Arsenic as an endocrine disruptor: arsenic disrupts retinoic acid receptor-and thyroid hormone receptor-mediated gene regulation and thyroid hormone-mediated amphibian tail metamorphosis.

Exposure to excess arsenic, principally from contaminated drinking water, is considered one of the top environmental health threats both in the United States and worldwide [Abernathy et al. 2003; Mukherjee et al. 2006; National Research Council (NRC) 1999, 2001; Smith et al. 2002; Watanabe et al. 2003]. The majority of this exposure is from natural geological sources of As that contaminate groundwater. Epidemiologic studies have linked chronic exposure to drinking-water As with increased risks of various cancers, including those of the lung, bladder, skin, and liver, as well as numerous other noncancer illnesses including vascular and cardiovascular disease, diabetes, developmental and reproductive problems, and neurologic and cognitive problems (Abernathy et al. 2003; NRC 1999, 2001; Smith et al. 2002; Tapio and Grosche 2006; Wasserman et al. 2004; Watanabe et al. 2003). Public water supplies in the United States and Europe currently have a regulatory limit of 10 ppb As (0.13 μM). However, a large segment of the population in the United States and worldwide obtains its drinking water from private unregulated wells. Also, many other areas of the world have higher regulatory limits or water supplies that are unregulated. Thus, As contamination continues to be a serious, ongoing public environmental health problem affecting hundreds of millions of people. There are a number of proposed mechanisms for the ability of As to influence so many diverse disease processes. These include alterations in cell signaling, cell cycle control, oxidative stress, DNA repair, and others (Abernathy et al. 1999; Aposhian and Aposhian 2006; Kitchin 2001; Rossman 2003). Moreover, it is becoming clear that there are important dose-, time-, and tissue-specific differences in effects of As, as well as important gene–environment and co-exposure interactions that complicate how As alters disease risk under any particular exposure circumstance (Andrew et al. 2003, 2006; Bodwell et al. 2004, 2006; Karagas et al. 2004; Waalkes et al. 2003). We previously reported that As is a potent endocrine disruptor, altering steroid hormone receptor (SR)-mediated gene regulation at very low, environmentally relevant concentrations in cell culture and in whole-animal models (Bodwell et al. 2004, 2006; Davey et al. 2007; Kaltreider et al. 2001). We have demonstrated that all five steroid receptors (SRs) [i.e., the receptors for glucocorticoid (GR), androgen (AR), progesterone (PR), mineralocorticoid (MR), and estrogen (ER) hormones] are affected in a similar manner, suggesting a broad effect on these pathways and also suggesting a common mechanism for these effects (Bodwell et al. 2004, 2006; Davey et al. 2007; Kaltreider et al. 2001). Given this strong disruption on this entire class of nuclear hormone receptors, we were interested in whether these effects extend to other members of the larger nuclear hormone receptor superfamily. In this study we examined the effects of As on gene regulation by two related class II receptors, the retinoic acid (RA) receptor (RAR) and the thyroid hormone (TH) receptor (TR). Both receptors normally partner with the retinoid X receptor (RXR) to form heterodimers that act as transcription factors, binding to the RA-response element (RARE) of RA-inducible genes or the TH-responsive element (TRE) of TH-inducible genes, respectively (Mark et al. 2006; Tsai and O’Malley 1994; Wong and Shi 1995; Zhang and Lazar 2000). We report here that As has significant effects on both RAR- and TR-mediated gene regulation at very low doses (0.01–2 μM), and that these effects are strikingly similar to those previously observed with the SRs, suggesting a common mechanism. We also investigated whether such As-induced alterations in hormone signaling would lead to pathophysiologic consequences, using amphibian tail metamorphosis as a model system. Anuran metamorphosis is highly dependent on TH- and TR-mediated processes (Buchholz et al. 2006; Buckbinder and Brown 1993; Wong and Shi 1995; Yaoita and Brown 1990) and is known to be perturbed by agents that interfere with TH or TR signaling (Buchholz et al. 2003; Lim et al. 2002). Because TH is also important for many aspects of mammalian embryonic development (Galton 2005; Oppenheimer and Samuels 1983; Porterfield and Hendrich 1993), this is a useful model for understanding possible effects on human development. Arsenic had profound effects on TH-mediated ex vivo tail metamorphosis at very low, environmentally relevant concentrations, suggesting that there are likely to be other developmental and pathophysiologic effects of low dose As endocrine disruption in vivo.