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Investigating the transgenerational inheritance of environmental cues in C. elegans

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In sexually reproducing organisms, germ cell development is vital for the faithful transmission of the genome and epigenome across generations. Recent studies have shown that germ cell development is affected by different environmental toxicants, resulting in a decrease in germ cell health and number. Here, we examine the transgenerational impact and mechanisms of two prevalent toxicants, the plastic manufacturing chemical Bisphenol A and ethanol, in Caenorhabditis elegans. Both have well-described impacts on the developing fetus; however, their effects on developing germ cells and subsequent generations are less explored. We hypothesize that exposure disrupts the epigenetic machinery in germ cells, causing changes in histone modifications, fertility defects, and germline dysfunction in a transgenerational manner. First, we show that BPA exposure causes a transgenerational two-fold increase in germline chromatin desilencing coupled with a reduction and redistribution of histone H3K9me3 and H3K27me3. We show that the alteration of repressive histone levels is required for the observed transgenerational 43% increase in germline apoptosis and 85% increase in embryonic lethality. By performing a genetic rescue using RNAi, we identified the chromatin modifying enzymes H3K9 and H3K27 demethylases (jmjd-2, jmjd-3, and utx-1) to be responsible for the transgenerational effects of BPA, since RNAi alone was able to restore the chromatin into a silenced state and rescue fertility defects. This confirms our idea that epigenetic memory is mediated by histone marks. Next, an increase in apoptosis suggests possible perturbations in the germline checkpoint machinery. To understand which checkpoint BPA perturbs, we used mutants of each checkpoint to rescue the effect. This revealed that BPA perturbs the synapsis checkpoint since a pch-2 mutant decreased BPA induced apoptosis by two-fold whereas mutants of the DNA damage checkpoint, spo-11 and cep-1, did not. Furthermore, visualization of the synaptonemal complex (SC) using a SYP-3::GFP strain revealed perturbations in proper SC assembly and aggregation of SC proteins resulting from ancestral BPA exposure. The formation of these aggregates was further associated with increases in embryonic lethality transgenerationally at the F3. In parallel, we also explored another common toxicant, ethanol, but instead we built the complete transgenerational transcriptional map of ethanol using single cell RNA-seq approaches. Together, my work identified the molecular drivers of environmental transgenerational effects on the germline machinery and reproductive health. We hope to further understand how it induces germline dysfunction, carrying important implications for human reproductive health in the context of environmental exposures.

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This item is under embargo until May 31, 2024.