Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility

Holm, Jacob Bak, Mazaud-Guittot, Severine, Danneskiold-Samsoe, Niels Banhos, Chalmey, Clementine, Jensen, Benjamin, Norregard, Mette Marie, Hansen, Cecilie Hurup, Styrishave, Bjarne, Svingen, Terje, Vinggaard, Anne Marie, Koch, Holger Martin, Bowles, Josephine, Koopman, Peter, Jegou, Bernard, Kristiansen, Karsten and Kristensen, David Mobjerg (2016) Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility. Toxicological Sciences, 150 1: 178-189. doi:10.1093/toxsci/kfv332


Author Holm, Jacob Bak
Mazaud-Guittot, Severine
Danneskiold-Samsoe, Niels Banhos
Chalmey, Clementine
Jensen, Benjamin
Norregard, Mette Marie
Hansen, Cecilie Hurup
Styrishave, Bjarne
Svingen, Terje
Vinggaard, Anne Marie
Koch, Holger Martin
Bowles, Josephine
Koopman, Peter
Jegou, Bernard
Kristiansen, Karsten
Kristensen, David Mobjerg
Title Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility
Journal name Toxicological Sciences   Check publisher's open access policy
ISSN 1096-6080
1096-0929
Publication date 2016-03-01
Year available 2016
Sub-type Article (original research)
DOI 10.1093/toxsci/kfv332
Open Access Status Not Open Access
Volume 150
Issue 1
Start page 178
End page 189
Total pages 12
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject 3005 Toxicology
Abstract Studies report that fetal exposure to paracetamol/acetaminophen by maternal consumption can interfere with male reproductive development. Moreover, recent biomonitoring data report widespread presence of paracetamol in German and Danish populations, suggesting exposure via secondary (nonpharmaceutical) sources, such as metabolic conversion from the ubiquitous industrial compound aniline. In this study, we investigated the extent to which paracetamol and aniline can interfere with female reproductive development. Intrauterine exposure to paracetamol by gavage of pregnant dams resulted in shortening of the anogenital distance in adult offspring, suggesting that fetal hormone signaling had been disturbed. Female offspring of paracetamol-exposed mothers had ovaries with diminished follicle reserve and reduced fertility. Fetal gonads of exposed animals had also reduced gonocyte numbers, suggesting that the reduced follicle count in adults could be due to early disruption of germ cell development. However, ex vivo cultures of ovaries from 12.5 days post coitum fetuses showed no decrease in proliferation or expression following exposure to paracetamol. This suggests that the effect of paracetamol occurs prior to this developmental stage. Accordingly, using embryonic stem cells as a proxy for primordial germ cells we show that paracetamol is an inhibitor of cellular proliferation, but without cytotoxic effects. Collectively, our data show that intrauterine exposure to paracetamol at levels commonly observed in pregnant women, as well as its precursor aniline, may block primordial germ cell proliferation, ultimately leading to reduced follicle reserves and compromised reproductive capacity later in life.
Formatted abstract
Studies report that fetal exposure to paracetamol/acetaminophen by maternal consumption can interfere with male reproductive development. Moreover, recent biomonitoring data report widespread presence of paracetamol in German and Danish populations, suggesting exposure via secondary (nonpharmaceutical) sources, such as metabolic conversion from the ubiquitous industrial compound aniline. In this study, we investigated the extent to which paracetamol and aniline can interfere with female reproductive development. Intrauterine exposure to paracetamol by gavage of pregnant dams resulted in shortening of the anogenital distance in adult offspring, suggesting that fetal hormone signaling had been disturbed. Female offspring of paracetamol-exposed mothers had ovaries with diminished follicle reserve and reduced fertility. Fetal gonads of exposed animals had also reduced gonocyte numbers, suggesting that the reduced follicle count in adults could be due to early disruption of germ cell development. However, ex vivo cultures of ovaries from 12.5 days post coitum fetuses showed no decrease in proliferation or expression following exposure to paracetamol. This suggests that the effect of paracetamol occurs prior to this developmental stage. Accordingly, using embryonic stem cells as a proxy for primordial germ cells we show that paracetamol is an inhibitor of cellular proliferation, but without cytotoxic effects. Collectively, our data show that intrauterine exposure to paracetamol at levels commonly observed in pregnant women, as well as its precursor aniline, may block primordial germ cell proliferation, ultimately leading to reduced follicle reserves and compromised reproductive capacity later in life.
Keyword Paracetamol
Acetaminophen
Reproduction
Aniline
Intrauterine exposure
Follicle reserves
Development
Endocrine-Disrupting Chemicals
Anti-Mullerian Hormone
Fetal Testis
Germ-Cells
N-Acetyl-4-Aminophenol Paracetamol
Sexual-Differentiation
Acetylsalicylic-Acid
Anogenital Distance
Mild Analgesics
Urine Samples
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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