Superfund Research Program
Arsenic as an Endocrine Disrupter
This project first reported in 2001 that arsenic acts as potent endocrine disruptor, and continues to focus on two aspects of this effect. The first goal is to determine the mechanistic basis for these effects, focusing on the cellular and molecular levels. The second is to determine the pathopysiological consequences of such endocrine disruption, and the overall role such effects play in the ability of arsenic to increase risk of the myriad of chronic and deadly diseases with which it has been associated in epidemiological studies. Dr. Joshua Hamilton and his laboratory have shown that arsenic profoundly affects the function of all five steroid hormone receptors, i.e., those for glucocorticoids, mineralocorticoids, androgen, estrogen and progesterone, in a very similar manner. The effects on the estrogen receptor were recently reported in a 2007 paper and accompanying commentary published in Toxicological Sciences (JC Davey et al. Toxicol Sci 98:75-86, 2007). More recently scientists have also shown that arsenic alters in a similar manner the ability to regulate gene transcription by the type 2 nuclear hormone receptors for thyroid hormone and retinoic acid, in a paper in press in Environmental Health Perspectives (JC Davey et al., Environ Hlth Perspect, e-pub on-line Oct 2007). It is likely, based on these results to date, that the mechanism for these arsenic effects involves a shared pathway or regulatory machinery given the lack of absolute structural homology among these diverse proteins. In addition, these results suggest that many other nuclear hormone receptors may be affected similarly by arsenic. Given the myriad of functions that these receptors and their hormones modulate in normal human biology, as well as the many diseases in which they have been shown to play a fundamental role, it is hypothesized that this is one of the major pathways by which arsenic increases the risk of various cancers, heart and vascular disease, reproductive and developmental problems, diabetes, and the growing list of other diseases associated with arsenic exposure. These results also predict that there will be human health effects at drinking water levels of arsenic at or below the current U.S. drinking water standard of 10 ppb since these effects were observed at levels far below 10 ppb in cell culture and at or below this level in several in vivo models. For example, toxicogenomics studies in the lab have shown that arsenic in drinking water at and below 10 ppb profoundly alters gene expression in mouse liver and lung in vivo after just five weeks of exposure, and produces altered patterns of gene expression that correlate with disruption of nuclear hormone signaling (JW Hamilton et al., manuscripts in preparation). A recent paper by Dr. Hamilton and his group showed such toxicogenomic effects at as low at 0.1 ppb in drinking water in this mouse model (AS Andrew et al., Toxicol Sci 100:75-87, 2007). The labatory’s current work is focusing on how arsenic perturbs the interaction of nuclear hormone receptors with the partner proteins that are required for modulating hormone-induced gene transcription.
Scientists have also examined the consequences of such disruption in several model in vivo systems. They recently demonstrated that arsenic at very low levels (2-10 ppb) disrupts thyroid hormone-mediated metamorphosis in a frog tadpole model (JC Davey et al., Environ Hlth Perspect, e-pub on-line Oct 2007). These effects may have significance to human fetal and postnatal development, since the levels of arsenic were so low, and since human development is also critically dependent on proper regulatory function of thyroid hormone, retinoic acid hormone and several steroid hormones. Similarly, they demonstrated, in collaboration with Arsenic and ABC Transporters, that arsenic profoundly alters glucocorticoid receptor-mediated regulation of the CFTR protein, a chloride channel that regulates salt balance in the model fish, killifish, and also in human lung (CR Stanton et al., Cell Physiol Biochem 17:269-278, 2006; JR Shaw JR et al., Am J Physiol Regul Integr Comp Physiol 292:R1052-1060, 2007). Mutations within the CFTR gene are responsible for the human disease, cystic fibrosis. Dysfunction of CFTR in killifish by low dose arsenic treatments led to the inability of these fish to adapt to their normal transition from freshwater to salt water, resulting in toxicity and lethality at doses that are otherwise not toxic. Likewise, arsenic altered expression and function of a related protein in killifish kidney that is involved in drug and xenobiotic transport (DS Miller et al., Toxicol Sci 97:103-110, 2007). Further work will explore in more detail the precise mechanism by which arsenic disrupts hormone receptor action, and also will examine the pathophysiological consequences of this disruption by focusing on key genes involved in specific disease processes such as carcinogenesis, diabetes and vascular disease. In addition to these primary objectives, Arsenic as an Endocrine Disruptor also collaborates with several other projects within the program to conduct toxicogenomics studies and other molecular investigations. Scientists have worked with Arsenic Epidemiology, Biomarkers and Exposure Assessmentto examine the effects of arsenic on DNA repair in lymphocytes of people exposed to arsenic in New Hampshire drinking water. They have worked with Trophic Transfer of Toxic Metals in Aquatic Food Webs to develop and use genomics tools in Daphnia to examine effects of metals on gene expression. The scientists have also worked with Arsenic and ABC Transporters to examine endocrine disruption by arsenic in killifish. These studies have enhanced their understanding of arsenic effects, while also providing powerful new tools and observations to these other projects.