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

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 an...

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Bibliographic Details
Published in:Scientific reports 2016-01, Vol.6 (1), p.19789, Article 19789
Main Authors: Dean, Afshan, van den Driesche, Sander, Wang, Yili, McKinnell, Chris, Macpherson, Sheila, Eddie, Sharon L, Kinnell, Hazel, Hurtado-Gonzalez, Pablo, Chambers, Tom J, Stevenson, Kerrie, Wolfinger, Elke, Hrabalkova, Lenka, Calarrao, Ana, Bayne, Rosey Al, Hagen, Casper P, Mitchell, Rod T, Anderson, Richard A, Sharpe, Richard M
Format: Article
Language:English
Subjects:
Acetaminophen
Analgesics
Analgesics - pharmacology
Animals
Cell Differentiation
Female
Fertility
Fetus
Fetuses
Germ cells
Germ Cells - cytology
Germ Cells - drug effects
Indomethacin
Male
Males
Maternal Exposure
Meiosis
Offspring
Oogonia
Ovaries
Phenotype
Pregnancy
Prenatal Exposure Delayed Effects
Prostaglandins - metabolism
Puberty
Rats
Reproduction - drug effects
Rodents
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep19789