyme phytochelatin synthase (PCS). Therefore, availability of glutathione is very essential for PCs synthesis in plants at least during their exposure to heavy metals. Here, I reviewed on effect of heavy metals exposure to plants and role of GSH and PCs in heavy metal stress tolerance. Further, genetic manipulations of GSH and PCs levels that help plants to ameliorate toxic effects of heavy metals have been presented.     

Mechanisms of metal resistance in plants: aluminum and heavy metals

Plants have evolved sophisticated mechanisms to deal with toxic levels of metals in the soil. In this paper, an overview of recent progress with regards to understanding fundamental molecular and physiological mechanisms underlying plant resistance to both aluminum (Al) and heavy metals is presented. The discussion of plant Al resistance will focus on recent advances in our understanding of a mechanism based on Al exclusion from the root apex, which is facilitated by Al-activated exudation of organic acid anions. The consideration of heavy metal resistance will focus on research into a metal hyperaccumulating plant species, the Zn/Cd hyperaccumulator, Thlaspi caerulescens, as an example for plant heavy metal research. Based on the specific cases considered in this paper, it appears that quite different strategies are used for Al and heavy metal resistance. For Al, our current understanding of a resistance mechanism based on excluding soil-borne Al from the root apex is presented. For heavy metals, a totally different strategy based on extreme tolerance and metal hyperaccumulation is described for a hyperaccumulator plant species that has evolved on naturally metalliferous soils. The reason these two strategies are the focus of this paper is that, currently, they are the best understood mechanisms of metal resistance in terrestrial plants. However, it is likely that other mechanisms of Al and/or heavy metal resistance are also operating in certain plant species, and there may be common features shared for dealing with Al and heavy resistance. Future research may uncover a number of novel metal resistance mechanisms in plants. Certainly the complex genetics of Al resistance in some crop plant species, such as rice and maize, suggests that a number of presently unidentified mechanisms are part of an overall strategy of metal resistance in crop plants.     

Environmental epigenetics in metal exposure

Although it is widely accepted that chronic exposure to arsenite, nickel, chromium and cadmium increases cancer incidence in individuals, the molecular mechanisms underlying their ability to transform cells remain largely unknown. Carcinogenic metals are typically weak mutagens, suggesting that genetic-based mechanisms may not be primarily responsible for metal-induced carcinogenesis. Growing evidence shows that environmental metal exposure involves changes in epigenetic marks, which may lead to a possible link between heritable changes in gene expression and disease susceptibility and development. Here, we review recent advances in the understanding of metal exposure affecting epigenetic marks and discuss establishment of heritable gene expression in metal-induced carcinogenesis.Key words: environmental metal, epigenetic, metal carcinogenesis, histone modification, DNA methylation, chromatin, gene expression     

Environmental epigenetics in metal exposure

Although it is widely accepted that chronic exposure to arsenite, nickel, chromium and cadmium increases cancer incidence in individuals, the molecular mechanisms underlying their ability to transform cells remain largely unknown. Carcinogenic metals are typically weak mutagens, suggesting that genetic-based mechanisms may not be primarily responsible for metal-induced carcinogenesis. Growing evidence shows that environmental metal exposure involves changes in epigenetic marks, which may lead to a possible link between heritable changes in gene expression and disease susceptibility and development. Here, we review recent advances in the understanding of metal exposure affecting epigenetic marks and discuss establishment of heritable gene expression in metal-induced carcinogenesis.     

Use of cell cultures,nuclear and radioanalytical techniques for metallotoxicological studies at the JRC-Ispra

This paper reviews the JRC-Ispra research activity on toxicological studies related to the environmental and occupational exposure of trace metals, as carried out by a combination of cell culture methodologies with nuclear and radioanalytical techniques.Applications concern the setting of uptake-effect relationships and the study of the mechanisms of toxicity of specific metals (Al, As, Cd, Co, Cr, Mo, Se, V), as well as the establishment of ranking of metal toxicity by carrying out systematic studies (screening tests).     

Sodium turnover rate determines sensitivity to acute copper and silver exposure in freshwater animals

The mechanisms of acute copper and silver toxicity in freshwater organisms appear similar. Both result in inhibition of branchial sodium (and chloride) uptake initiating a cascade of effects leading to mortality. The inhibition of the branchial Na/K-ATPase in the basolateral membrane is generally accepted as the key component responsible for the reduced sodium uptake. We propose that branchial carbonic anhydrase and the apical sodium channel may also be important targets for both copper and silver exposure. Several attempts have been made to predict metal sensitivity. A prominent example is the geochemical-biotic ligand model. The geochemical-biotic ligand modeling approach has been successful in explaining variations in tolerance to metal exposure for specific groups of animals exposed at different water chemistries. This approach, however, cannot explain the large observed variation in tolerance to these metals amongst different groups of freshwater animals (i.e. Daphnia vs. fish). Based on the detailed knowledge of physiological responses to acute metal exposure, the present review offers an explanation for the observed variation in tolerance. Smaller animals are more sensitive than large animals because they exhibit higher sodium turnover rates. The same relative inhibition of sodium uptake results in faster depletion of internal sodium in animals with higher sodium turnover. We present a way to improve predictions of acute metal sensitivity, noting that sodium turnover rate is the key predictor for variation in acute copper and silver toxicity amongst groups of freshwater animals. We suggest that the presented sodium turnover model is used in conjunction with the Biotic Ligand Model for risk management decisions.     

Insights into the Roles of Melatonin in Alleviating Heavy Metal Toxicity in Crop Plants

Alleviating heavy metal pollution in farmland soil, and heavy metal toxicity in plants is the focus of global agricultural environmental research. Melatonin is a kind of indoleamine compound that wide exists in organisms; it is currently known as an endogenous free radical scavenger with the strongest antioxidant effect. As a new plant growth regulator and signaling molecule, melatonin plays an important role in plant resistance to biotic or abiotic stress. Recent studies indicate that melatonin can effectively alleviate heavy metal toxicity in crop plants, which provides a new strategy to minimize heavy metal pollution in crop plants. This study summarizes the research progress on the role of melatonin in alleviating heavy metal toxicity in crop plants and the related physiological and ecological mechanisms such as reducing the concentration of heavy metals in the rhizosphere, fixing and regionally isolating of heavy metals, maintaining the mineral element balance, enhancing the antioxidant defense system and interacting with hormonal signaling. Furthermore, future prospects for the mechanism of melatonin in regulating heavy metal toxicity, the pathway regulating synthesis and catabolism, and the interaction mechanism of melatonin signaling and other phytohormones are presented in this paper, with the goal of providing a theoretical basis for controlling heavy metal ion accumulation in crop plants grown in contaminated soil.     

Co-selection of antibiotic and metal resistance

There is growing concern that metal contamination functions as a selective agent in the proliferation of antibiotic resistance. Documented associations between the types and levels of metal contamination and specific patterns of antibiotic resistance suggest that several mechanisms underlie this co-selection process. These co-selection mechanisms include co-resistance (different resistance determinants present on the same genetic element) and cross-resistance (the same genetic determinant responsible for resistance to antibiotics and metals). Indirect but shared regulatory responses to metal and antibiotic exposure such as biofilm induction also represent potential co-selection mechanisms used by prokaryotes. Metal contamination, therefore, represents a long-standing, widespread and recalcitrant selection pressure with both environmental and clinical importance that potentially contributes to the maintenance and spread of antibiotic resistance factors.     

Metal toxicity and ectomycorrhizas

Metal toxicity (Al and heavy metals) is a major constraint affecting root growth in a number of natural or managed ecosystems. Fine roots of the majority of plant species are associated with mycorrhizal fungi, which may modify the sensitivity of roots to metal stress. In this review, we summarise the available evidence demonstrating beneficial effects of ectomycorrhizas in alleviation of metal toxicity in forest tree seedlings. We identify experimental shortcomings of past research (e.g. the use of shoot metal concentrations as a measure of metal uptake, use of microanalytical techniques biased by element redistribution) that may confound major conclusions drawn from these experiments. Although there is no doubt that in many cases ectomycorrhizal fungi indeed ameliorate metal stress in their host plants, the mechanism(s) involved remain(s) unclear. The role of metal sorption on fungal tissues thought to reduce metal exposure of the host plant is critically reviewed. As direct evidence (both under artificial and soil conditions) supporting a unique role of fungal immobilisation of metals is lacking so far, there is an urgent need to also test alternative tolerance mechanisms such as the release of metal chelating substances, or nutritional and hormonal effects mediated by mycorrhizal fungi.     

The relationship between co-exposure to multiple heavy metals and liver damage

BackgroundThe impact of heavy metal exposure on human health has attracted widespread attention of researchers, and the impact of heavy metal exposure on liver function has also been confirmed, however, more attention is paid to the impact of single or two heavy metal exposures, and most epidemiological studies focus on heavy metal pollution areas. In this study, rural residents in non-heavy metal-contaminated areas in Northwest China were selected as the research objects to explore the comprehensive effects of co-exposure to multiple heavy metals on the liver, which can provide certain reference and support for related research.ObjectivesThis study used a Bayesian nuclear machine model (BKMR) to evaluate the relationship between exposure to heavy metal mixtures and indicators of liver function in a population in rural Northwest China.ResultsExposure to higher concentrations of metal mixtures was positively correlated with total bilirubin, direct bilirubin, and aspartate aminotransferase, and negatively correlated with alanine aminotransferase, with Pb contributing the most to indicators of liver function. We also observed a possible interaction of Cd with other heavy metals in the effect of heavy metal mixtures on DB levels.ConclusionsConcurrent exposure to higher concentrations of heavy metal mixtures (Cr, Co, Cd, and Pb) in rural China was associated with indicators representing poor liver function, of which the effect of lead on liver function should be focused. More prospective epidemiological studies and animal experiments need to be carried out to determine this relationship and possible mechanism.     

Molecular defense systems are expressed in the king bolete (Boletus edulis) growing near metal smelters

The induction of defense systems against metal exposure was investigated in 48 wild-growing fruiting bodies of the king bolete (Boletus edulis) from two areas polluted with several transition metals from smelters, as well as five reference areas. To determine the degree of metal exposure, cadmium (Cd), zinc (Zn), and copper (Cu) were determined in caps of fruiting bodies by atomic absorption spectrophotometry (AAS), whereas mercury (Hg) was determined by cold vapor atomic fluorescence spectrometry (CVAFS). Caps were analyzed further with respect to relative activities of the antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), as well as concentrations of total glutathione (GSHTOT = GSH + GSSG) and relative concentrations of heat shock protein 70 kDa (HSP70). The results showed that concentrations of the four metals, as well as SOD, CAT and HSP70, were significantly elevated in the exposed group (Mann-Whitney, P < or = 0.001). In contrast, GSHTOT was significantly lowered in the exposed group (P < or = 0.05). Significant positive correlations were established between concentrations of Cd, Zn, Hg, or Cu and activities of SOD (Spearman's P < or = 0.01 for the association between SOD and Cd, P < or = 0.001 for all other metal exposure parameters), CAT (P < or = 0.001 for all exposure parameters), or expression of HSP70 (P < or = 0.001 for all exposure parameters). Significant negative correlations were found between total GSH and Cd (P < or = 0.001), Zn (P < or = 0.001), or Hg (P < or = 0.05). We conclude that antioxidant enzymes are induced in wild-growing B. edulis exposed to environmentally relevant concentrations of potentially toxic transition metals; whereas the net consumption of GSH that occurs with increasing metal exposure may reflect GSH consumption by mechanisms of metal detoxification. Finally, the induction of HSP70 suggests that the antioxidant response and the mechanisms in which GSH is consumed are insufficient for protection against the harmful effects of severe metal stress.     

Prevention of progression in Parkinson’s disease

Environmental influences affecting genetically susceptible individuals seem to contribute significantly to the development of Parkinson’s disease (PD). Xenobiotic exposure including transitional metal deposition into vulnerable CNS regions appears to interact with PD genes. Such exposure together with mitochondrial dysfunction evokes a destructive cascade of biochemical events, including oxidative stress and degeneration of the sensitive dopamine (DA) production system in the basal ganglia. Recent research indicates that the substantia nigra degeneration can be decelerated by treatment with iron binding compounds such as deferiprone. Interestingly compounds known to decrease PD risk including caffeine, niacin, nicotine and salbutamol also possess iron binding properties. Adequate function of antioxidative mechanisms in the vulnerable brain cells can be restored by acetylcysteine supplementation to normalize intracellular glutathione activity. Other preventive measures to reduce deterioration of dopaminergic neurons may involve life-style changes such as intake of natural antioxidants and physical exercise. Further research is recommended to identify therapeutic targets of the proposed interventions, in particular protection of the DA biosynthesis by oxygen radical scavengers and iron binding agents.     

A molecular mechanism of aluminium-induced Alzheimer's disease?

An abundance of research has continued to link aluminium (Al) with Alzheimer's disease (AD) (Strong et al., J. Toxicol. Environ. Health 48 (1996) 599; Savory et al., J. Toxicol. Environ. Health 48 (1996) 615). Animals loaded with Al develop both symptoms and brain lesions that are similar to those found in AD. However, these animal models of Al intoxication are not representative of human exposure to Al. They have not addressed the significance of a truly chronic exposure to Al. If Al is a cause of AD it is effective at the level of our everyday exposure to the metal and AD will be one possible outcome of the life-long presence of a low, though burgeoning, brain Al burden. Individual susceptibility to AD will be as much to do with differences in brain physiology as with changes in our everyday exposure to the metal. There will be a chemical response and indeed biochemical/physiological response in the brain to Al. The question is whether brain Al homeostasis could impact upon brain function. In reviewing the recent literature covering the neurotoxicity of Al and, in particular, of the known and probable mechanisms involved in brain Al homeostasis I have identified a mechanism through which a truly chronic exposure to Al would bring about subtle and persistent changes in neurotransmission which, in time, could instigate the cascade of events known collectively as AD. This mechanism involves the potentiation of the activities of neurotransmitters by the action of Al-ATP at adenosine 5'-triphosphate (ATP) receptors in the brain.     

Heavy metal detoxification mechanisms in halophytes: an overview

Heavy metals are among the major pollutants from anthropogenic inputs that reach mangrove ecosystem by urban and agricultural runoff, industrial effluents, boating, mining and other processes. To minimize the detrimental effects of heavy metal exposure and their accumulations, plants in general have evolved biological detoxification mechanisms, which include avoidance or exclusion, excretion and accumulation. To protect the cellular components from oxidative damage by heavy metal contamination, biological systems have developed enzymatic and non-enzymatic antioxidant mechanisms. Another detoxification mechanisms produced in plants are osmoprotectants, which are the compatible solutes which maintain a favourable water potential gradient and protect cellular structures from toxic ions. Besides these mechanisms, another heavy metal detoxification system in plants involves the chelation of metals by metal binding molecules like metallothioneins (MTs) and phytochelatins (PCs). To limit the heavy metal toxicity from mangrove ecosystem, it was found that phytoremediation is a most useful technology where in plants are used to remove pollutants from the environment and it is considered as a comparatively new, low-cost and highly promising technology for the remediation of heavy metal. Rhizofiltration, phytovolatilization, phytoextraction and phytostabilization are the important phytoremediation techniques. Among these phytoextraction and phytostabilization are found highly important in the case of mangroves and are promising means of phytoremediation.     

植物对重金属锌耐性机理的研究进展

Zn是植物必需的营养元素,同时也是一种常见的有毒重金属元素.由于长期的环境选择和适应进化,植物相应对Zn~(2+)产生了耐性,可减轻或避免Zn~(2+)的毒害.植物对锌耐性机制有:菌根和细胞膜对Zn~(2+)吸收的阻止和控制,其中控制Zn~(2+)的细胞膜跨膜转运器主要有(ZIP)类、阳离子扩散促进器(CDF)类和B-type ATPase (HMA)类;金属硫蛋白(MTs)、植物螯合素(PCs)和有机酸等Zn~(2+)螯合物质的体内螯合解毒;体内区室化分隔以及通过抗氧化系统和渗透调节物质的代谢调节等.本文从生理和分子水平上综述了植物对Zn~(2+)耐性机理的研究进展,并在此基础上提出目前存在的问题和今后研究的重点领域,为该领域的相关研究提供资料和借鉴.     

Decrease in repair processes in lymphocytes of workers exposed to heavy metals

Mechanisms of DNA repair in lymphocytes of persons having occupational contact with heavy metal salts for at least 10 years were investigated. The long-term exposure to heavy metal salts did not result in development of mechanisms of adaptation to the respective metals, as shown by increased DNA sensitivity to these compounds and by decrease in the repair activity. However, in some cases, resistance to other mutagens, 4-NQO, in particular, was observed.