Intergenerational effects on fertility in male and female mice after chronic exposure to environmental doses of NSAIDs and 17α-ethinylestradiol mixtures

Pascal Philibert; Isabelle Stévant; Stéphanie Déjardin; Mélissa Girard; Eli Sellem; Quentin Durix; Aurélie Messager; Anne Alicia Gonzalez; Xavier Mialhe; Alain Pruvost; Francis Poulat; Brigitte Boizet-Bonhoure

doi:10.1016/j.fct.2023.114085

Intergenerational effects on fertility in male and female mice after chronic exposure to environmental doses of NSAIDs and 17α-ethinylestradiol mixtures

Pascal Philibert, Isabelle Stévant, Stéphanie Déjardin, Mélissa Girard, Eli Sellem, Quentin Durix, Aurélie Messager, Anne Alicia Gonzalez, Xavier Mialhe, Alain Pruvost, Francis Poulat, Brigitte Boizet-Bonhoure

The Mina and Everard Goodman Faculty of Life Sciences

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) and 17α-ethinylestradiol (EE2) are extensively used in human and veterinary medicine. Due to their partial removal by wastewater treatment plants, they are frequent environmental contaminants, particularly in drinking water. Here, we investigated the adverse outcomes of chronic exposure to mixtures of NSAIDs (ibuprofen, 2hydroxy-ibuprofen, diclofenac) and EE2 at two environmentally relevant doses in drinking water, on the reproductive organ development and fertility in F1-exposed male and female mice and in their F2 offspring. In male and female F1 mice, which were exposed to these mixtures, reproductive organ maturation, estrous cyclicity, and spermiogenesis were altered. These defects were observed also in F2 animals, in addition to some specific sperm parameter alterations in F2 males. Transcriptomic analysis revealed significant changes in gene expression patterns and associated pathways implicated in testis and ovarian physiology. Chronic exposure of mice to NSAID and EE2 mixtures at environmental doses intergenerationally affected male and female fertility (i.e. total number of pups and time between litters). Our study provides new insights into the adverse effects of these pharmaceuticals on the reproductive health and will facilitate the implementation of a future regulatory environmental risk assessment of NSAIDs and EE2 for human health.

Original language	English
Article number	114085
Journal	Food and Chemical Toxicology
Volume	182
DOIs	https://doi.org/10.1016/j.fct.2023.114085
State	Published - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Ltd

Funding

We are grateful to the staff (particularly Elodie Belan, Karim Mesbah) of the IGH/IGF animal care facility. Montpellier GenomiX (MGX) acknowledges financial support from France Génomique National infrastructure , funded as part of “Investissement d’Avenir” program managed by Agence Nationale pour la Recherche (contract ANR-10-INBS-09 ). We also thank Dr Marie-Pierre Blanchard and Amélie Sarrazin from the IGH Imaging facility (MRI Montpellier) for their help with microscopy analyses, and Drs Nelly Pirot and Florence Bernex from the Réseau d’Histologie de Montpellier (RHEM) for advice on histology staining and analysis. This project was supported by the French National Research Program for Environmental and Occupational Health of ANSES ( PNREST ANSES, 2020/01/025 ) to B. B.-B, and by the CNRS and University of Montpellier . This project was supported by the French National Research Program for Environmental and Occupational Health of ANSES (PNREST ANSES, 2020/01/025) to B. B.-B, and by the CNRS and University of Montpellier.We are grateful to the staff (particularly Elodie Belan, Karim Mesbah) of the IGH/IGF animal care facility. Montpellier GenomiX (MGX) acknowledges financial support from France Génomique National infrastructure, funded as part of “Investissement d'Avenir” program managed by Agence Nationale pour la Recherche (contract ANR-10-INBS-09). We also thank Dr Marie-Pierre Blanchard and Amélie Sarrazin from the IGH Imaging facility (MRI Montpellier) for their help with microscopy analyses, and Drs Nelly Pirot and Florence Bernex from the Réseau d'Histologie de Montpellier (RHEM) for advice on histology staining and analysis.

Funders	Funder number
University of Montpellier.We
Agence Nationale de la Recherche	ANR-10-INBS-09
Centre National de la Recherche Scientifique
Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail	2020/01/025
Université de Montpellier

Keywords

EE2
Environmental doses
Fertility
Gonad transcriptome
Mice
NSAIDs
Ovary
Testis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.fct.2023.114085

Cite this

Philibert, P., Stévant, I., Déjardin, S., Girard, M., Sellem, E., Durix, Q., Messager, A., Gonzalez, A. A., Mialhe, X., Pruvost, A., Poulat, F., & Boizet-Bonhoure, B. (2023). Intergenerational effects on fertility in male and female mice after chronic exposure to environmental doses of NSAIDs and 17α-ethinylestradiol mixtures. Food and Chemical Toxicology, 182, Article 114085. https://doi.org/10.1016/j.fct.2023.114085

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abstract = "Non-steroidal anti-inflammatory drugs (NSAIDs) and 17α-ethinylestradiol (EE2) are extensively used in human and veterinary medicine. Due to their partial removal by wastewater treatment plants, they are frequent environmental contaminants, particularly in drinking water. Here, we investigated the adverse outcomes of chronic exposure to mixtures of NSAIDs (ibuprofen, 2hydroxy-ibuprofen, diclofenac) and EE2 at two environmentally relevant doses in drinking water, on the reproductive organ development and fertility in F1-exposed male and female mice and in their F2 offspring. In male and female F1 mice, which were exposed to these mixtures, reproductive organ maturation, estrous cyclicity, and spermiogenesis were altered. These defects were observed also in F2 animals, in addition to some specific sperm parameter alterations in F2 males. Transcriptomic analysis revealed significant changes in gene expression patterns and associated pathways implicated in testis and ovarian physiology. Chronic exposure of mice to NSAID and EE2 mixtures at environmental doses intergenerationally affected male and female fertility (i.e. total number of pups and time between litters). Our study provides new insights into the adverse effects of these pharmaceuticals on the reproductive health and will facilitate the implementation of a future regulatory environmental risk assessment of NSAIDs and EE2 for human health.",

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Philibert, P, Stévant, I, Déjardin, S, Girard, M, Sellem, E, Durix, Q, Messager, A, Gonzalez, AA, Mialhe, X, Pruvost, A, Poulat, F & Boizet-Bonhoure, B 2023, 'Intergenerational effects on fertility in male and female mice after chronic exposure to environmental doses of NSAIDs and 17α-ethinylestradiol mixtures', Food and Chemical Toxicology, vol. 182, 114085. https://doi.org/10.1016/j.fct.2023.114085

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T1 - Intergenerational effects on fertility in male and female mice after chronic exposure to environmental doses of NSAIDs and 17α-ethinylestradiol mixtures

AU - Philibert, Pascal

AU - Stévant, Isabelle

AU - Déjardin, Stéphanie

AU - Girard, Mélissa

AU - Sellem, Eli

AU - Durix, Quentin

AU - Messager, Aurélie

AU - Gonzalez, Anne Alicia

AU - Mialhe, Xavier

AU - Pruvost, Alain

AU - Poulat, Francis

AU - Boizet-Bonhoure, Brigitte

PY - 2023/12

Y1 - 2023/12

N2 - Non-steroidal anti-inflammatory drugs (NSAIDs) and 17α-ethinylestradiol (EE2) are extensively used in human and veterinary medicine. Due to their partial removal by wastewater treatment plants, they are frequent environmental contaminants, particularly in drinking water. Here, we investigated the adverse outcomes of chronic exposure to mixtures of NSAIDs (ibuprofen, 2hydroxy-ibuprofen, diclofenac) and EE2 at two environmentally relevant doses in drinking water, on the reproductive organ development and fertility in F1-exposed male and female mice and in their F2 offspring. In male and female F1 mice, which were exposed to these mixtures, reproductive organ maturation, estrous cyclicity, and spermiogenesis were altered. These defects were observed also in F2 animals, in addition to some specific sperm parameter alterations in F2 males. Transcriptomic analysis revealed significant changes in gene expression patterns and associated pathways implicated in testis and ovarian physiology. Chronic exposure of mice to NSAID and EE2 mixtures at environmental doses intergenerationally affected male and female fertility (i.e. total number of pups and time between litters). Our study provides new insights into the adverse effects of these pharmaceuticals on the reproductive health and will facilitate the implementation of a future regulatory environmental risk assessment of NSAIDs and EE2 for human health.

AB - Non-steroidal anti-inflammatory drugs (NSAIDs) and 17α-ethinylestradiol (EE2) are extensively used in human and veterinary medicine. Due to their partial removal by wastewater treatment plants, they are frequent environmental contaminants, particularly in drinking water. Here, we investigated the adverse outcomes of chronic exposure to mixtures of NSAIDs (ibuprofen, 2hydroxy-ibuprofen, diclofenac) and EE2 at two environmentally relevant doses in drinking water, on the reproductive organ development and fertility in F1-exposed male and female mice and in their F2 offspring. In male and female F1 mice, which were exposed to these mixtures, reproductive organ maturation, estrous cyclicity, and spermiogenesis were altered. These defects were observed also in F2 animals, in addition to some specific sperm parameter alterations in F2 males. Transcriptomic analysis revealed significant changes in gene expression patterns and associated pathways implicated in testis and ovarian physiology. Chronic exposure of mice to NSAID and EE2 mixtures at environmental doses intergenerationally affected male and female fertility (i.e. total number of pups and time between litters). Our study provides new insights into the adverse effects of these pharmaceuticals on the reproductive health and will facilitate the implementation of a future regulatory environmental risk assessment of NSAIDs and EE2 for human health.

KW - EE2

KW - Environmental doses

KW - Fertility

KW - Gonad transcriptome

KW - Mice

KW - NSAIDs

KW - Ovary

KW - Testis

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SN - 0278-6915

VL - 182

JO - Food and Chemical Toxicology

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M1 - 114085

ER -

Intergenerational effects on fertility in male and female mice after chronic exposure to environmental doses of NSAIDs and 17α-ethinylestradiol mixtures

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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Cite this