Chemical exposure disruption of the placental circadian clock

ABSTRACT Adverse reproductive outcomes, including preeclampsia and hypertension, preterm birth, growth restriction, and small for gestational age birth contribute significantly to maternal and infant morbidity and mortality and can lead to long term health consequences for both mother and offspring. The placenta plays a central role in successful pregnancy outcomes, fetal development, and it is increasingly being recognized for playing an important role in developmental programming of the fetus and contributing to childhood health and disease. Environmental chemicals are known to contribute to the risk for adverse reproductive outcomes and these chemicals may be eliciting their toxic effects through impacts on the function of the placenta. One particular function of the placenta that is only beginning to be fully understood is its role as a peripheral molecular clock. Disruptions to the molecular clock are recognized to be involved in several adverse reproductive outcomes and recent data suggests that deregulation of molecular clock genes impacts important placental cellular processes such as cell migration. There is also evidence to suggest that the epidermal growth factor (EGF) maybe a central regulator of the placental molecular clock and that a mixture of toxic chemicals, including pesticides, alters the placental molecular clock through inhibition of EGF signaling through the EGF receptor (EGFR). These findings support the premise that a properly functioning molecular clock is required for placental health. However, it remains unknown if environmental chemicals cause placental dysfunction via molecular clock disruption. This consortium, consisting of a placental toxicologist (Veiga-Lopez), circadian biologist (Hoffmann), and pregnancy molecular epidemiologist (Marsit), has developed a project that will lead to an understanding of how gestational environmental exposures impact the molecular clock resulting in placental dysfunction, by examining the overall hypothesis that chemicals that interfere with molecular clock signaling through EGFR lead to placental cell dysfunction in a gestational age- and placenta layer-specific manner. In a mouse model, we will examine how gestational age, placenta layer, and sex impacts molecular clock sensitivity to chemical exposures. In human placenta cellular models, we will identify mechanisms through which the molecular clock proteins PER1, PER2, and PER3 impact cellular function upon chemical exposures. Finally, using a pregnancy cohort of farm-working women and their offspring, we will determine the association between pesticide exposure and placental molecular clock gene dysregulation and build causal evidence by comparing results to those from the mouse model. Through this new and exciting collaboration, there is a unique opportunity to comprehensively demonstrate the importance of the placenta as a peripheral clock and to provide evidence that exposures relevant to the human population impact the placental molecular clock which has lifelong implications for health and disease.