title: Developmental programming by androgen affects the circadian timing system in female mice.
abstract: Circadian clocks play essential roles in the timing of events in the mammalian hypothalamo-pituitary-ovarian (HPO) axis. The molecular oscillator driving these rhythms has been localized to tissues of the HPO axis. It has been suggested that synchrony among these oscillators is a feature of normal reproductive function. The impact of fertility disorders on clock function and the role of the clock in the etiology of endocrine pathology remain unknown. Polycystic ovarian syndrome (PCOS) is a particularly devastating fertility disorder, affecting 5%-10% of women at childbearing age with features including a polycystic ovary, anovulation, and elevated serum androgen. Approximately 40% of these women have metabolic syndrome, marked by hyperinsulinemia, dyslipidemia, and insulin resistance. It has been suggested that developmental exposure to excess androgen contributes to the etiology of fertility disorders, including PCOS. To better define the role of the timing system in these disorders, we determined the effects of androgen-dependent developmental programming on clock gene expression in tissues of the metabolic and HPO axes. Female PERIOD2::luciferase (PER2::LUC) mice were exposed to androgen (dihydrotestosterone [DHT]) in utero (Days 16-18 of gestation) or for 9-10 wk (DHT pellet) beginning at weaning (pubertal androgen excess [PAE]). As expected, both groups of androgen-treated mice had disrupted estrous cycles. Analysis of PER2::LUC expression in tissue explants revealed that excess androgen produced circadian misalignment via tissue-dependent effects on phase distribution. In vitro treatment with DHT differentially affected the period of PER2::LUC expression in tissue explants and granulosa cells, indicating that androgen has direct and tissue-specific effects on clock gene expression that may account for the effects of developmental programming on the timing system.
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, New York.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Mereness
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, New York.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Murphy
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, New York michael_sellix@urmc.rochester.edu.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Sellix
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics; D009924:Organ Culture Techniques; D010053:Ovary / Q000187:drug effects; D056950:Period Circadian Proteins / Q000235:genetics; D011085:Polycystic Ovary Syndrome / Q000235:genetics; D012741:Sexual Maturation / Q000187:drug effects
chemical_list: D000728:Androgens; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D008156:Luciferases
keywords: PCOS; PER2::luciferase; androgens/androgen receptors; circadian rhythm; clock genes; developmental origins of health and disease; female reproductive tract; fertility; mechanisms of hormone action; mouse; reproduction