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Submitted on March 22, 2005
Accepted on May 3, 2005
Yale University School of Medicine
* To whom correspondence should be addressed. E-mail: hugh.taylor{at}yale.edu.
Methoxychlor (MXC) is a pesticide that has adverse effects on reproductive capability in mice. MXC and its metabolites bind the estrogen receptor and function as endocrine disruptors. MXC diminishes the uterine decidual cell response, necessary for the support of pregnancy. Hoxa10 is an estrogen regulated gene that is an essential mediator of the decidual response and necessary for pregnancy. Here we demonstrate that a mechanism by which MXC disrupts uterine function is by suppressing Hoxa10 expression. MXC treatment of mice produced a mild uterotropic response as measured by increased uterine weight and epithelial height. MXC treatment of uterine Ishikawa cells in vitro induced Hoxa10 expression. Estrogen receptor (ER) binding to the HOXA10 estrogen response element (ERE) was promoted by treatment with estradiol (E2), however MXC disrupted E2/ER/ERE complex formation and gel shift. MXC alone allowed weak ER/ERE binding. In vivo MXC blocked the effect of E2 on Hoxa10 expression. Neonatal MXC treatment resulted in an immediate suppression and cellular restriction of Hoxa10 expression as well as a permanent generalized decrease in expression that persisted in the adult. MXC inhibited the expression of Hoxa10, a gene necessary for uterine development and function. One common mechanism by which endocrine disrupting chemicals produce lasting reproductive tract defects is through permanent alteration of developmental gene expression.
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