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Effect of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on the Expression of Follicle-Stimulating Hormone Receptors during Cell Differentiation in Cultured Granulosa Cells¹

Department of Obstetrics and Gynecology (T.H., T.M., K.A., H.K., K.I., Y.I.), School of Medicine, Gunma University, Maebashi, Gunma 371-8511; and Department of Biochemistry (K.M.), Fukui Medical University, Fukui 910-1193, Japan

Address all correspondence and requests for reprints to: Takashi Minegishi, Department of Obstetrics and Gynecology, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan. E-mail: tminegis{at}sb.gunma-u.ac.jp

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) is a common environmental pollutant causing public concern. Using a cell culture system derived from rat granulosa cells that provides unique advantages for studying the molecular mechanisms underlying the action of TCDD, the influences of TCDD on FSH receptor (FSH-R) induction were examined. The treatment with FSH produced, as expected, a substantial increase in specific FSH-R expression, whereas concurrent treatment with the environmental amount of TCDD (10 pM) resulted in a significant decrease in FSH-R after being cultured from 24–72 h. Cotreatment with FSH (30 ng/ml) and increasing doses of TCDD inhibited the levels of FSH-induced FSH-R messenger RNA (mRNA) in a dose-dependent manner. Treatment with 8-Br-cAMP (1 mM) produced a significant increase in FSH-R mRNA; concurrent treatment with TCDD (10 pM) produced a significant attenuation of 8-Br-cAMP action. These findings suggest that the ability of TCDD to interfere with FSH action, as regards the induction of FSH-Rs, is exerted at sites distal to those involved in cAMP generation. Because a single transcript of 5.2 kb was seen for the Ah receptor in this granulosa cell system, the effects of TCDD may be mediated by this specific receptor. The rates of FSH-R mRNA gene transcription, assessed by nuclear run-on transcription assay, were decreased by the addition of TCDD. The effect of TCDD on FSH-R mRNA stability was determined by measuring the decay of FSH-R mRNA under conditions known to inhibit transcription. The decay curve for the 2.4-kb FSH-R mRNA transcript was not significantly changed after the addition of TCDD. These findings showed that the effect of TCDD on FSH-R mRNA was, at least in part, the result of decreased transcription.

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