Fetal hypothyroidism induces sex-specific epigenetic and transcriptomic alterations in the porcine placenta

The placenta is critical for fetal development, supporting nutrient transport, while also isolating the developing conceptus from adverse maternal signals. The porcine placenta creates an enzymatic barrier for thyroid hormones following activation of the fetal endocrine system in early gestation. Perturbation of the fetal thyroid system can have significant developmental consequences. However, research examining the relationship between fetal thyroid hormone availability, the placental epigenome, and global effects on placental gene expression is limited, particularly in swine. Existing work on select placental genes suggests a potential compensatory response to fetal endocrine disruption during late gestation. We hypothesize that global placental epigenetic and transcriptomic changes may arise in response to induced fetal hypothyroidism. To address this hypothesis, we analyzed placental tissues from gestation day 86 fetuses exposed to 21-day maternal methimazole (MMI) treatment and matched controls. CUT&RUN profiling revealed differential histone mark enrichment, with enrichment of both marks predominantly gained in MMI samples. The placental histone mark status from female fetuses was more substantially altered in response to maternal MMI treatment than placental tissue from male fetuses. In contrast, while differential gene expression was apparent between control and MMI conditions, transcriptional changes were more pronounced in placental tissue from male fetuses. Integration of these datasets revealed treatment- and sex-dependent epigenetic and transcriptional variation. This work expands our understanding of the intricate interplay between fetal thyroid hormone levels and placental gene expression regulation and provides novel insights into the existence of sex-specific differences in placental epigenetic and transcriptomic responses to fetal endocrine disruption.