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Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model
CONTEXT: Acetaminophen (APAP, paracetamol) is widely used by pregnant women. Although long considered safe, growing evidence indicates that APAP is an endocrine disruptor since in utero exposure may be associated with a higher risk of male genital tract abnormalities. In rodents, fetal exposure has...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113793/ https://www.ncbi.nlm.nih.gov/pubmed/35147701 http://dx.doi.org/10.1210/clinem/dgac080 |
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author | Lecante, Laetitia L Leverrier-Penna, Sabrina Gicquel, Thomas Giton, Frank Costet, Nathalie Desdoits-Lethimonier, Christèle Lesné, Laurianne Fromenty, Bernard Lavoué, Vincent Rolland, Antoine D Mazaud-Guittot, Séverine |
author_facet | Lecante, Laetitia L Leverrier-Penna, Sabrina Gicquel, Thomas Giton, Frank Costet, Nathalie Desdoits-Lethimonier, Christèle Lesné, Laurianne Fromenty, Bernard Lavoué, Vincent Rolland, Antoine D Mazaud-Guittot, Séverine |
author_sort | Lecante, Laetitia L |
collection | PubMed |
description | CONTEXT: Acetaminophen (APAP, paracetamol) is widely used by pregnant women. Although long considered safe, growing evidence indicates that APAP is an endocrine disruptor since in utero exposure may be associated with a higher risk of male genital tract abnormalities. In rodents, fetal exposure has long-term effects on the reproductive function of female offspring. Human studies have also suggested harmful APAP exposure effects. OBJECTIVE: Given that disruption of fetal ovarian development may impact women’s reproductive health, we investigated the effects of APAP on fetal human ovaries in culture. DESIGN AND SETTING: Human ovarian fragments from 284 fetuses aged 7 to 12 developmental weeks (DW) were cultivated ex vivo for 7 days in the presence of human-relevant concentrations of APAP (10(−8) to 10(−3) M) or vehicle control. MAIN OUTCOME MEASURES: Outcomes included examination of postculture tissue morphology, cell viability, apoptosis, and quantification of hormones, APAP, and APAP metabolites in conditioned culture media. RESULTS: APAP reduced the total cell number specifically in 10- to 12-DW ovaries, induced cell death, and decreased KI67-positive cell density independently of fetal age. APAP targeted subpopulations of germ cells and disrupted human fetal ovarian steroidogenesis, without affecting prostaglandin or inhibin B production. Human fetal ovaries were able to metabolize APAP. CONCLUSIONS: Our data indicate that APAP can impact first trimester human fetal ovarian development, especially during a 10- to 12-DW window of heightened sensitivity. Overall, APAP behaves as an endocrine disruptor in the fetal human ovary. |
format | Online Article Text |
id | pubmed-9113793 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-91137932022-05-18 Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model Lecante, Laetitia L Leverrier-Penna, Sabrina Gicquel, Thomas Giton, Frank Costet, Nathalie Desdoits-Lethimonier, Christèle Lesné, Laurianne Fromenty, Bernard Lavoué, Vincent Rolland, Antoine D Mazaud-Guittot, Séverine J Clin Endocrinol Metab Clinical Research Article CONTEXT: Acetaminophen (APAP, paracetamol) is widely used by pregnant women. Although long considered safe, growing evidence indicates that APAP is an endocrine disruptor since in utero exposure may be associated with a higher risk of male genital tract abnormalities. In rodents, fetal exposure has long-term effects on the reproductive function of female offspring. Human studies have also suggested harmful APAP exposure effects. OBJECTIVE: Given that disruption of fetal ovarian development may impact women’s reproductive health, we investigated the effects of APAP on fetal human ovaries in culture. DESIGN AND SETTING: Human ovarian fragments from 284 fetuses aged 7 to 12 developmental weeks (DW) were cultivated ex vivo for 7 days in the presence of human-relevant concentrations of APAP (10(−8) to 10(−3) M) or vehicle control. MAIN OUTCOME MEASURES: Outcomes included examination of postculture tissue morphology, cell viability, apoptosis, and quantification of hormones, APAP, and APAP metabolites in conditioned culture media. RESULTS: APAP reduced the total cell number specifically in 10- to 12-DW ovaries, induced cell death, and decreased KI67-positive cell density independently of fetal age. APAP targeted subpopulations of germ cells and disrupted human fetal ovarian steroidogenesis, without affecting prostaglandin or inhibin B production. Human fetal ovaries were able to metabolize APAP. CONCLUSIONS: Our data indicate that APAP can impact first trimester human fetal ovarian development, especially during a 10- to 12-DW window of heightened sensitivity. Overall, APAP behaves as an endocrine disruptor in the fetal human ovary. Oxford University Press 2022-02-11 /pmc/articles/PMC9113793/ /pubmed/35147701 http://dx.doi.org/10.1210/clinem/dgac080 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Clinical Research Article Lecante, Laetitia L Leverrier-Penna, Sabrina Gicquel, Thomas Giton, Frank Costet, Nathalie Desdoits-Lethimonier, Christèle Lesné, Laurianne Fromenty, Bernard Lavoué, Vincent Rolland, Antoine D Mazaud-Guittot, Séverine Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model |
title | Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model |
title_full | Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model |
title_fullStr | Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model |
title_full_unstemmed | Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model |
title_short | Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model |
title_sort | acetaminophen (apap, paracetamol) interferes with the first trimester human fetal ovary development in an ex vivo model |
topic | Clinical Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113793/ https://www.ncbi.nlm.nih.gov/pubmed/35147701 http://dx.doi.org/10.1210/clinem/dgac080 |
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