Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences.

Afshan Dean,Lenka Hrabalkova,Kerrie Stevenson,Hazel Kinnell,Richard A Anderson,Yili Wang,Tom J Chambers,Rosey Al Bayne,Sheila Macpherson,Rod T Mitchell,Ana Calarrao,Pablo Hurtado-Gonzalez,Chris Mckinnell,Elke Wolfinger,Sharon L Eddie,Richard M Sharpe,Casper P Hagen,Sander Van Den Driesche

doi:10.1038/srep19789

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.

Highlights

IntroductionAcetaminophen is available over-the-counter (OTC), and is incorporated into a range of OTC medicines
MRC Centre for Reproductive Health, The Queen’s Medical Research Institute University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. †Present address: Research Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ. §Present address: Centre for Cancer Research and Cell Biology, Queen’s University Belfast. ‡Present address: Department of Growth and Reproduction, Rigshospitalet, Faculty of Health and Medical Science, University of Copenhagen, Denmark. *These authors contributed to this work
There are no reports on altered germ cell number or function in either men or women but we have previously reported expression of the prostaglandin (PG) synthetic enzymes cyclooxygenase-2 (COX2) and PTGES and PG receptors in oocytes in the human fetal ovary, and that prostaglandins may be involved in human oocyte development prior to primordial follicle formation[22]

Summary

Introduction

Acetaminophen is available over-the-counter (OTC), and is incorporated into a range of OTC medicines Many of these issues apply to non-steroidal anti-inflammatory compounds (NSAIDs) such as ibuprofen, aspirin and indomethacin, as some of these are available OTC and are widely used in pregnancy, even if they are not recommended for such use other than on medical advice[13]. The present study shows that COX2 and PG receptors are present in fetal germ and/or somatic cells of both male and female rats, suggesting that PGs might play a common and conserved role in fetal germ cell development. This observation prompted us to investigate the effects of analgesic exposure on germ cell development in male and female rats. Our results show that fetal germ cell development in either sex is affected by analgesic exposure and this results in reproductive changes, in exposed individuals, and in F2 progeny which they later give rise to

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Conclusion