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

催产素和甲状腺干扰室内阻燃剂的母体转移影响后代社交大脑

• 批准号: 10607974
• 负责人: Elena V Kozlova
• 金额: $ 3.97万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-07-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607974
• 关键词: Adolescent; Affect; Age; Amygdaloid structure; Animals; Behavior; Behavioral Assay; Biological; Biological Assay; Brain; Centers for Disease Control and Prevention (U.S.); Chemical Exposure; Chemicals; Child; Cues; Data; Development; Disease; Dose; Emotional; Emotions; Endocrine Disruptors; Environment; Environmental Exposure; Environmental Risk Factor; Exposure to; Female; Flame Retardants; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Goals; Human; Human Milk; Hypothalamic structure; Incidence; Individual; Knowledge; Link; Mediating; Mental disorders; Molecular; Mus; Mutate; National Institute of Mental Health; Neuroanatomy; Neurodevelopmental Deficit; Neurodevelopmental Disorder; Neurons; Neuropeptides; Odors; Oxytocin; Oxytocin Receptor; Pathogenesis; Perinatal; Pharmaceutical Preparations; Phenotype; Predisposition; Prevalence; Prevention approach; Process; Receptor Signaling; Reporting; Research Domain Criteria; Risk; Risk Factors; Role; Signal Transduction; Social Behavior; Social Development; Social Discrimination; Social Interaction; Societies; Stereotyping; Structural defect; Structure; Supplementation; Symptoms; System; Testing; Therapeutic; Thyroid Gland; Thyroid Hormones; Time; Translating; Vasopressins; Xenobiotics; autism spectrum disorder; critical developmental period; developmental neurotoxicity; disabling symptom; disorder risk; early life exposure; emotional behavior; epidemiology study; immunoreactivity; interdisciplinary approach; interest; male; malformation; memory recognition; modifiable risk; mouse development; mouse model; neural circuit; neural network; neurochemistry; neurodevelopment; neurodevelopmental effect; novel; novel strategies; offspring; paraventricular nucleus; persistent organic pollutants; polybrominated diphenyl ether; programs; psychosocial; receptor; receptor expression; repetitive behavior; response; sex; sexual dimorphism; social; social cognition; social communication; social deficits; social structure; thyroid disruption; toxicant

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.

社会认知是物种生存的基本过程。社会处理中的干扰