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Preconception exposures of female mice to a panel of metabolic disruptors induce sexually dimorphic metabolic perturbations in their offspring

ABSTRACT: In recent years, there has been a growing emphasis on research investigating the transmission across generations of the effects of exposure to environmental factors, which may predispose to chronic diseases. It has been hypothesized that the propagation of such effects is mediated by alterations in gene regulatory elements, such as DNA methylation, histone modifications, and non-coding RNAs. Studies in Drosophila and mice have demonstrated that the compartmentalization of eukaryotic genomes into heterochromatin and euchromatin can mediate multigenerational metabolism-disrupting effects elicited by exposure to various metabolism disruptors. These findings suggest that eukaryotic nuclear genomes may possess the capacity to integrate the impact of environmental cues in a metastable manner that is phenotypically relevant. Here, we present the results of a murine model to assess whether preconception exposure to three metabolism disruptors of distinct nature, including dietary factors and environmental toxicants, intended to emulate the complexity of human exposures, results in metabolic alterations in the offspring of exposed individuals. Our findings align with our central hypothesis but also open an unexpected avenue to explore whether preconception exposure to metabolism disruptors predisposes the offspring of exposed individuals to not only typical metabolic diseases such as obesity but also to complex metabolic-psychiatric conditions such as anorexia.

ORGANISM(S): Mus musculus

PROVIDER: GSE324852 | GEO | 2026/03/16

REPOSITORIES: GEO

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Project description:Prenatal development is influenced by various paternal factors, including environmental exposures, lifestyle, and epigenetic modifications. This dissertation investigates the impact of chronic paternal alcohol (EtOH) consumption on offspring development, with a particular focus on placental function, mitochondrial health, and microRNA (miRNA) mediated epigenetic inheritance. Using a previously established mouse model, we explored how preconception paternal alcohol exposure alters sperm-inherited small RNA population and its downstream consequences on placental structure and function. Our findings demonstrate that chronic paternal EtOH consumption induces significant changes in sperm small RNA populations, particularly miRNAs known to regulate early embryonic development. These alterations correlate with disruptions in fetal growth and placental histology, suggesting an intergenerational transmission of stress-induced epigenetic modifications. Furthermore, we identified sex-specific differences in fetoplacental development, where male offspring exhibited pronounced placental inefficiencies and metabolic disruptions. A key aspect of this research involves the role of nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of oxidative stress. We show that paternal NRF2 loss-of-function phenocopies the effects of chronic alcohol exposure, reinforcing the hypothesis that oxidative stress-induced epigenetic alterations mediate the observed developmental outcomes. Placental mitochondrial function, a vital determinant of fetal energy supply, was also significantly impaired in alcohol-exposed offspring. Notably, these defects persisted into adulthood, implicating long-term metabolic consequences. To assess the genetic and epigenetic basis of these outcomes, we conducted proteomic and transcriptomic analyses, revealing dysregulated pathways involved in mitochondrial bioenergetics, redox balance, and cellular metabolism. Our results highlight that paternal alcohol exposure not only disrupts placental architecture but also modifies the epigenetic landscape of the developing embryo, leading to systemic physiological alterations. These findings underscore the importance of considering paternal contributions to reproductive health and fetal development. By elucidating the mechanisms underlying alcohol-induced epigenetic inheritance, this research provides novel insights into the role of paternal environmental exposures in shaping offspring health trajectories. Ultimately, this work advocates for broader perspectives on preconception health, emphasizing the need for preventive strategies to mitigate paternal influences on developmental disorders.

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Preconception exposures of female mice to a panel of metabolic disruptors induce sexually dimorphic metabolic perturbations in their offspring

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