Maternal Transfer of Oxytocin and Thyroid-disrupting Indoor Flame Retardants Affecting Offspring Social Brain

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Social cognition is a fundamental process essential for species survival. Disturbances in social processing have been identified by the NIMH Research Domain Criteria Initiative as a major domain disrupted across psychiatric disorders including neurodevelopmental disorders (NDDs) such as autism spectrum disorders (ASD). ASD prevalence continues to increase at an alarming rate, affecting 1 in 54 U.S. children, and characterized by an unexplained sexual dimorphism. While ASD has a strong genetic component, the disorder is in most cases, multifactorial, resulting from sex-specific genetic susceptibilities interacting with environmental factors during critical developmental periods. Thus environmental exposures, including exposures to endocrine disrupting chemicals (EDCs), may contribute to the rising prevalence of ASD. However, experimental evidence has not established a direct link with specific chemicals and mechanisms remain elusive. PBDEs are commercial flame retardants found in human breast milk that are associated with developmental deficits in children. Our lab has shown that the commercial PBDE mixture, DE-71, produces ASD-relevant phenotypes that include deficient social recognition memory, exaggerated repetitive behavior, and altered neuromolecular profiles for the social neuropeptides, oxytocin (OXT) and vasopressin, and their receptors. PBDEs structurally resemble thyroid hormones (TH), which are both critical for neurodevelopment of social brain circuits and regulate OXT and AVP. Therefore, I will test the novel hypothesis that developmental PBDEs produce a hypothyroid state, which disrupts signaling in the central OXTergic system and malformation of social neural circuits leading to deficient socioemotional behavior. In mechanistic studies under Aim 1, I will examine the TH targets of PBDEs and the contribution of TH disruption to altered behavior and neuropeptide phenotypes of PBDE-exposed male and female offspring using maternal thyroid supplementation. Chemogenetic activation of OXT release within the PVN will be employed in an attempt to rescue PBDE-induced abnormal phenotypes. In circuit-level studies using retrograde tract-tracing under Aim 2, I will examine PBDE reprogramming of the reciprocal preflimbic cortex to basolateral amygdala circuit, which is critical for social recognition ability. Since this circuit depends on OXT receptor (OXTR) signaling and is purported to receive OXTergic projections from PVN, I will determine if developmental intranasal OXT rescues structural changes produced by PBDEs. These studies will investigate the neurodevelopmental effects of maternal transfer of PBDEs across multiple levels of biological organization and developmental ages to begin to understand mechanisms and critical windows of risk. My findings will provide critical mechanistic information necessary to break through gaps in knowledge about the possible environmental risk to NDDs. They will also inform about the role of oxytocin underlying social and emotion recognition behavior and the mechanisms altering circuit-level function during neurodevelopment. Finally, the findings may eventually translate to the development of alternative therapeutic approaches to treat psychosocial NDDs.