title: Xenoestrogens Ethinyl Estradiol and Zearalenone Cause Precocious Puberty in Female Rats via Central Kisspeptin Signaling.
abstract: 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.
authors.affiliation: Laboratory of Molecular Neuroendocrinology (R.K., Z.W., A.P., D.K., S.F., K.J.K.) and Department of Endocrine Neurobiology (C.M., E.H., I.K.), Institute of Experimental Medicine, and Faculty of Information Technology and Bionics (A.P.), Tamás Roska Doctoral School of Sciences and Technology, Pázmány Péter Catholic University, Budapest H-1083, Hungary; Soft Flow Hungary Research and Development Ltd (Z.S.), Pécs H-7628, Hungary; János Szentágothai Doctoral School of Neurosciences (R.K., Z.W., D.K.), Semmelweis University, H-1085 Budapest, Hungary.
authors.forename: Rókus
authors.initials: R
authors.lastname: Kriszt
authors.affiliation: Laboratory of Molecular Neuroendocrinology (R.K., Z.W., A.P., D.K., S.F., K.J.K.) and Department of Endocrine Neurobiology (C.M., E.H., I.K.), Institute of Experimental Medicine, and Faculty of Information Technology and Bionics (A.P.), Tamás Roska Doctoral School of Sciences and Technology, Pázmány Péter Catholic University, Budapest H-1083, Hungary; Soft Flow Hungary Research and Development Ltd (Z.S.), Pécs H-7628, Hungary; János Szentágothai Doctoral School of Neurosciences (R.K., Z.W., D.K.), Semmelweis University, H-1085 Budapest, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Winkler
authors.affiliation: Laboratory of Molecular Neuroendocrinology (R.K., Z.W., A.P., D.K., S.F., K.J.K.) and Department of Endocrine Neurobiology (C.M., E.H., I.K.), Institute of Experimental Medicine, and Faculty of Information Technology and Bionics (A.P.), Tamás Roska Doctoral School of Sciences and Technology, Pázmány Péter Catholic University, Budapest H-1083, Hungary; Soft Flow Hungary Research and Development Ltd (Z.S.), Pécs H-7628, Hungary; János Szentágothai Doctoral School of Neurosciences (R.K., Z.W., D.K.), Semmelweis University, H-1085 Budapest, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Polyák
authors.affiliation: Laboratory of Molecular Neuroendocrinology (R.K., Z.W., A.P., D.K., S.F., K.J.K.) and Department of Endocrine Neurobiology (C.M., E.H., I.K.), Institute of Experimental Medicine, and Faculty of Information Technology and Bionics (A.P.), Tamás Roska Doctoral School of Sciences and Technology, Pázmány Péter Catholic University, Budapest H-1083, Hungary; Soft Flow Hungary Research and Development Ltd (Z.S.), Pécs H-7628, Hungary; János Szentágothai Doctoral School of Neurosciences (R.K., Z.W., D.K.), Semmelweis University, H-1085 Budapest, Hungary.
authors.forename: Dániel
authors.initials: D
authors.lastname: Kuti
authors.affiliation: Laboratory of Molecular Neuroendocrinology (R.K., Z.W., A.P., D.K., S.F., K.J.K.) and Department of Endocrine Neurobiology (C.M., E.H., I.K.), Institute of Experimental Medicine, and Faculty of Information Technology and Bionics (A.P.), Tamás Roska Doctoral School of Sciences and Technology, Pázmány Péter Catholic University, Budapest H-1083, Hungary; Soft Flow Hungary Research and Development Ltd (Z.S.), Pécs H-7628, Hungary; János Szentágothai Doctoral School of Neurosciences (R.K., Z.W., D.K.), Semmelweis University, H-1085 Budapest, Hungary.
authors.forename: Csilla
authors.initials: C
authors.lastname: Molnár
authors.affiliation: Laboratory of Molecular Neuroendocrinology (R.K., Z.W., A.P., D.K., S.F., K.J.K.) and Department of Endocrine Neurobiology (C.M., E.H., I.K.), Institute of Experimental Medicine, and Faculty of Information Technology and Bionics (A.P.), Tamás Roska Doctoral School of Sciences and Technology, Pázmány Péter Catholic University, Budapest H-1083, Hungary; Soft Flow Hungary Research and Development Ltd (Z.S.), Pécs H-7628, Hungary; János Szentágothai Doctoral School of Neurosciences (R.K., Z.W., D.K.), Semmelweis University, H-1085 Budapest, Hungary.
authors.forename: Erik
authors.initials: E
authors.lastname: Hrabovszky
authors.affiliation: Laboratory of Molecular Neuroendocrinology (R.K., Z.W., A.P., D.K., S.F., K.J.K.) and Department of Endocrine Neurobiology (C.M., E.H., I.K.), Institute of Experimental Medicine, and Faculty of Information Technology and Bionics (A.P.), Tamás Roska Doctoral School of Sciences and Technology, Pázmány Péter Catholic University, Budapest H-1083, Hungary; Soft Flow Hungary Research and Development Ltd (Z.S.), Pécs H-7628, Hungary; János Szentágothai Doctoral School of Neurosciences (R.K., Z.W., D.K.), Semmelweis University, H-1085 Budapest, Hungary.
authors.forename: Imre
authors.initials: I
authors.lastname: Kalló
authors.affiliation: Laboratory of Molecular Neuroendocrinology (R.K., Z.W., A.P., D.K., S.F., K.J.K.) and Department of Endocrine Neurobiology (C.M., E.H., I.K.), Institute of Experimental Medicine, and Faculty of Information Technology and Bionics (A.P.), Tamás Roska Doctoral School of Sciences and Technology, Pázmány Péter Catholic University, Budapest H-1083, Hungary; Soft Flow Hungary Research and Development Ltd (Z.S.), Pécs H-7628, Hungary; János Szentágothai Doctoral School of Neurosciences (R.K., Z.W., D.K.), Semmelweis University, H-1085 Budapest, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Szőke
authors.affiliation: Laboratory of Molecular Neuroendocrinology (R.K., Z.W., A.P., D.K., S.F., K.J.K.) and Department of Endocrine Neurobiology (C.M., E.H., I.K.), Institute of Experimental Medicine, and Faculty of Information Technology and Bionics (A.P.), Tamás Roska Doctoral School of Sciences and Technology, Pázmány Péter Catholic University, Budapest H-1083, Hungary; Soft Flow Hungary Research and Development Ltd (Z.S.), Pécs H-7628, Hungary; János Szentágothai Doctoral School of Neurosciences (R.K., Z.W., D.K.), Semmelweis University, H-1085 Budapest, Hungary.
authors.forename: Szilamér
authors.initials: S
authors.lastname: Ferenczi
authors.affiliation: Laboratory of Molecular Neuroendocrinology (R.K., Z.W., A.P., D.K., S.F., K.J.K.) and Department of Endocrine Neurobiology (C.M., E.H., I.K.), Institute of Experimental Medicine, and Faculty of Information Technology and Bionics (A.P.), Tamás Roska Doctoral School of Sciences and Technology, Pázmány Péter Catholic University, Budapest H-1083, Hungary; Soft Flow Hungary Research and Development Ltd (Z.S.), Pécs H-7628, Hungary; János Szentágothai Doctoral School of Neurosciences (R.K., Z.W., D.K.), Semmelweis University, H-1085 Budapest, Hungary.
authors.forename: Krisztina J
authors.initials: KJ
authors.lastname: Kovács
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D006062:Gonadotropins / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017403:In Situ Hybridization; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012741:Sexual Maturation / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014599:Uterus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D015262:Xenobiotics / Q000494:pharmacology; D015025:Zearalenone / Q000494:pharmacology*
chemical_list: D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D006062:Gonadotropins; C491406:Kiss1 protein, rat; C492247:Kiss1r protein, rat; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D015262:Xenobiotics; D007987:Gonadotropin-Releasing Hormone; D004997:Ethinyl Estradiol; D015025:Zearalenone