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Submitted on December 16, 2004
Accepted on July 13, 2005
Department of Developmental & Cell Biology, University of California, Irvine, Irvine, CA 92697-2300
* To whom correspondence should be addressed. E-mail: blumberg{at}uci.edu.
Endocrine disrupting chemicals are commonly considered to be compounds that mimic or block the transcriptional activation elicited by naturally circulating steroid hormones by binding to steroid hormone receptors. For example, the Food Quality Protection Act of 1996 defines endocrine disrupting chemicals as those, which "may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effect as the Administrator may designate". The definition of endocrine disrupting chemicals was later expanded to include those that act on the estrogen, androgen, and thyroid hormone receptors. In this minireview, we discuss new avenues through which xenobiotic chemicals influence these and other hormone-dependent signaling pathways. Endocrine disrupting chemicals can increase or block the metabolism of naturally occurring steroid hormones and other xenobiotic chemicals by activating or antagonizing nuclear hormone receptors. Endocrine disrupting chemicals affect the transcriptional activity of nuclear receptors by modulating proteasome-mediated degradation of nuclear receptors and their co-regulators. Xenobiotics and environmental contaminants can act as hormone sensitizers by inhibiting histone deacetylase activity and stimulating mitogen-activated protein kinase activity. Some endocrine disrupters can have genome-wide effects on DNA methylation status. Others can modulate lipid metabolism and adipogenesis, perhaps contributing to the current epidemic of obesity. Further elucidation of these new modes of endocrine disruption will be key in understanding the nature of xenobiotic effects on the endocrine system.
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