Éditeur(s) : HAL CCSD
Résumé : International audience
Studies report that foetal exposure to paracetamol 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 (non-pharmaceutical) 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 foetal hormone signalling had been disturbed. Female offspring of paracetamol-exposed mothers had ovaries with diminished follicle reserve and reduced fertility. Foetal 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 foetuses 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
Toxicological Sciences

hal-01259211
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01259211
DOI : 10.1093/toxsci/kfv332
PUBMED : 26732887

Éditeur(s) : HAL CCSD BioScientifica
Résumé : International audience
Paracetamol/acetaminophen (N-Acetyl-p-Aminophenol; APAP) is the preferred analgesic for pain relief and fever during pregnancy. It has therefore caused concern that several studies have reported that prenatal exposure to APAP results in developmental alterations in both the reproductive tract and the brain. Genitals and nervous system of male mammals are actively masculinised during foetal development and early postnatal life by the combined actions of prostaglandins and androgens, resulting in the male-typical reproductive behaviour seen in adulthood. Both androgens and prostaglandins are known to be inhibited by APAP. Through intrauterine exposure experiments in C57BL/6 mice, we found that exposure to APAP decreased neuronal number in the sexually dimorphic nucleus (SDN) of the preoptic area (POA) in the anterior hypothalamus of male adult offspring. Likewise, exposure to the environmental pollutant and precursor of APAP, aniline, resulted in a similar reduction. Decrease in neuronal number in the SDN-POA is associated with reductions in male sexual behaviour. Consistent with the changes, male mice exposed in uteri to APAP exhibited changes in urinary marking behaviour as adults and had a less aggressive territorial display towards intruders of the same gender. Additionally, exposed males had reduced intromissions and ejaculations during mating with females in oestrus. Together, these data suggest that prenatal exposure to APAP may impair male sexual behaviour in adulthood by disrupting the sexual neurobehavioral programming. These findings add to the growing body of evidence suggesting the need to limit the widespread exposure and use of APAP by pregnant women.
ISSN: 1470-1626

hal-01560285
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560285
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560285/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560285/file/Prenatal%20exposures%20to%20paracetamol-accepted.pdf
DOI : 10.1530/REP-17-0165

Éditeur(s) : HAL CCSD
Résumé : Pregnancy is a sensitive and critical period for the development of the child and the health of adults-to-be. The biological and physiological adaptation of the body dealing physical and psychosocial stressors during this period may exert its effects in adulthood (and possibly over several generations). This delayed toxicity presupposes intrinsically the need to study the effects of exposure to environmental risk factors during fetal life using a holistic approach involving risk factors at both the micro (individual characteristics) and the macro level (physical and psycho-social context). Given the heterogeneity of the Breton territory in which this work was conducted, we explored whether the impact of social inequalities and the physical environment (air pollution) on birth outcomes (fetal growth and the risk of prematurity) could be modified according to an urban or rural place of residence. This work was based on data collected as part of the Breton mother-child cohort PELAGIE, which had included 3421 pregnant women between 2002- 2006. The anthropometric parameters and gestational age at birth were measured by medical personnel at delivery. We defined urban and rural areas according to the definition of “urban units” from the National Census Bureau (INSEE). The annual concentrations of air pollution (nitrogen dioxide (NO2)) were estimated using a land-use regression modeled at a 100 m scale and developed as part of an European project. Finally, neighbourhood deprivation was estimated using a composite index developed at census blocks level and whose use was legitimated over both urban and rural areas. Neighbourhood deprivation was associated with an increased risk of infants with fetal growth restriction, only for women living in rural areas. We also observed an increased risk of preterm birth associated with NO2 concentrations > 16.4 μg.m-3, only among women residing in urban areas. The associations between air pollution and fetal growth, although sex-specific, did not seem on the other hand, to vary significantly according to the urban-rural spectrum. This work confirms the need to explore the influence of both social and environmental inequalities on intrauterine development, and to assess the role of place-based factors, such as the urban-rural context, in shaping these inequalities.
La grossesse est une période sensible et déterminante pour le développement de l’enfant et l’état de santé à l’âge adulte. L'adaptation biologique et physiologique de l'organisme face à des « stresseurs » physiques et psychosociaux au cours de cette période peut ainsi exercer ses effets à l'âge adulte (et possiblement sur plusieurs générations). Cette toxicité différée suppose intrinsèquement la nécessité d’étudier les conséquences des expositions environnementales au cours de la vie foetale et ce suivant une approche holistique intégrant autant les facteurs de risque à des niveaux micro (caractéristiques individuelles) et macro (expositions physiques externes et contexte psycho-social). Etant donné l’hétérogénéité du territoire breton dans lequel s’inscrit ce travail de thèse, nous avons cherché à explorer l’impact des inégalités sociales et de l’environnement physique (pollution atmosphérique) sur l’issue de la grossesse (croissance foetale et risque de prématurité) indépendamment chez des femmes enceintes résidant dans des zones urbaines et rurales. Ce travail s’est appuyé sur les données issues de la cohorte bretonne mère-enfant PELAGIE, qui a inclus 3421 femmes enceintes entre 2002- 2006. Les paramètres anthropométriques et l’âge gestationnel à la naissance ont été renseignés à l’accouchement par le personnel médical. Le contexte urbain et rural breton a été caractérisé à partir de la définition des unités urbaines de l’INSEE. Les concentrations annuelles de pollution atmosphérique (dioxyde d’azote (NO2)) ont été modélisées à une échelle de 100 m à partir d’un modèle de "land-use regression" développé à l’échelle européenne. Enfin, le niveau socio-économique des IRIS a été estimé à l’aide d’un indice de désavantage social - construit à partir des données du recensement de l’INSEE et dont la validité et l’adaptabilité à des territoires à la fois urbains et ruraux a été examinée au préalable. Nos résultats suggèrent une influence délétère d’un contexte de vie socioéconomique défavorable sur la croissance intra-utérine, spécifiquement chez les femmes résidant en milieu rural. Nous avons également observé une augmentation du risque de prématurité associée à des niveaux > 16.4 μg.m-3 de NO2 dans l’air, à l’inverse, uniquement chez les femmes résidant dans des zones urbaines. Les associations entre l’exposition à la pollution atmosphérique et les marqueurs de la croissance intra-utérine, bien que sexe-spécifiques, ne semblent en revanche pas varier sensiblement suivant le gradient urbain-rural. Ce travail confirme la nécessité d’évaluer l’influence des inégalités sociales et environnementales sur le développement intra-utérin et de considérer l’importance et le rôle du contexte de vie, notamment urbain-rural, dans la formation de ces inégalités.
https://tel.archives-ouvertes.fr/tel-01308518

NNT : 2015REN1B010
tel-01308518
https://tel.archives-ouvertes.fr/tel-01308518
https://tel.archives-ouvertes.fr/tel-01308518/document
https://tel.archives-ouvertes.fr/tel-01308518/file/BERTIN_M--lanie.pdf

Éditeur(s) : HAL CCSD
Résumé : International audience
Industrial use of aniline is increasing worldwide with production estimated to surpass 5.6 million metric tons in 2016. Exposure to aniline occurs via air, diet and water augmenting the risk of exposing a large number of individuals. Early observations suggest that aniline is metabolised to paracetamol/acetaminophen, likely explaining the omnipresence of low concentrations of paracetamol in European populations. This is of concern as recent studies implicate paracetamol as a disrupter of reproduction. Here we show through steroidogenic profiling that exposure to aniline led to increased levels of the Δ4 steroids, suggesting that the activity of CYP21 was decreased. By contrast, paracetamol decreased levels of androgens likely through inhibition of CYP17A1 activity. We confirm that aniline in vivo is rapidly converted to paracetamol by the liver. Intrauterine exposure to aniline and paracetamol in environmental and pharmaceutical relevant doses resulted in shortening of the anogenital distance in mice, a sensitive marker of fetal androgen levels that in humans is associated with reproductive malformations and later life reproductive disorders. In conclusion, our results provide evidence for a scenario where aniline, through its conversion into anti-androgenic paracetamol, impairs male reproductive development
Toxicological Sciences: An Official Journal of the Society of Toxicology

hal-01187305
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187305
DOI : 10.1093/toxsci/kfv179
PUBMED : 26259604

Éditeur(s) : HAL CCSD
Résumé : International audience
Paracetamol and NSAIDs, in particular acetylsalicylic acid (aspirin) and ibuprofen, are among the most used and environmentally released pharmaceutical drugs. The differences in international trends in the sale and consumption of mild analgesics reflect differences in marketing, governmental policies, habits, accessibility, disease patterns and the age distribution of each population. Biomonitoring indicates ubiquitous and high human exposure to paracetamol and to salicylic acid, which is the main metabolite of acetylsalicylic acid. Furthermore, evidence suggests that analgesics can have endocrine disruptive properties capable of altering animal and human reproductive function from fetal life to adulthood in both sexes. Medical and public awareness about these health concerns should be increased, particularly among pregnant women.
Nature Reviews Endocrinology

hal-01359566
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359566
DOI : 10.1038/nrendo.2016.55
PUBMED : 27150289