SUN-109 - Environmental Disruption of Placental Circadian Rhythms as A Mechanism Underlying Adverse Pregnancy Outcomes

The placenta is a central regulator of pregnancy success, integrating maternal and environmental signals to support fetal growth, endocrine function, and the timing of parturition. Increasing evidence links placental circadian rhythm disruption to pregnancy complications, including preeclampsia, fetal growth restriction, and preterm birth. However, the mechanisms by which environmental perturbations alter placental circadian rhythms remain poorly understood. To address this, we investigated the effects of environmental stressors on placental circadian rhythms by using our newly established human extravillous trophoblast (EVT) cell line expressing a PER2::Luciferase circadian reporter (hEVT-PER2::Luciferase reporter), and a translational mouse model of chronic irregular light–dark exposure designed to mimic human irregular sleep-wake cycles.

The epidermal growth factor receptor (EGFR) which is highly expressed in trophoblast cells, is a target of several endocrine disrupting chemicals including benzotriazole UV stabilizers (BUVs). We found that in primary human term cytotrophoblasts, a 24-h exposure to EGF downregulated Per2 and Cry1 expression, while a mixture of six EGFR-disrupting chemicals upregulated Clock and Cry1 expression. Consistent with these findings, EVTs exhibited circadian EGFR expression, and exposure to BUV-327 promoted a non-significant, phase advancement of PER2::Luciferase rhythms, suggesting that EGFR-targeting chemicals can affect placental clock dynamics.

Next, a novel mouse placenta explant model was used to determine whether circadian disruption represents a generalizable environmental mechanism rather than a chemical-specific effect. This model showed sex- and gestation day-dependent changes in placenta layer circadian rhythms, which were modulated by EGF on gestation day 14. Further, our translational mouse model was used to determine if other environmental disruptors can impact Egf expression and placenta circadian rhythms in vivo.

Our irregular light-dark mouse model exhibited high rates of labor dystocia, and placenta and fetal thrombosis. Preliminary placental transcriptomic analyses indicated that irregular light-dark-induced circadian disruption did not impact Egf or Egfr, but did alter molecular clock gene expression in a sex-specific manner. These findings demonstrate that environmental stressors during pregnancy can trigger sexually dimorphic placental adaptations, which are linked to labor complications and differential neonatal outcomes. Together, these data identify the placental molecular clock as a sensitive environmental sensor and a mechanistic link between environmental disruption and pregnancy complications.

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