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Mol. Hum. Reprod. Advance Access originally published online on April 23, 2008
Molecular Human Reproduction 2008 14(5):269-280; doi:10.1093/molehr/gan020
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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In utero exposure to low doses of environmental pollutants disrupts fetal ovarian development in sheep

Paul A. Fowler1,9, Natalie J. Dorà1, Helen McFerran1, Maria R. Amezaga1, David W. Miller3, Richard G. Lea4, Phillip Cash5, Alan S. McNeilly2, Neil P. Evans6, Corinne Cotinot7, Richard M. Sharpe2 and Stewart M. Rhind8

1Department of Obstetrics and Gynaecology, Institute of Medical Sciences, CLSM, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK 2MRC Human Reproductive Sciences Unit, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK 3School of Veterinary and Biomedical Sciences, Murdoch University, Murdoch, WA 6150, Australia 4School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Leicestershire LE12 5RD, UK 5Department of Medical Microbiology, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK 6Division of Cell Sciences, Institute of Comparative Medicine, University of Glasgow Veterinary School, Glasgow G61 1QH, UK 7INRA, UMR 1198, Biologie du Développement et de la Reproduction, 78350, Jouy-en-Josas, France 8 Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK

9 Correspondence address. Tel: +44-1224-552633; Fax: +44-1224-555844; E-mail: p.a.fowler{at}abdn.ac.uk

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.

Key words: environmental chemicals/fetal development/oocyte/granulosa cell/sewage sludge

Submitted on February 26, 2008; resubmitted on March 28, 2008; accepted on April 15, 2008.


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