Arsenic as an Endocrine Disruptor: Arsenic Disrupts Retinoic Acid Receptor–and Thyroid Hormone Receptor–Mediated Gene Regulation and Thyroid Hormone–Mediated Amphibian Tail Metamorphosis

Abstract

BackgroundChronic exposure to excess arsenic in drinking water has been strongly associated with increased risks of multiple cancers, diabetes, heart disease, and reproductive and developmental problems in humans. We previously demonstrated that As, a potent endocrine disruptor at low, environmentally relevant levels, alters steroid signaling at the level of receptor-mediated gene regulation for all five steroid receptors.ObjectivesThe goal of this study was to determine whether As can also disrupt gene regulation via the retinoic acid (RA) receptor (RAR) and/or the thyroid hormone (TH) receptor (TR) and whether these effects are similar to previously observed effects on steroid regulation.Methods and resultsHuman embryonic NT2 or rat pituitary GH3 cells were treated with 0.01–5 μM sodium arsenite for 24 hr, with or without RA or TH, respectively, to examine effects of As on receptor-mediated gene transcription. At low, noncytotoxic doses, As significantly altered RAR-dependent gene transcription of a transfected RAR response element–luciferase construct and the native RA-inducible cytochrome P450 CYP26A gene in NT2 cells. Likewise, low-dose As significantly altered expression of a transfected TR response element–luciferase construct and the endogenous TR-regulated type I deiodinase (DIO1) gene in a similar manner in GH3 cells. An amphibian ex vivo tail metamorphosis assay was used to examine whether endocrine disruption by low-dose As could have specific pathophysiologic consequences, because tail metamorphosis is tightly controlled by TH through TR. TH-dependent tail shrinkage was inhibited in a dose-dependent manner by 0.1– 4.0 μM As.ConclusionsAs had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are critical for both normal human development and adult function and their dysregulation is associated with many disease processes, disruption of these hormone receptor–dependent processes by As is also potentially relevant to human developmental problems and disease risk.

Antioxidative Effect of Rice Bran Oil and Medium Chain Fatty Acid Rich Rice Bran Oil in Arsenite Induced Oxidative Stress in Rats

“…In modern days, exposure to sufficiently high concentrations of inorganic As in natural environments such as in water, sediment and soil has proved to be harmful to the organisms 2,3 . The main pathways of exposure to the human beings include ingestion of drinking water and consumption of foods and to a lesser extent, inhalation of air 4 .…”

Actions of Estrogenic Endocrine Disrupting Chemicals on Human Prostate Stem/Progenitor Cells and Prostate Carcinogenesis

“…However, due to the lack of long term carcinogenic animal studies, the mechanism for the biotransformation of arsenic is not completely understood. Importantly, it has been documented that arsenic may mediate some of these effects through endocrine disruption, specifically through interaction with ER and activation of estrogen-regulated genes [112,113]. Thus, it remains a possibility that endocrine disruption by arsenic can contribute to prostate cancer risk and further research on this topic is essential.…”

Actions of Estrogenic Endocrine Disrupting Chemicals on Human Prostate Stem/Progenitor Cells and Prostate Carcinogenesis

“…Importantly, it has been documented that arsenic may mediate some of these effects through endocrine disruption, specifically through interaction with ER and activation of estrogen--regulated genes [112,113]. Thus, it remains a possibility that endocrine disruption by arsenic can contribute to prostate cancer risk and further research on this topic is essential.…”