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


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          Chronic 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.


          The 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 results

          Human 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.


          As 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.

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          Most cited references73

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          Cancer risks from arsenic in drinking water.

          Ingestion of arsenic, both from water supplies and medicinal preparations, is known to cause skin cancer. The evidence assessed here indicates that arsenic can also cause liver, lung, kidney, and bladder cancer and that the population cancer risks due to arsenic in U.S. water supplies may be comparable to those from environmental tobacco smoke and radon in homes. Large population studies in an area of Taiwan with high arsenic levels in well water (170-800 micrograms/L) were used to establish dose-response relationships between cancer risks and the concentration of inorganic arsenic naturally present in water supplies. It was estimated that at the current EPA standard of 50 micrograms/L, the lifetime risk of dying from cancer of the liver, lung, kidney, or bladder from drinking 1 L/day of water could be as high as 13 per 1000 persons. It has been estimated that more than 350,000 people in the United States may be supplied with water containing more than 50 micrograms/L arsenic, and more than 2.5 million people may be supplied with water with levels above 25 micrograms/L. For average arsenic levels and water consumption patterns in the United States, the risk estimate was around 1/1000. Although further research is needed to validate these findings, measures to reduce arsenic levels in water supplies should be considered.
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            Nuclear retinoid receptors and the transcription of retinoid-target genes.

            The pleiotropic effects of retinoids are mediated by nuclear retinoid receptors (RARs and RXRs) which are ligand-activated transcription factors. In response to retinoid binding, RAR/RXR heterodimers undergo major conformational changes and orchestrate the transcription of specific gene networks, through binding to specific DNA response elements and recruiting cofactor complexes that act to modify local chromatin structure and/or engage the basal transcription machinery. Then the degradation of RARs and RXRs by the ubiquitin-proteasome controls the magnitude and the duration of the retinoid response. RARs and RXRs also integrate a variety of signaling pathways through phosphorylation events which cooperate with the ligand for the control of retinoid-target genes transcription. These different modes of regulation reveal unexpected levels of complexity in the dynamics of retinoid-dependent transcription.
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              Water Arsenic Exposure and Children’s Intellectual Function in Araihazar, Bangladesh

              Exposure to arsenic has long been known to have neurologic consequences in adults, but to date there are no well-controlled studies in children. We report results of a cross-sectional investigation of intellectual function in 201 children 10 years of age whose parents participate in our ongoing prospective cohort study examining health effects of As exposure in 12,000 residents of Araihazar, Bangladesh. Water As and manganese concentrations of tube wells at each child’s home were obtained by surveying all wells in the study region. Children and mothers came to our field clinic, where children received a medical examination in which weight, height, and head circumference were measured. Children’s intellectual function on tests drawn from the Wechsler Intelligence Scale for Children, version III, was assessed by summing weighted items across domains to create Verbal, Performance, and Full-Scale raw scores. Children provided urine specimens for measuring urinary As and creatinine and were asked to provide blood samples for measuring blood lead and hemoglobin concentrations. Exposure to As from drinking water was associated with reduced intellectual function after adjustment for sociodemographic covariates and water Mn. Water As was associated with reduced intellectual function, in a dose–response manner, such that children with water As levels > 50 μg/L achieved significantly lower Performance and Full-Scale scores than did children with water As levels < 5.5 μg/L. The association was generally stronger for well-water As than for urinary As.

                Author and article information

                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                February 2008
                26 October 2007
                : 116
                : 2
                : 165-172
                Department of Pharmacology & Toxicology, and Center for Environmental Health Sciences, Dartmouth Medical School, Hanover, New Hampshire, USA
                Author notes
                Address correspondence to J.W. Hamilton, Department of Pharmacology & Toxicology, 7650 Remsen Building, Room 514, Dartmouth Medical School, Hanover NH 03755-3835 USA. Telephone: (603) 650-1316. Fax: (603) 650-1129. E-mail: josh.hamilton@ 123456dartmouth.edu

                The authors declare they have no competing financial interests.

                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.
                : 1 February 2007
                : 25 October 2007

                Public health
                cyp26a,retinoic acid (ra),deiodinase (dio1),steroid,endocrine,arsenic (as),thyroid (th)
                Public health
                cyp26a, retinoic acid (ra), deiodinase (dio1), steroid, endocrine, arsenic (as), thyroid (th)


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