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Increased Level of Cellular Bip Critically Determines Estrogenic Potency for a Xenoestrogen Kepone in the Mouse Uterus

Division of Reproductive and Developmental Biology, Departments of Pediatrics (S.R., F.X., P.L., H.W., N.S.S., S.K.D.) and Cancer Biology (S.R., F.X., P.L., S.K.D.), Vanderbilt University Medical Center, Nashville, Tennessee 37232-2678

Address all correspondence and requests for reprints to: Sanjoy K. Das, Department of Pediatrics, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, MCN-D4100, Nashville, Tennessee 37232-2678. E-mail: sanjoy.das{at}vanderbilt.edu.

Xenoestrogen mimics estrogen-like activities primarily based on alterations of gene expression and interactions with estrogen receptor (ER)- and -ß. However, the requirement for large concentrations to induce estrogenic phenotypes and low affinity for ERs has challenged the notion that prevailing xenoestrogens are significant health hazards. Here in this study, we show that under certain conditions, exposure of xenoestrogen could be potentially harmful in respect to enhanced uterine estrogenicity. Previously, we have demonstrated that estradiol-17ß up-regulates uterine Bip, a stress-related endoplasmic reticulum protein, via an ER-independent mechanism in mice. Moreover, this protein essentially involves in estradiol-17ß-mediated uterine growth response and ER-dependent gene transcription. Here, we demonstrate that among three tested xenoestrogens, only kepone (>15–30 mg/kg) exerts sustained inductive response for uterine Bip expression. Interestingly, this kepone-induced Bip strongly correlates with ER-dependent growth and gene expressional responses in the mouse uterus. Furthermore, these effects were strongly suppressed after knockdown of uterine Bip, via the adenovirus approach. Although kepone at 7.5 mg/kg was not effective, it was strongly stimulatory by the adenovirus-driven forced expression of uterine Bip. In contrast, the control green fluorescence protein virus was not effective in the aforementioned responses. Furthermore, the induction of uterine Bip by stress-related signals also revealed the onset of uterine growth in mice when exposed to a sublethal dose of kepone. Collectively, studies provide novel molecular evidence that Bip acts as a critical regulator to amplify estrogenic potency for a weak xenoestrogen kepone.