Vascular system function involves complex interactions among the vascular endothelium, smooth muscle, the immune system, and the nervous system. The toxic metals cadmium (Cd), arsenic (As), and lead (Pb) can target the vascular system in a variety of ways, ranging from hemorrhagic injury to subtle pathogenic remodeling and metabolic changes. Acute Cd exposure results in hemorrhagic injury to the testis, although some strains of animals are resistant to this effect. A comparison of Cd-sensitive with Cd-resistant mouse strains showed that expression of the Slc39a8 gene, encoding the ZIP8 transporter, in the testis vasculature endothelium is responsible for this difference. Endogenously, ZIP8 is a Mn(2+)/HCO(3)(-)symporter that may also contribute to Cd damage in the kidney. Chronic Cd exposure is associated with various cardiovascular disorders such as hypertension and cardiomyopathy and it is reported to have both carcinogenic and anticarcinogenic activities. At noncytotoxic concentrations of 10-100nM, Cd can inhibit chemotaxis and tube formation of vascular endothelial cells. These angiostatic effects may be mediated through disruption of vascular endothelial cadherin, a Ca(2+)-dependent cell adhesion molecule. With regard to As, ingestion of water containing disease-promoting concentrations of As promotes capillarization of the liver sinusoidal endothelium. Because capillarization is a hallmark precursor for liver fibrosis and contributes to an imbalance of lipid metabolism, this As effect on hepatic endothelial cells may be a pathogenic mechanism underlying As-related vascular diseases. With regard to Pb, perinatal exposure may cause sustained elevations in adult blood pressure, and genetically susceptible animals may show enhanced sensitivity to this effect. Taken together, these data indicate that the vascular system is a critical target of metal toxicity and that actions of metals on the vascular system may play important roles in mediating the pathophysiologic effects of metals in specific target organs.

Mercury in both organic and inorganic forms is neurotoxic. Methylmercury (MeHg) is a commonly encountered form of mercury in the environment. Early electrophysiological experiments revealed that MeHg potently affects the release of neurotransmitter from presynaptic nerve terminals. Recently, the hypothesis that these alterations may be mediated by changes in the intracellular concentration of Ca2+ ([Ca2+]i) has been supported. MeHg alters [Ca2+]i by at least two mechanisms. First, it disrupts regulation of Ca2+ from an intracellular Ca2+ pool and second, it increases the permeability of the plasma membrane to Ca2+. MeHg also blocks plasma membrane voltage-dependent Ca2+ and Na+ channels in addition to activating a nonspecific transmembrane cation conductance. Chronic MeHg exposure results in ultrastructural changes and accumulation of MeHg within mitochondria. In vitro, MeHg inhibits several mitochondrial enzymes and depolarizes the mitochondria membrane subsequently reducing ATP production and Ca2+ buffering capacity. Inhibition of protein synthesis is observed after in vivo or in vitro exposures of MeHg and may be an early effect of MeHg. Thus, the early cellular effects of exposure to MeHg are diverse and cell damage likely occurs by more than one mechanism, the effects of which may be additive or synergistic.

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Exposure to an environmental toxicant as a risk factor in the development of amyotrophic lateral sclerosis (ALS) was first hinted (demonstrated) in the Chamorro indigenous people of Guam. During the 1950s and 1960s these indigenous people presented an extremely high incidence of ALS which was presumed to be associated with the consumption of flying fox and cycad seeds. No other strong association between ALS and environmental toxicants has since been reported, although circumstantial epidemiological evidence has implicated exposure to heavy metals such as lead and mercury, industrial solvents and exposure to pesticides especially organophosphates and certain occupations such as playing soccer. Given that only ~10% of all ALS diagnosis has a genetic basis, a gene-environmental interaction provides a plausible explanation for the other 90% of cases. This mini-review provides an overview of our current knowledge of environmental etiologies of ALS with emphasis on the effects of mercury, lead and pesticides as potential risk factors in developing ALS. Epidemiologic and experimental evidence from animal models investigating the possible association between exposure to environmental toxicant and ALS disease has proven inconclusive. Nonetheless, there are indications that there may be causal links, and a need for more research.

ABSTRACTand was abolished by mitochondrial depolarization. The secondary increase was associated with spreading of the dye from punctate staining to whole-cell distribution, and was delayed significantly by the MTP inhibitor cyclosporin A and the smooth endoplasmic reticulum Ca 2ϩ ATPase inhibitor thapsigargin. We conclude that MeHg causes release of Ca 2ϩ from the mitochondria through opening of the MTP, which contributes the bulk of the elevated [Ca 2ϩ ] i observed during MeHg neurotoxicity. Additionally, the Ca 2ϩ that enters the mitochondria seems to originate in the smooth endoplasmic reticulum, providing a mechanism for the observed mitochondrial Ca 2ϩ overload.