Arsenic as an Endocrine Disruptor: Effects of Arsenic on Estrogen Receptor–Mediated Gene Expression In Vivo and in Cell Culture

Abstract

Arsenic (As) contamination of drinking water is considered a serious worldwide environmental health threat that is associated with increased disease risks including skin, lung, bladder, and other cancers; type 2 diabetes; vascular and cardiovascular diseases; reproductive and developmental effects; and neurological and cognitive effects. Increased health risks may occur at as low as 10-50 ppb, while biological effects have been observed in experimental animal and cell culture systems at much lower levels. We previously reported that As is a potent endocrine disruptor, altering gene regulation by the closely related glucocorticoid, mineralocorticoid, progesterone, and androgen steroid receptors (SRs) at concentrations as low as 0.01 microM ( approximately 0.7 ppb). Very low doses enhanced hormone-mediated gene transcription, whereas slightly higher but still noncytotoxic doses were suppressive. We report here that As also disrupts the more distally related estrogen receptor (ER) both in vivo and in cell culture. At noncytotoxic doses (1-50 micromol/kg arsenite) As strongly suppressed ER-dependent gene transcription of the 17beta-estradiol (E2)-inducible vitellogenin II gene in chick embryo liver in vivo. In cell culture, noncytotoxic levels (0.25-3 microM, approximately 20-225 ppb) of As significantly inhibited E2-mediated gene activation of an ER-regulated reporter gene and the native ER-regulated GREB1 gene in human breast cancer MCF-7 cells. While the effects of As on ER-dependent gene regulation were generally similar to As effects on the other SRs, there were specific differences, particularly the lack of significant enhancement at the lowest doses, that may provide insights into possible mechanisms.

Arsenic inhibits in vitro spermatogenesis and induces germ cell apoptosis in Japanese eel (Anguilla japonica)

“…Arsenic induces a broad range of effects including endocrine disruption (Kaltreider et al 2001, Bodwell et al 2006, Davey et al 2007. Endocrine disruptors are defined as any substance that can interfere with normal hormone function.…”

Occurrence and Fate of Selected Endocrine-Disrupting Chemicals in Water and Sediment from an Urban Lake

“…All compounds were found more persistent under anoxic conditions than under oxic conditions. Endocrine-disrupting chemicals (EDCs), which can interfere with the body's endocrine system, are receiving growing concerns due to their potential to cause adverse developmental, reproductive, neurological, and immune effects to both humans and wildlife (Anway et al 2005;Davey et al 2007;Falconer et al 2006). A variety of chemicals, such as certain pesticides, herbicides, surfactants, plasticizers, flame retardants, and pharmaceuticals, can potentially act as EDCs.…”

Ground Water Arsenic Poisoning in ?Tilak Rai Ka Hatta? Village of Buxar District, Bihar, India Causing Severe Health Hazards and Hormonal Imbalance

“…Metals have not previously been shown to act as endocrine disrupters. Blocking the actions of the glucocorticoid receptor by arsenic in this unique way could explain, at least in part, many of the health effects observed in arsenic-exposed human populations [46][47][48].…”