title: Maternal Vitamin D Deficiency Programs Reproductive Dysfunction in Female Mice Offspring Through Adverse Effects on the Neuroendocrine Axis.
abstract: Vitamin D (VitD) deficiency affects more than 1 billion people worldwide with a higher prevalence in reproductive-aged women and children. The physiological effects of maternal VitD deficiency on the reproductive health of the offspring has not been studied. To determine whether maternal VitD deficiency affects reproductive physiology in female offspring, we monitored the reproductive physiology of C57BL/6J female offspring exposed to diet-induced maternal VitD deficiency at three specific developmental stages: 1) in utero, 2) preweaning, or 3) in utero and preweaning. We hypothesized that exposure to maternal VitD deficiency disrupts reproductive function in exposed female offspring. To test this hypothesis, we assessed vaginal opening and cytology and ovary and pituitary function as well as gonadotropin and gonadal steroid levels in female offspring. The in utero, preweaning, and in utero and preweaning VitD deficiency did not affect puberty. However, all female mice exposed to maternal VitD deficiency developed prolonged and irregular estrous cycles characterized by oligoovulation and extended periods of diestrus. Despite similar gonadal steroid levels and GnRH neuron density, females exposed to maternal VitD deficiency released less LH on the evening of proestrus. When compared with control female offspring, there was no significant difference in the ability of females exposed to maternal VitD deficiency to respond robustly to exogenous GnRH peptide or controlled ovarian hyperstimulation. These findings suggest that maternal VitD deficiency programs reproductive dysfunction in adult female offspring through adverse effects on hypothalamic function.
authors.affiliation: Department of Developmental and Molecular Biology (C.N.), Albert Einstein College of Medicine, and Department of Obstetrics and Gynecology (M.P.), Montefiore Medical Center, Bronx, New York 10461; Medical College of Wisconsin (J.D.), Milwaukee, Wisconsin 53226; Seattle Reproductive Medicine (T.F.), Seattle, Washington 98109; Department of Reproductive Endocrinology and Infertility (T.S.), University Hospitals Case Medical Center University Hospitals Ahuja Medical Center, Beachwood, Ohio 44106; Department of Pediatrics and Physiology (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Department of Obstetrics and Gynecology (Y.S., G.N.-P.), University of Washington, Seattle, Washington 98195-6460.
authors.forename: Cari
authors.initials: C
authors.lastname: Nicholas
authors.affiliation: Department of Developmental and Molecular Biology (C.N.), Albert Einstein College of Medicine, and Department of Obstetrics and Gynecology (M.P.), Montefiore Medical Center, Bronx, New York 10461; Medical College of Wisconsin (J.D.), Milwaukee, Wisconsin 53226; Seattle Reproductive Medicine (T.F.), Seattle, Washington 98109; Department of Reproductive Endocrinology and Infertility (T.S.), University Hospitals Case Medical Center University Hospitals Ahuja Medical Center, Beachwood, Ohio 44106; Department of Pediatrics and Physiology (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Department of Obstetrics and Gynecology (Y.S., G.N.-P.), University of Washington, Seattle, Washington 98195-6460.
authors.forename: Joseph
authors.initials: J
authors.lastname: Davis
authors.affiliation: Department of Developmental and Molecular Biology (C.N.), Albert Einstein College of Medicine, and Department of Obstetrics and Gynecology (M.P.), Montefiore Medical Center, Bronx, New York 10461; Medical College of Wisconsin (J.D.), Milwaukee, Wisconsin 53226; Seattle Reproductive Medicine (T.F.), Seattle, Washington 98109; Department of Reproductive Endocrinology and Infertility (T.S.), University Hospitals Case Medical Center University Hospitals Ahuja Medical Center, Beachwood, Ohio 44106; Department of Pediatrics and Physiology (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Department of Obstetrics and Gynecology (Y.S., G.N.-P.), University of Washington, Seattle, Washington 98195-6460.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fisher
authors.affiliation: Department of Developmental and Molecular Biology (C.N.), Albert Einstein College of Medicine, and Department of Obstetrics and Gynecology (M.P.), Montefiore Medical Center, Bronx, New York 10461; Medical College of Wisconsin (J.D.), Milwaukee, Wisconsin 53226; Seattle Reproductive Medicine (T.F.), Seattle, Washington 98109; Department of Reproductive Endocrinology and Infertility (T.S.), University Hospitals Case Medical Center University Hospitals Ahuja Medical Center, Beachwood, Ohio 44106; Department of Pediatrics and Physiology (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Department of Obstetrics and Gynecology (Y.S., G.N.-P.), University of Washington, Seattle, Washington 98195-6460.
authors.forename: Thalia
authors.initials: T
authors.lastname: Segal
authors.affiliation: Department of Developmental and Molecular Biology (C.N.), Albert Einstein College of Medicine, and Department of Obstetrics and Gynecology (M.P.), Montefiore Medical Center, Bronx, New York 10461; Medical College of Wisconsin (J.D.), Milwaukee, Wisconsin 53226; Seattle Reproductive Medicine (T.F.), Seattle, Washington 98109; Department of Reproductive Endocrinology and Infertility (T.S.), University Hospitals Case Medical Center University Hospitals Ahuja Medical Center, Beachwood, Ohio 44106; Department of Pediatrics and Physiology (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Department of Obstetrics and Gynecology (Y.S., G.N.-P.), University of Washington, Seattle, Washington 98195-6460.
authors.forename: Marilena
authors.initials: M
authors.lastname: Petti
authors.affiliation: Department of Developmental and Molecular Biology (C.N.), Albert Einstein College of Medicine, and Department of Obstetrics and Gynecology (M.P.), Montefiore Medical Center, Bronx, New York 10461; Medical College of Wisconsin (J.D.), Milwaukee, Wisconsin 53226; Seattle Reproductive Medicine (T.F.), Seattle, Washington 98109; Department of Reproductive Endocrinology and Infertility (T.S.), University Hospitals Case Medical Center University Hospitals Ahuja Medical Center, Beachwood, Ohio 44106; Department of Pediatrics and Physiology (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Department of Obstetrics and Gynecology (Y.S., G.N.-P.), University of Washington, Seattle, Washington 98195-6460.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Developmental and Molecular Biology (C.N.), Albert Einstein College of Medicine, and Department of Obstetrics and Gynecology (M.P.), Montefiore Medical Center, Bronx, New York 10461; Medical College of Wisconsin (J.D.), Milwaukee, Wisconsin 53226; Seattle Reproductive Medicine (T.F.), Seattle, Washington 98109; Department of Reproductive Endocrinology and Infertility (T.S.), University Hospitals Case Medical Center University Hospitals Ahuja Medical Center, Beachwood, Ohio 44106; Department of Pediatrics and Physiology (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Department of Obstetrics and Gynecology (Y.S., G.N.-P.), University of Washington, Seattle, Washington 98195-6460.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wolfe
authors.affiliation: Department of Developmental and Molecular Biology (C.N.), Albert Einstein College of Medicine, and Department of Obstetrics and Gynecology (M.P.), Montefiore Medical Center, Bronx, New York 10461; Medical College of Wisconsin (J.D.), Milwaukee, Wisconsin 53226; Seattle Reproductive Medicine (T.F.), Seattle, Washington 98109; Department of Reproductive Endocrinology and Infertility (T.S.), University Hospitals Case Medical Center University Hospitals Ahuja Medical Center, Beachwood, Ohio 44106; Department of Pediatrics and Physiology (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Department of Obstetrics and Gynecology (Y.S., G.N.-P.), University of Washington, Seattle, Washington 98195-6460.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Neal-Perry
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D007031:Hypothalamus / Q000196:embryology / Q000254:growth & development / Q000503:physiopathology; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009490:Neurosecretory Systems / Q000196:embryology / Q000254:growth & development / Q000503:physiopathology*; D010053:Ovary / Q000196:embryology / Q000254:growth & development / Q000503:physiopathology; D010902:Pituitary Gland / Q000196:embryology / Q000254:growth & development / Q000503:physiopathology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology*; D012098:Reproduction / Q000502:physiology*; D012741:Sexual Maturation / Q000502:physiology; D013997:Time Factors; D014808:Vitamin D Deficiency / Q000503:physiopathology*; D014886:Weaning
chemical_list: D007986:Luteinizing Hormone