Mechanism of transgenerational inheritance of reproductive dysfunction stemming from environmental BPA exposure in C. elegans
The transfer of environmental information from one generation to the next has been observed following exposure to natural stimuli in a variety of model systems. Mechanisms behind the transfer of information from natural cues have highlighted the central role played by the epigenome, including DNA methylation-based pathways as well as through the regulation of histone modifications. This transfer can induce specific phenotypes across generations that can result from multigenerational exposures (from a pregnant mother to her offspring) or transgenerational exposures (transmitted through the germ line in the absence of direct exposure). Interestingly, effects from man-made environmental chemicals remain controversial as studies in mammalian settings have not been consistently repeated, have not provided a clear mechanism of inheritance, and have solely focused on DNA methylation ignoring the potential involvement of other epigenetic marks.
The work presented here focuses on the development and validation of a C. elegans epigenetic reporter to address the need for a quick and efficient method to test chemicals in our environment for their effects on the germline epigenome. We characterize the epigenetic maintenance of a C. elegans strain carrying a repetitive transgene that can be manipulated by chemical exposure and allows for easy visualization of GFP expression. With an epigenetic reporter, we then characterize the mechanisms by which environmental exposure to the model chemical Bisphenol A (BPA) can cause heritable effects lasting for several generations after direct exposure. Specifically, we found that BPA causes reproductive defects and a heritable decrease in repressive histone marks in the germlines of worms that are ancestrally exposed. The inherited decrease in repressive histone marks and reproductive defects can be rescued by modulating the activity of histone modifying enzymes. Lastly, our work investigates the specific mechanisms through which BPA can induce reproductive defects that are inherited through the germline. We find that BPA affects the maintenance of meiotic processes, partly through disruption of double strand break repair pathways in a transgenerational manner. This in turn indicates the need for a larger transgenerational assessment focusing on the entire meiotic process that includes researching pairing, synapsis, recombination, and checkpoint pathways. These findings shine a light on how artificial environmental exposures can be biologically integrated and transgenerationally inherited. It highlights the importance of comprehensively examining our chemical environmental for its potential effects on our germline epigenome, which can in turn allow us to find interventional means to prevent transmission of effects to future generations.