TOXICOLOGICAL HIGHLIGHT Arsenic: Extension of its Endocrine Disruption Potential to Interference with Estrogen Receptor-Mediated Signaling

Human exposure to arsenic (As) has become an important public health concern. Exposures most commonly occur through consumption of drinking water where the current maximum contaminant level of As, set by the U.S. Environmental Health Administration and the World Health Organization, is 10 lg/l. However, contamination from natural sources in various areas of the United States such as New England and the Southwest, and regions of the world, such as Bangladesh and Taiwan can reach hundreds of micrograms/ liter in wells. Exposures can also occur in occupational settings where arsenic is used to manufacture pesticides and wood preservatives, and superfund sites where industrial waste was disposed. An example of the issue and concern is represented by this recent headline which appeared in the Baltimore Sun on Friday, 20 April 2007. ‘‘ARSENIC FORCES CLOSING OF PARK—Tests show high levels in soil; city locks gates of Swann Park. ’’ Swann Park is located next to a site where arsenic was used in the manufacture of pesticides. Exposure to high levels of As has been associated with various human diseases including cardiovascular and diabetes, and cancers of the skin, lung, bladder, kidney, and liver (see reviews by Huang et al., 2004; Rossman, 2003; Tapio and Grosche, 2006). Recent systematic reviews of the epidemiologic evidence for associations of As exposure with cardiovascular disease (Navas-Acien et al., 2005) and diabetes (Navas-Acien et al., 2006) detected increased risks associated with the highest As exposure categories in Taiwan, but were inconclusive in other populations. While the Taiwan studies suffered from several methodological limitations that made exposure estimates uncertain, the observations from these studies indicate the importance of conducting additional, well-designed investigations. In New Hampshire, where drinking water levels are commonly elevated, an association was observed between the highest category of As exposure, as determined by As levels in toenail clippings, and bladder cancer among smokers, but not among never smokers (Karagas et al., 2004). The authors concluded that ‘‘ingestion of low to moderate arsenic levels may affect bladder cancer incidence, and that cigarette smoking may act as a co-carcinogen’’ (Karagas et al., 2004). This latter observation is particularly interesting in light of the findings that As exposure has been associated with decreased expression of the DNA excision repair gene ERCC1 (excision repair cross-complement 1) and decreased DNA repair capacity in human lymphocytes from Asexposed individuals (Andrew et al., 2006), representing a possible, but not necessarily exclusive, mechanism by which As exposure could exert cocarcinogenic effects. The metabolism of As almost certainly contributes to the adverse health effects seen in populations exposed to inorganic arsenic. Inorganic arsenic (iAs) exists in two valence states: iAs(III) and iAs(V). In humans, iAs(III) is oxidatively methylated to monomethyl As(V), reduced to monomethyl As(III), methylated again to dimethyl As(V), and then reduced to dimethyl As(III). In general, trivalent As species are more toxic than pentavalent species, and organic forms are more toxic than inorganic forms. The enzyme responsible for both methylation steps is arsenic(III)methyltransferase (AS3MT) (Li et al., 2005). Several enzymes have been shown to reduce pentavalent As species to trivalent As, but recent evidence suggests that AS3MT itself may be capable of catalyzing the reduction, provided there is a source of reducing equivalents such as glutathione or thioredoxin. Differences in As metabolism may contribute to differences in individual susceptibility to disease development. In addition, several polymorphisms have been identified in AS3MT and several classes of glutathione Stransferases that influence the profile of urinary As metabolites and contribute to differences in susceptibility to adverse health effects associated with As exposure (Engstrom et al., 2007; McCarty et al., 2007). The metabolism of As and its contribution to adverse effects is an area of active investigation, and experimental studies may contribute to differences observed in the effects of As in different cells lines. 1 For correspondence via e-mail: wwatson@jhsph.edu.