Paternal Epigenetic Inheritance: A man’s life experiences may impact health of his unborn children and grandchildren

Informations projet

PATER

N° de convention de subvention: 805057

DOI

10.3030/805057

Projet clôturé

Date de signature de la CE 12 Decembre 2018

Date de début 1 Janvier 2019

Date de fin 30 Juin 2025

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 500 000,00

Contribution de l’UE

€ 1 500 000,00

Coordonné par

STOCKHOLMS UNIVERSITET
Sweden

Periodic Reporting for period 4 - PATER (Paternal Epigenetic Inheritance: A man’s life experiences may impact health of his unborn children and grandchildren)

Période du rapport: 2023-07-01 au 2025-06-30

Résumé du contexte et des objectifs généraux du projet

Epigenetic inheritance may not only occur in plants but also in vertebrates including mammals. While the effects of maternal lifestyle and in utero exposures have been extensively studied, paternal epigenetic inheritance is a novel research field, particularly in the context of chemical exposures. Many environmental pollutants exhibit anti-androgenic activity. Despite the crucial role of androgens in spermatogenesis, the impact of adult anti-androgen exposure on the sperm epigenome and offspring phenotype remains poorly understood.

At conception, gametes deliver not only genetic material but also epigenetic information that can reflect parental exposures and life experiences. Interest in paternal epigenetic transmission arose from epidemiological studies linking paternal smoking to increased body mass index (BMI) in sons and showing associations between grandfathers’ food availability and mortality in grandsons. Furthermore, children of older fathers have an elevated risk of various neuropsychiatric disorders. Notably, age-related changes in sperm DNA methylation at genes implicated in these disorders have been reported.

The overall objective of this project is to determine whether, and by what mechanisms, male life experiences such as exposure to anti-androgenic pollutants affect offspring through paternal epigenetic inheritance. We hypothesize that common anti-androgenic pollutants can induce alterations in sperm biomolecules, which are transmitted during embryogenesis and subsequently influence offspring phenotype via epigenetic mechanisms.

Our studies provide compelling cross-species evidence of paternal epigenetic inheritance. In frogs, we observed that paternal exposures had significant effects, highlighting potential ecological and evolutionary implications. In mice, exposure of adult males to an anti-androgenic compound found in plastics altered the sperm epigenome and reprogrammed immune and metabolic systems in offspring across multiple generations. These results carry important public health implications, supporting the need for stricter regulation of anti-androgenic chemicals and for male preconceptional health interventions. Importantly, this research also has a gender equality dimension. It underscores that both parents’ health and exposures contribute to offspring well-being. Responsibility for reproductive health should not rest solely on mothers, who may be unfairly blamed when a child experiences health problems.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We used frogs to show that the effects of the anti-androgenic pesticide linuron extend beyond directly exposed males to their offspring and grand-offspring. Offspring displayed reduced fertility, impaired spermatogenesis, altered body weight, and metabolic disruption, providing the first evidence of transgenerational paternal epigenetic inheritance in amphibians. Follow-up work identified widespread DNA methylation changes in F2 brains, testes, and pancreas, affecting genes linked to growth, thyroid signaling, spermatogenesis, and metabolic regulation, as well as genes controlling the epigenetic machinery itself. These findings demonstrate that linuron induces heritable epigenetic alterations across multiple organs, with long-term effects on fertility, growth, and metabolism.

In parallel, we established a mouse model to study the transgenerational effects of adult male anti-androgen exposure. Exposed males showed hepatic stress, oxidative damage, and metabolic dysfunction, including features consistent with non-alcoholic fatty liver disease. They also developed persistent immunosuppression, with reduced leukocytes and T cells, expansion of immunosuppressive myeloid-derived suppressor cells, cytokine alterations, and evidence of oxidative stress–driven lymphocyte arrest. Follow-up work revealed profound microbiome disruption, suggesting interactions between gut bacteria and immune impairment. Importantly, dose-dependent epigenetic changes in sperm were also observed, and offspring of exposed males displayed similar metabolic and immune alterations, many persisting into the F2 generation, demonstrating transgenerational inheritance.

Together, these cross-species studies provide strong evidence that anti-androgenic pollutants directly impair male reproductive, metabolic, hepatic, and immune health, and induce heritable epigenetic alterations across generations. The results link molecular changes in sperm, brain, testis, pancreas, liver, and immune system to long-term effects on fertility, growth, metabolism, and immunity, with broad implications for both ecology and human health. We have disseminated our findings through peer-reviewed publications, international conferences, TV and radio news, and press releases, ensuring broad visibility among scientists, policymakers, and the public. Moving forward, we will continue to share outcomes from our unpublished studies through publications, media outreach, and stakeholder engagement, maximizing their scientific, societal, and regulatory impact.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

This project has provided the first cross-species evidence of paternal epigenetic inheritance in vertebrates, with profound ecological and evolutionary implications. We demonstrated that male exposure to pesticides can impair the fitness of unexposed future generations, revealing how human activities may drive biodiversity loss through subtle, epigenetically mediated mechanisms. This is particularly urgent as nearly half of all amphibian species are currently threatened with extinction. Our results show that environmentally relevant concentrations of agrochemicals can induce multigenerational health effects in frogs, supporting a causal role for environmental contamination in the global decline of amphibians. Reduced fertility and metabolic disturbances are likely to affect population dynamics and may act synergistically with other extinction drivers such as infectious disease and climate change. These findings challenge current paradigms in chemical safety assessment and highlight the need to incorporate multigenerational toxicity testing into regulatory frameworks, which is not currently required.

Importantly, this was the first project to specifically investigate the transgenerational effects of adult male exposure to anti-androgens in detail. Using our established rodent model, we showed that such exposures cause persistent direct effects on male health, including hepatic stress, metabolic dysfunction, and immunosuppression. Moreover, when exposed males were mated with unexposed females, their offspring displayed similar alterations in metabolism and immune function, many of which persisted into the F2 generation. These findings move the field beyond correlative epidemiology by providing mechanistic insights into paternal epigenetic inheritance, including alterations in sperm DNA methylation, histone modifications, and small RNAs.

Overall, the project has delivered a mechanistic framework for understanding how paternal life experiences, particularly chemical exposures, can shape the health of future generations. The findings have broad implications for ecology, evolutionary biology, chemical safety, and public health, and they provide a scientific foundation for stricter regulation of anti-androgenic chemicals and male preconceptional health interventions.

Sperm fertilizing an oocyte