title: Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences.
abstract: Analgesics which affect prostaglandin (PG) pathways are used by most pregnant women. As germ cells (GC) undergo developmental and epigenetic changes in fetal life and are PG targets, we investigated if exposure of pregnant rats to analgesics (indomethacin or acetaminophen) affected GC development and reproductive function in resulting offspring (F1) or in the F2 generation. Exposure to either analgesic reduced F1 fetal GC number in both sexes and altered the tempo of fetal GC development sex-dependently, with delayed meiotic entry in oogonia but accelerated GC differentiation in males. These effects persisted in adult F1 females as reduced ovarian and litter size, whereas F1 males recovered normal GC numbers and fertility by adulthood. F2 offspring deriving from an analgesic-exposed F1 parent also exhibited sex-specific changes. F2 males exhibited normal reproductive development whereas F2 females had smaller ovaries and reduced follicle numbers during puberty/adulthood; as similar changes were found for F2 offspring of analgesic-exposed F1 fathers or mothers, we interpret this as potentially indicating an analgesic-induced change to GC in F1. Assuming our results are translatable to humans, they raise concerns that analgesic use in pregnancy could potentially affect fertility of resulting daughters and grand-daughters.
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Afshan
authors.initials: A
authors.lastname: Dean
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Sander
authors.initials: S
authors.lastname: van den Driesche
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Yili
authors.initials: Y
authors.lastname: Wang
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: McKinnell
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Sheila
authors.initials: S
authors.lastname: Macpherson
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Eddie
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Hazel
authors.initials: H
authors.lastname: Kinnell
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Pablo
authors.initials: P
authors.lastname: Hurtado-Gonzalez
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Chambers
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Kerrie
authors.initials: K
authors.lastname: Stevenson
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Elke
authors.initials: E
authors.lastname: Wolfinger
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Lenka
authors.initials: L
authors.lastname: Hrabalkova
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Calarrao
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Rosey Al
authors.initials: RA
authors.lastname: Bayne
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Casper P
authors.initials: CP
authors.lastname: Hagen
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Rod T
authors.initials: RT
authors.lastname: Mitchell
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sharpe
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation; D005260:Female; D005333:Fetus; D005854:Germ Cells / Q000166:cytology* / Q000187:drug effects*; D008297:Male; D018811:Maternal Exposure; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D012098:Reproduction / Q000187:drug effects*
chemical_list: D000700:Analgesics; D011453:Prostaglandins
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