Title: The Role of the Human Placenta in Regulating Fetal Exposure to Maternal Hormones and Implications for Child Neurobehavioral Outcomes
Description: Prenatal exposure to sex hormones has profound effects on neurodevelopment with lifelong implications for mental health. Fetal exposure to aberrant levels of sex hormones alters sexual dimorphism (i.e. degree of feminization or masculinization; sex differences in brain and behavior) and may contribute to the differential susceptibility of males and females to psychiatric risk and neurodevelopmental disorders, including autism. During fetal development, the in-utero environment is regulated by the placenta, a maternal-fetal endocrine structure that serves as a “gate-keeper” between the maternal and fetal circulatory systems. The placenta expresses high levels of aromatase, an enzyme that converts testosterone to estrogen, and it has been proposed that placental aromatase precludes the transfer of maternal testosterone to the fetus. However, this view does not account for individual differences in placental aromatase expression or maternal hormone levels that may account for altered neurobehavioral outcomes.

Retinoic acid-related orphan receptor-alpha (RORA) has been identified as a transcription factor that regulates aromatase and as an autism candidate gene – yet the role of RORA in the placenta as a regulator of the prenatal hormonal environment has yet to be determined. The research presented in this thesis aimed to evaluate 1) the relationship between maternal and neonatal hormone concentrations, 2) whether placental aromatase/RORA influences the relationship between maternal and neonatal hormones concentrations, 3) the relationship between maternal sex hormones during pregnancy and neurobehavioral outcomes in the offspring, and 4) the relationship between placental aromatase/RORA and neurobehavioral outcomes in the offspring. Chapters 1 and 2 of this thesis provide a review of the literature pertaining to the sources of and neurodevelopmental consequences of fetal exposure to hormones and the methods used to address our research questions. Chapters 3, 4, and 5 of this thesis used in vivo and in vitro methods to investigate the role of placental aromatase and RORA in regulating fetal exposure to maternal hormones.

Results from these studies indicate that maternal testosterone is a strong predictor of neonatal testosterone levels at birth and that aromatase and RORA expression in the human placenta subtly influence the relationship between maternal and neonatal testosterone and estradiol in a sex-dependent manner. Results from our studies using an in vitro approach call into question the widely proposed role of placental aromatase in converting maternal testosterone intro estradiol. Chapters 6 and 7 of this thesis aimed to determine whether variability in maternal testosterone and placental aromatase/RORA expression was associated with increased neurodevelopmental risk as a result of elevated fetal hormone exposure. For the first time in the literature, we report a direct association between elevated maternal testosterone and poorer childhood neurodevelopmental outcome in a sex-dependent manner. We also report that the effects of placental aromatase and RORA expression on childhood outcomes vary depending on the neurobehavioral domain being assessed.

Taken together, these studies support the notion that fetal exposure to sex hormones, especially those of maternal origin, can affect neonatal hormone production as well as long-term child neurobehavior. The specific mechanisms by which the placenta regulates fetal exposure require further investigation.