Arinzeh, N. | bioRxiv Science

bioRxiv2025

Sex-Specific Induction of H3K27me1 in the Prefrontal Cortex Mediates the Enduring Effects of Early Life Stress

Early life stress (ELS) is a strong risk factor for several neurodevelopmental and psychiatric disorders and is associated with persistent molecular alterations in corticolimbic regions, including the prefrontal cortex (PFC). Here, we combined unbiased proteomics profiling and viral-mediated gene transfer to characterize the enduring epigenetic changes in the PFC of male and female mice previously exposed to ELS. We found that ELS induced sex-specific and age-dependent accumulation of monomethylation of lysine 27 at histone H3 (H3K27me1), with a transient increase in adolescent females, and a delayed but enduring effect in adult males. ELS-induced H3K27me1 accumulation in the PFC involved changes of SUZ12, a subunit of the polycomb repressive complex 2 (PRC2), which controls H3K27 methylation patterns. Indeed, expression of the catalytic domain of SUZ12, VEFS, in PFC neurons during adolescence led to sex differences in social and cognitive alterations in adulthood. Together, our results demonstrate that H3K27me1 functions as a "chromatin scar" in the PFC, where it mediates lifelong susceptibility to ELS in a sex-specific manner.

neuroscience↗

bioRxiv2024

Mixtures of phthalates disrupt expression of genes related to lipid metabolism and peroxisome proliferator-activated receptor signaling in mouse granulosa cells

Phthalates are a class of known endocrine disrupting chemicals that are found in common everyday products. Several studies associate phthalate exposure with detrimental effects on ovarian functions, including growth and development of the follicle and production of steroid hormones. We hypothesized that dysregulation of the ovary by phthalates may be mediated by phthalate toxicity towards granulosa cells, a major cell type in ovarian follicles responsible for key steps of hormone production and nourishing the developing oocyte. To test the hypothesis that phthalates target granulosa cells, we harvested granulosa cells from adult CD-1 mouse ovaries and cultured them for 96 hours in vehicle control, a phthalate mixture, or a phthalate metabolite mixture (0.1-100 g/mL). After culture, we measured metabolism of the phthalate mixture into monoester metabolites by the granulosa cells, finding that granulosa cells do not significantly contribute to ovarian metabolism of phthalates. Immunohistochemistry of phthalate metabolizing enzymes in whole ovaries confirmed that these enzymes are not strongly expressed in granulosa cells of antral follicles and that ovarian metabolism of phthalates likely occurs primarily in the stroma. RNA sequencing of treated granulosa cells identified 407 differentially expressed genes, with overrepresentation of genes from lipid metabolic processes, cholesterol metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Expression of significantly differentially expressed genes related to these pathways were confirmed using qPCR. Our results agree with previous findings that phthalates and phthalate metabolites have different effects on the ovary and interfere with PPAR signaling in granulosa cells.

pharmacology and toxicology↗