Xenoestrogens from synthetic or natural origin represent an increasing risk of disrupted endocrine functions including the physiological activity of the hypothalamo-pituitary-gonad axis. Ethinyl estradiol (EE2) is a synthetic estrogen used in contraceptive pills, whereas zearalenone (ZEA) is a natural mycoestrogen found with increasing prevalence in various cereal crops. Both EE2 and ZEA are agonists of estrogen receptor- and accelerate puberty. However, the neuroendocrine mechanisms that are responsible for this effect remain unknown. Immature female Wistar rats were treated with EE2 (10 mg/kg), ZEA (10 mg/kg), or vehicle for 10 days starting from postnatal day 18. As a marker of puberty, thevaginalopeningwasrecordedandneuropeptideandrelatedtranscription factormRNAlevelswere measured by quantitative real time PCR and in situ hybridization histochemistry. Both ZEA and EE2 accelerated the vaginal opening, increased the uterine weight and the number of antral follicles in the ovary, and resulted in the increased central expression of gnrh. These changes occurred in parallel with an earlier increase of kiss1mRNAin the anteroventral and rostral periventricular hypothalamus and an increased kisspeptin (KP) fiber densityandKP-GnRHappositions inthepreoptic area.Thesechangesare compatible withamechanisminwhichxenoestrogens overstimulate the developmentally unprepared reproductive system, which results in an advanced vaginal opening and an enlargement of the uterus at the periphery. Within the hypothalamus, ZEA and EE2 directly activate anteroventral and periventricularKPneuronsto stimulateGnRHmRNA.However,GnRHandgonadotropinreleaseandovulation are disrupted due to xenoestrogen-mediated inhibitory KP signaling in the arcuate nucleus.
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