title: In utero exposure to low doses of environmental pollutants disrupts fetal ovarian development in sheep.
abstract: Epidemiological studies of the impact of environmental chemicals on reproductive health demonstrate consequences of exposure but establishing causative links requires animal models using 'real life' in utero exposures. We aimed to determine whether prolonged, low-dose, exposure of pregnant sheep to a mixture of environmental chemicals affects fetal ovarian development. Exposure of treated ewes (n = 7) to pollutants was maximized by surface application of processed sewage sludge to pasture. Control ewes (n = 10) were reared on pasture treated with inorganic fertilizer. Ovaries and blood were collected from fetuses (n = 15 control and n = 8 treated) on Day 110 of gestation for investigation of fetal endocrinology, ovarian follicle/oocyte numbers and ovarian proteome. Treated fetuses were 14% lighter than controls but fetal ovary weights were unchanged. Prolactin (48% lower) was the only measured hormone significantly affected by treatment. Treatment reduced numbers of growth differentiation factor (GDF9) and induced myeloid leukaemia cell differentiation protein (MCL1) positive oocytes by 25-26% and increased pro-apoptotic BAX by 65% and 42% of protein spots in the treated ovarian proteome were differently expressed compared with controls. Nineteen spots were identified and included proteins involved in gene expression/transcription, protein synthesis, phosphorylation and receptor activity. Fetal exposure to environmental chemicals, via the mother, significantly perturbs fetal ovarian development. If such effects are replicated in humans, premature menopause could be an outcome.
authors.affiliation: Department of Obstetrics and Gynaecology, Institute of Medical Sciences, CLSM, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. p.a.fowler@abdn.ac.uk
authors.forename: Paul A
authors.initials: PA
authors.lastname: Fowler
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Dorà
authors.forename: Helen
authors.initials: H
authors.lastname: McFerran
authors.forename: Maria R
authors.initials: MR
authors.lastname: Amezaga
authors.forename: David W
authors.initials: DW
authors.lastname: Miller
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lea
authors.forename: Phillip
authors.initials: P
authors.lastname: Cash
authors.forename: Alan S
authors.initials: AS
authors.lastname: McNeilly
authors.forename: Neil P
authors.initials: NP
authors.lastname: Evans
authors.forename: Corinne
authors.initials: C
authors.lastname: Cotinot
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sharpe
authors.forename: Stewart M
authors.initials: SM
authors.lastname: Rhind
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D020567:Fetal Weight / Q000187:drug effects; D018811:Maternal Exposure / Q000009:adverse effects*; D008431:Maternal-Fetal Exchange / Q000502:physiology; D008940:Mitotic Index; D008954:Models, Biological; D009865:Oocytes / Q000166:cytology / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D006080:Ovarian Follicle / Q000166:cytology / Q000187:drug effects; D010053:Ovary / Q000187:drug effects / Q000196:embryology* / Q000502:physiology; D011247:Pregnancy; D012722:Sewage / Q000009:adverse effects; D012756:Sheep / Q000196:embryology
chemical_list: D004785:Environmental Pollutants; D012722:Sewage