Mercury is a toxic and hazardous metal that occurs naturally in the earth's crust. Natural phenomena such as erosion and volcanic eruptions, and anthropogenic activities like metal smelting and industrial production and use may lead to substantial contamination of the environment with mercury. Through consumption of mercury in food, the populations of many areas, particularly in the developing world, have been confronted with catastrophic outbreaks of mercury-induced diseases and mortality. Countries such as Japan, Iraq, Ghana, the Seychelles, and the Faroe Islands have faced such epidemics, which have unraveled the insidious and debilitating nature of mercury poisoning. Its creeping neurotoxicity is highly devastating, particularly in the central and peripheral nervous systems of children. Central nervous system defects and erethism as well as arrythmias, cardiomyopathies, and kidney damage have been associated with mercury exposure. Necrotizing bronchitis and pneumonitis arising from inhalation of mercury vapor can result in respiratory failure. Mercury is also considered a potent immunostimulant and -suppressant, depending on exposure dose and individual susceptibility, producing a number of pathologic sequelae including lymphoproliferation, hypergammaglobulinemia, and total systemic hyper- and hyporeactivities. In this review we discuss the sources of mercury and the potential for human exposure; its biogeochemical cycling in the environment; its systemic, immunotoxic, genotoxic/carcinogenic, and teratogenic health effects; and the dietary influences on its toxicity; as well as the important considerations in risk assessment and management of mercury poisoning.

Review: Environmental exposure to mercury and its toxicopathologic implications for public health

The observation that revelation of immunocryptic epitopes in self antigens may initiate the autoimmune response has prompted the search for processes which induce novel fragmentation of autoantigens as potential initiators of autoimmunity. The reversible ischemia reperfusion which characterizes scleroderma has focused attention on reactive oxygen species as molecules which might induce autoantigen fragmentation. We demonstrate that several of the autoantigens targeted in diffuse scleroderma are uniquely susceptible to cleavage by reactive oxygen species, in a metal-dependent manner. Multiple features of the fragmentation reaction and its inhibition indicate that these autoantigens possess metal-binding sites, which focus metal-catalyzed oxidation reactions (and consequent fragmentation) to specific regions of the antigens. These data suggest that the autoantibody response in scleroderma is the immune marker of unique protein fragmentation, induced by ischemia reperfusion in the presence of appropriate metals, and focus attention on abnormal metal status as a potential pathogenic principle in this disease.

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Scleroderma Autoantigens Are Uniquely Fragmented by Metal-catalyzed Oxidation Reactions: Implications for Pathogenesis

Owing to the prevalence of mercury in the environment, the risk of human exposure to this toxic metal continues to increase. Following exposure to mercury, this metal accumulates in numerous organs, including brain, intestine, kidneys, liver, and placenta. Although a number of mechanisms for the transport of mercuric ions into target organs were proposed in recent years, these mechanisms have not been characterized completely. This review summarizes the current literature related to the transport of inorganic and organic forms of mercury in various tissues and organs. This review identifies known mechanisms of mercury transport and provides information on additional mechanisms that may potentially play a role in the transport of mercuric ions into target cells.

Transport of Inorganic Mercury and Methylmercury in Target Tissues and Organs

The developing brain is uniquely susceptible to the neurotoxic hazard posed by mercurials. Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes. How population-based variability affects the safety of the ethylmercury-containing vaccine preservative, thimerosal, is unknown. Reported increases in the prevalence of autism, a highly heritable neuropsychiatric condition, are intensifying public focus on environmental exposures such as thimerosal. Immune profiles and family history in autism are frequently consistent with autoimmunity. We hypothesized that autoimmune propensity influences outcomes in mice following thimerosal challenges that mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed growth delay; reduced locomotion; exaggerated response to novelty; and densely packed, hyperchromic hippocampal neurons with altered glutamate receptors and transporters. Strains resistant to autoimmunity, C57BL/ 6J and BALB/cJ, were not susceptible. These findings implicate genetic influences and provide a model for investigating thimerosal-related neurotoxicity. Molecular Psychiatry advance online publication, 8 June 2004; doi:10.1038/sj.mp.4001529

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L J Bell

Papers

Murine susceptibility to mercury. I. Autoantibody profiles and systemic immune deposits in inbred, congenic, and intra-H-2 recombinant strains.

Murine Susceptibility to Mercury: II. Autoantibody Profiles and Renal Immune Deposits in Hybrid, Backcross, and H-2d Congenic Mice