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

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.