Intrauterine exposure to paracetamol and aniline impairs female reproductive development by reducing follicle reserves and fertility

Jacob Bak Holm; Severine Mazaud-Guittot; Niels Banhos Danneskiold-Samsøe; Clementine Chalmey; Benjamin Anderschou Holbech Jensen; Mette Marie Nørregård; Cecilie Hurup Hansen; Bjarne Styrishave; Terje Svingen; Anne Marie Vinggaard; Holger Martin Koch; Josephine Bowles; Peter Koopman; Bernard Jégou; Karsten Kristiansen; David Møbjerg Kristensen

doi:10.1093/toxsci/kfv332

Intrauterine exposure to paracetamol and aniline impairs female reproductive development by reducing follicle reserves and fertility

Jacob Bak Holm, Severine Mazaud-Guittot, Niels Banhos Danneskiold-Samsøe, Clementine Chalmey, Benjamin Anderschou Holbech Jensen, Mette Marie Nørregård, Cecilie Hurup Hansen, Bjarne Styrishave, Terje Svingen, Anne Marie Vinggaard, Holger Martin Koch, Josephine Bowles, Peter Koopman, Bernard Jégou, Karsten Kristiansen, David Møbjerg Kristensen

Genome Research and Molecular Bio Medicine

36 Citations (Scopus)

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.

Original language	English
Journal	Toxicological Sciences
Volume	150
Issue number	1
Pages (from-to)	178-189
Number of pages	12
ISSN	1096-6080
DOIs	https://doi.org/10.1093/toxsci/kfv332
Publication status	Published - 1 Mar 2016

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Holm, J. B., Mazaud-Guittot, S., Danneskiold-Samsøe, N. B., Chalmey, C., Jensen, B. A. H., Nørregård, M. M., Hansen, C. H., Styrishave, B., Svingen, T., Vinggaard, A. M., Koch, H. M., Bowles, J., Koopman, P., Jégou, B., Kristiansen, K., & Kristensen, D. M. (2016). Intrauterine exposure to paracetamol and aniline impairs female reproductive development by reducing follicle reserves and fertility. Toxicological Sciences, 150(1), 178-189. https://doi.org/10.1093/toxsci/kfv332

Intrauterine exposure to paracetamol and aniline impairs female reproductive development by reducing follicle reserves and fertility. / Holm, Jacob Bak; Mazaud-Guittot, Severine; Danneskiold-Samsøe, Niels Banhos et al.
In: Toxicological Sciences, Vol. 150, No. 1, 01.03.2016, p. 178-189.

Research output: Contribution to journal › Journal article › Research › peer-review

Holm, JB, Mazaud-Guittot, S, Danneskiold-Samsøe, NB, Chalmey, C, Jensen, BAH, Nørregård, MM, Hansen, CH, Styrishave, B, Svingen, T, Vinggaard, AM, Koch, HM, Bowles, J, Koopman, P, Jégou, B, Kristiansen, K & Kristensen, DM 2016, 'Intrauterine exposure to paracetamol and aniline impairs female reproductive development by reducing follicle reserves and fertility', Toxicological Sciences, vol. 150, no. 1, pp. 178-189. https://doi.org/10.1093/toxsci/kfv332

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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.",

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AU - Chalmey, Clementine

AU - Jensen, Benjamin Anderschou Holbech

AU - Nørregård, Mette Marie

AU - Hansen, Cecilie Hurup

AU - Styrishave, Bjarne

AU - Svingen, Terje

AU - Vinggaard, Anne Marie

AU - Koch, Holger Martin

AU - Bowles, Josephine

AU - Koopman, Peter

AU - Jégou, Bernard

AU - Kristiansen, Karsten

AU - Kristensen, David Møbjerg

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N2 - 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.

AB - 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.

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Intrauterine exposure to paracetamol and aniline impairs female reproductive development by reducing follicle reserves and fertility

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