Xenoestrogens Ethinyl Estradiol and Zearalenone Cause Precocious Puberty in Female Rats via Central Kisspeptin Signaling

• Published in: Endocrinology (Philadelphia) Vol. 156; no. 11; pp. 3996 - 4007
• Main Authors: Kriszt, Rókus, Winkler, Zsuzsanna, Polyák, Ágnes, Kuti, Dániel, Molnár, Csilla, Hrabovszky, Erik, Kalló, Imre, Szőke, Zsuzsanna, Ferenczi, Szilamér, Kovács, Krisztina J
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.11.2015
• Subjects: Animals; Arcuate Nucleus of Hypothalamus - drug effects; Arcuate Nucleus of Hypothalamus - metabolism; Estrogens - pharmacology; Estrogens, Non-Steroidal - pharmacology; Ethinyl Estradiol - pharmacology; Female; Gene Expression - drug effects; Gonadotropin-Releasing Hormone - genetics; Gonadotropin-Releasing Hormone - metabolism; Gonadotropins - metabolism; Hypothalamus - cytology; Hypothalamus - drug effects; Hypothalamus - metabolism; In Situ Hybridization; Kisspeptins - genetics; Kisspeptins - metabolism; Microscopy, Confocal; Neurons - drug effects; Neurons - metabolism; Rats, Wistar; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Kisspeptin-1; Reverse Transcriptase Polymerase Chain Reaction; Sexual Maturation - drug effects; Signal Transduction - drug effects; Signal Transduction - genetics; Uterus - drug effects; Uterus - growth & development; Uterus - metabolism; Xenobiotics - pharmacology; Zearalenone - pharmacology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2015-1330

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-α and accelerate puberty. However, the neuroendocrine mechanisms that are responsible for this effect remain unknown. Immature female Wistar rats were treated with EE2 (10 μg/kg), ZEA (10 mg/kg), or vehicle for 10 days starting from postnatal day 18. As a marker of puberty, the vaginal opening was recorded and neuropeptide and related transcription factor mRNA levels were 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 kiss1 mRNA in the anteroventral and rostral periventricular hypothalamus and an increased kisspeptin (KP) fiber density and KP-GnRH appositions in the preoptic area. These changes are compatible with a mechanism in which xenoestrogens 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 periventricular KP neurons to stimulate GnRH mRNA. However, GnRH and gonadotropin release and ovulation are disrupted due to xenoestrogen-mediated inhibitory KP signaling in the arcuate nucleus.