PCBs Exert an Estrogenic Effect through Repression of the Wnt7a Signaling Pathway in the Female Reproductive Tract

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Abstract
Polychlorinated biphenyls (PCBs) have been proposed to have a weak estrogenic activity and therefore pose a risk as potential environmental endocrine disruptors to the perinatal development of the female reproductive tract. Perinatal exposure to high concentrations of the potent synthetic estrogen diethylstilbestrol (DES) induces abnormal development of the female reproductive tract via a mechanism that acts through the down-regulation of Wnt7a (wingless-type MMTV integration site family, member 7A). To test the hypothesis that PCBs act as weak estrogens, we injected neonatal mice with a commercial PCB mixture (Aroclor 1254) or with low levels of DES and measured effects of exposure on Wnt7a expression and uterine morphology. We report here that neonatal PCB or low-level DES exposure resulted in the down-regulation of Wnt7a expression. In addition, both PCB and low-level DES exposure induced changes in the uterine myometrium and gland formation. These data reveal that weak estrogens such as the PCBs act through a Wnt7a-dependent pathway and suggest that Wnt7a regulation is a sensitive biomarker for testing weak estrogenic candidate compounds. The morphologic changes that were elicited by PCBs and DES were different immediately after exposure, suggesting that Wnt7a-independent pathways are also activated by one or both of these compounds. Although Wnt7a down-regulation is transient after estrogenic exposure, subsequent morphologic changes became more pronounced during postnatal and adult life, suggesting that the female reproductive tract is permanently reprogrammed after exposure even to weak estrogenic compounds. In addition, Wnt7a heterozygous mice were more sensitive to PCB exposure, revealing an important genetic predisposition to risks of environmental endocrine disruptors.

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