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

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

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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.

Original languageEnglish
Article number19789
Number of pages12
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 27 Jan 2016

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Germ Cells
Analgesics
Nuclear Family
Prostaglandins
Fertility
Cell Count
Oogonia
Litter Size
Sexual Development
Puberty
Acetaminophen
Epigenomics
Fathers
Indomethacin
Pregnant Women
Cell Differentiation
Ovary
Mothers
Pregnancy

Cite this

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. / Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences. In: Scientific Reports. 2016 ; Vol. 6.
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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.",
author = "Afshan Dean and {van den Driesche}, Sander and Yili Wang and Chris McKinnell and Sheila Macpherson and Eddie, {Sharon L} and Hazel Kinnell and Pablo Hurtado-Gonzalez and Chambers, {Tom J} and Kerrie Stevenson and Elke Wolfinger and Lenka Hrabalkova and Ana Calarrao and Bayne, {Rosey Al} and Hagen, {Casper P} and Mitchell, {Rod T} and Anderson, {Richard A} and Sharpe, {Richard M}",
year = "2016",
month = "1",
day = "27",
doi = "10.1038/srep19789",
language = "English",
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Dean, A, van den Driesche, S, Wang, Y, McKinnell, C, Macpherson, S, Eddie, SL, Kinnell, H, Hurtado-Gonzalez, P, Chambers, TJ, Stevenson, K, Wolfinger, E, Hrabalkova, L, Calarrao, A, Bayne, RA, Hagen, CP, Mitchell, RT, Anderson, RA & Sharpe, RM 2016, 'Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences', Scientific Reports, vol. 6, 19789. https://doi.org/10.1038/srep19789

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

In: Scientific Reports, Vol. 6, 19789, 27.01.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences

AU - Dean, Afshan

AU - van den Driesche, Sander

AU - Wang, Yili

AU - McKinnell, Chris

AU - Macpherson, Sheila

AU - Eddie, Sharon L

AU - Kinnell, Hazel

AU - Hurtado-Gonzalez, Pablo

AU - Chambers, Tom J

AU - Stevenson, Kerrie

AU - Wolfinger, Elke

AU - Hrabalkova, Lenka

AU - Calarrao, Ana

AU - Bayne, Rosey Al

AU - Hagen, Casper P

AU - Mitchell, Rod T

AU - Anderson, Richard A

AU - Sharpe, Richard M

PY - 2016/1/27

Y1 - 2016/1/27

N2 - 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.

AB - 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.

U2 - 10.1038/srep19789

DO - 10.1038/srep19789

M3 - Article

C2 - 26813099

VL - 6

JO - Nature Scientific Reports

JF - Nature Scientific Reports

SN - 2045-2322

M1 - 19789

ER -