Wednesday, April 24, 2024
4/24/2024
PROJECT SUMMARY/ABSTRACT Bisphenol A, BPA, is an endocrine disruptor widely used in consumer products that can be found in the lining of canned goods, plastic water bottles, and medical equipment. Exposure to BPA has been linked to adverse health effects in humans such as cancer, heart disease, autism, and obesity. Parental exposure also leads to adverse health effects in their unexposed offspring , though the molecular mechanism responsible is poorly understood. Exposing pregnant mice from E7.5-E13.5, when the fetal germline is reprogrammed, induces an obesity epiphenotype that can be inherited stably for 6 generations. BPA is an endocrine dirsputor that is known to interact with several nuclear hormone receptors, therefore, we hypothesized that in utero BPA exposure altered the distribution of these transcription factors in the germline. Also, the altered transcription factor occupancy could lead to other changes to the transcriptome, histone modification, DNA methylation, or other epigenetic alterations. Data in male germline support this hypothesis. Our lab has characterized 12 candidate sites that gain accessibility and are depleted of DNA methylation. These sites correlate with the transmission of the obesity phenotype, correspond to other epigenetic alterations in the male germline, and are near genes obesity-related genes. Despite what has been established in the male germline, it is possible that the mechanism of transmission in the female germline is unique. When we observe the transmission through the male and female germline indenpendently, we observe that the obesity epiphenotype is much more robost when it transmitted through the female germline. In preliminary ATAC-seq data in GV oocytes from BPA F2 mice and control, we define many alterations to accessibility, 1,245 sites that gained and 9 sites lost in the BPA F2. In order to understand which epigenetic alterations are responsible for transmission through the female germline, we proposed the following. In AIM 1, to characterize how changes to accessibility, DNA methylation, and the transcriptome correspond to the transmission of the obesity phenotype through the female germline, we will create ATAC-seq, BS-seq, and RNA-seq libraries in the GV and MII oocytes of control mice and the progeny of BPA-exposed mice. This will allow use to determine which alterations might be responsible. In AIM 2, we will characterize the accessibility, transcriptome, and distribution of histone modification in the embryos from BPA F2 female outcrosses and control intercrosses. With this, we will characterize which alterations to accessibility already defined in the BPA F2 oocyte persist in the embryo and if any of the epigenetic alterations transmitted from the oocyte correspond to changes in transcriptome or chromatin landscape in the preimplantation embryo. The completion of these aims will allow us to characterize how BPA exposure can stably alter epigenetic information in the oocyte, and if this information can be transmitted to the embryo and ellict the functional changes that leads to obesity.
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