Periodic Reporting for period 3 - PATER (Paternal Epigenetic Inheritance: A man’s life experiences may impact health of his unborn children and grandchildren)
Período documentado: 2022-01-01 hasta 2023-06-30
Epigenetic inheritance may not only occur in plants but also in vertebrates including mammals. While the effect of maternal lifestyle and in utero exposures is well studied, paternal epigenetic inheritance is a novel research field, especially in regard to chemical exposures. Many environmental pollutants exhibit anti-androgenic function. However, despite the vital role of androgens in spermatogenesis, the effects of adult anti-androgen exposure on the sperm epigenome and offspring phenotype have been scarcely studied. At conception, the gametes deliver not only the genetic material to form an embryo, but also additional epigenetic information that could reflect the exposures and experiences of both parents. Interest in paternal transmission of life experience via epigenetic mechanisms originates from epidemiological studies associating paternal smoking with increased body mass index (BMI) in sons and relating grandfather’s food availability to mortality in grandsons. In addition, various neuropsychiatric disorders have increased incidence in children of older fathers. Intriguingly, age-related changes in sperm DNA methylation located at genes associated with these diseases have also been reported. Paternal epigenetic transfer of life experiences such as exposures to environmental pollutants can be much more important than previously considered. Consequently, a healthy working/living environment and lifestyle for men in reproductive age may be of utter importance.
The overall objective of this project is to increase the understanding of if, and how, male life experiences such as exposure to anti-androgenic model compounds and pollutants may affect offspring through paternal epigenetic inheritance. The hypothesis is that common anti-androgenic pollutants, can induce alterations in sperm biomolecules, which are transferred to the next generation during embryogenesis and affect phenotype of the offspring via epigenetic mechanisms. To test the hypothesis, the project integrates animal and human studies. It will also be examined if identified effects can be further propagated to the subsequent generation. The project can contribute to mechanistic understanding of how male life experiences may affect offspring through epigenetic inheritance. The findings may have important public health implications via new regulations of anti-androgenic chemicals and male preconceptional interventions to protect health of offspring.
The overall objective of this project is to increase the understanding of if, and how, male life experiences such as exposure to anti-androgenic model compounds and pollutants may affect offspring through paternal epigenetic inheritance. The hypothesis is that common anti-androgenic pollutants, can induce alterations in sperm biomolecules, which are transferred to the next generation during embryogenesis and affect phenotype of the offspring via epigenetic mechanisms. To test the hypothesis, the project integrates animal and human studies. It will also be examined if identified effects can be further propagated to the subsequent generation. The project can contribute to mechanistic understanding of how male life experiences may affect offspring through epigenetic inheritance. The findings may have important public health implications via new regulations of anti-androgenic chemicals and male preconceptional interventions to protect health of offspring.
During this period, we have used frogs (Xenopus tropicalis) as a model organism and demonstrated that the effects of the anti-androgenic pesticide linuron are not limited to the exposed males, but are passed on to their offspring and grand-offspring. The first generation offspring had reduced body weight, decreased fertility, impaired spermatogenesis, and signs of endocrine system disruption, while the next generation had increased body weight and a disrupted fat and carbohydrate metabolism (Karlsson et al., STOTEN 2021). This study provides the first evidence of paternal epigenetic inheritance in frogs. The results indicate that the pesticide affect the function of testosterone and thyroid hormones in the exposed male frogs and that these effects are passed on to future generations via sperm and epigenetic mechanisms.
In addition to this published work, we have established a mouse model, and characterized phenotypic alterations in offspring of males exposed to an anti-androgen in detail. The unpublished data suggest altered development of the reproductive system in offspring. We have also clearly confirmed an effect on the metabolic system and revealed behavior effects in the offspring. The work is currently focused on investigating detailed underlying molecular mechanisms, including alterations in sperm biomolecules.
In addition to this published work, we have established a mouse model, and characterized phenotypic alterations in offspring of males exposed to an anti-androgen in detail. The unpublished data suggest altered development of the reproductive system in offspring. We have also clearly confirmed an effect on the metabolic system and revealed behavior effects in the offspring. The work is currently focused on investigating detailed underlying molecular mechanisms, including alterations in sperm biomolecules.
Our unique frog study provides important cross-species evidence of paternal epigenetic inheritance, which may have profound ecological and evolutionary consequences. This is the first time that anyone has been able to demonstrate that male exposure to pesticides can adversely impact the fitness of future unexposed generations and it shows how human activities can drive the ongoing loss of vertebrate populations through complex mechanisms. Almost half of all amphibian species—of which frogs are a significant part—are threatened by extinction. The project results show that agrochemicals, at concentrations found in the environment, can induce adverse health effects in frogs over several generations, which supports a causal role of environmental contamination in the rapid worldwide amphibian decline. Reduced fertility impacts on the population dynamics and other sub-lethal metabolic effects may possibly interact and aggravate the effects of other suggested drivers of vertebrate extinctions such as infectious disease and climate change. The results further underscore the importance of considering multigenerational toxicity in chemical risk assessment, which is not the case in current chemical regulations.
It is debated if epigenetic alterations in humans can cross the generational border to children or even grandchildren. The spermatogenesis and embryogenesis are relatively conserved within mammals, and our established rodent model clearly shows important phenotypic alterations in the offspring of males exposed to an anti-androgen. This project is expected to contribute to mechanistic understanding of how male life experiences may affect children through paternal epigenetic inheritance.
It is debated if epigenetic alterations in humans can cross the generational border to children or even grandchildren. The spermatogenesis and embryogenesis are relatively conserved within mammals, and our established rodent model clearly shows important phenotypic alterations in the offspring of males exposed to an anti-androgen. This project is expected to contribute to mechanistic understanding of how male life experiences may affect children through paternal epigenetic inheritance.