title: The effect of perinatal exposure to ethinyl oestradiol or a mixture of endocrine disrupting pesticides on kisspeptin neurons in the rat hypothalamus.
abstract: Early life exposure to endocrine disruptors is considered to disturb normal development of hormone sensitive parameters and contribute to advanced puberty and reduced fecundity in humans. Kisspeptin is a positive regulator of the hypothalamic-pituitary-gonadal axis, and plays a key role in the initiation of puberty. In the adult, Kiss1 gene expression occurs in two hypothalamic nuclei, namely the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC), which are differentially regulated by peripheral sex steroid hormones. In this study we determined the effects on puberty onset and Kiss1 mRNA levels in each of the two nuclei after long-term perinatal exposure of rats to ethinyl oestradiol (EE2) or to five different pesticides, individually and in a mixture. Rat dams were per orally administered with three doses of EE2 (5, 15 or 50 μg/kg/day) or with the pesticides epoxiconazole, mancozeb, prochloraz, tebuconazole, and procymidone, alone or in a mixture of the five pesticides at three different doses. Kiss1 mRNA expression was determined in the AVPV and in the ARC of the adult male and female pups in the EE2 experiment, and in the adult female pups in the pesticide experiment. We find that perinatal EE2 exposure did not affect Kiss1 mRNA expression in this study designed to model human exposure to estrogenic compounds, and we find only minor effects on puberty onset. Further, the Kiss1 system does not exhibit persistent changes and puberty onset is not affected after perinatal exposure to a pesticide mixture in this experimental setting. However, we find that the pesticide mancozeb tends to increase Kiss1 expression in the ARC, presumably through neurotoxic mechanisms rather than via classical endocrine disruption, calling for increased awareness that Kiss1 expression can be affected by environmental pollutants through multiple mechanisms.
authors: Neurobiology Research Unit, University Hospital Rigshospitalet, Building 9201, Juliane Maries Vej 24, 2100 Copenhagen, Denmark.
authors: Agnete
authors: A
authors: Overgaard
authors: Klaus
authors: K
authors: Holst
authors: Karen R
authors: KR
authors: Mandrup
authors: Julie
authors: J
authors: Boberg
authors: Sofie
authors: S
authors: Christiansen
authors: Pernille R
authors: PR
authors: Jacobsen
authors: Ulla
authors: U
authors: Hass
authors: Jens D
authors: JD
authors: Mikkelsen
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D004997:Ethinyl Estradiol / Q000633:toxicity*; D005260:Female; D007031:Hypothalamus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010575:Pesticides / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012741:Sexual Maturation
chemical_list: D052244:Endocrine Disruptors; C491406:Kiss1 protein, rat; D059648:Kisspeptins; D010575:Pesticides; D012333:RNA, Messenger; D004997:Ethinyl Estradiol