Friday, April 4, 2025
4/4/2025
Molecular mechanisms underlying metabolic reprogramming by paternal benzene exposure - ABSTRACT There is a major gap in our understanding of how paternal experiences leads to the increased risk of metabolic disease in offspring. Here we focus on the heritable metabolic effects of benzene. Using a novel mouse model for paternal benzene exposure, we provide convincing evidence for a causal relationship between paternal benzene exposure and a sex specific offspring phenotype of impaired glycemic control when under metabolic stress. We provide evidence for clear transcriptional signatures of metabolic disease, specifically in male offspring. Based on these data we hypothesize that paternal benzene exposure triggers a specific signal in sperm, which when transferred leads to predisposition to metabolic disease. To test the hypothesis, we will utilize state of the art exposure system, a novel mouse model of intergenerational benzene exposure, and pharmacological intervention to critically address the mechanism and pathophysiological significance underlying metabolic programming triggered by benzene exposure. First we will perform in depth metabolic and energy homeostasis phenotyping to identify the physiological consequences of paternal benzene exposure in unexposed offspring. Second, we will identify the transcriptional signatures of intergenerational benzene exposure in insulin sensitive tissues from offspring. Finally we will test if treatment of paternal metabolic disease with a well characterized diabetes drug prevents the offspring phenotype; To define the mechanistic basis for benzene-induced intergenerational reprograming, we will identify germline and epigenetic signatures of benzene exposure, and mechanistically connect the epigenetic changes in the germline to offspring transcriptional rewiring. The proposed research will, for the first time, define the causal relationship between paternal exposure to benzene, and offspring metabolic disease susceptibility. Such a study will be of importance to understand how paternal exposure drives non-genetic, metabolic reprogramming across generations.
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