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The placenta: a novel target of sex specific neurotoxicity by fire retardants

胎盘：阻燃剂性别特异性神经毒性的新靶点

基本信息

批准号：
9749999
负责人：
Heather B Patisaul
金额：
$ 42.79万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9749999
关键词：
Anabolism Animal Behavior Animal Model Anxiety Attention deficit hyperactivity disorder Behavior Behavior Disorders Behavioral Biological Markers Brain Cells Chemical Exposure Chemicals Child Cognition Disorders Communication Data Deltastab Development Disease Dose Endocrine disruption Environment Environmental Pollution Esters Exposure to Female Fetal Development Fetus Flame Retardants Goals Human Hyperactive behavior Incidence Infant Life Link Neurodevelopmental Disorder Oral Organophosphates Outcome Parents Pathway interactions Patients Pharmacology Phase Phenotype Placenta Plasticizers Predisposition Pregnancy Prosencephalon Rattus Research Risk Rodent Serotonin Sex Differences Source Synapses Testing Therapeutic Intervention Tissues Toxic effect Toxicokinetics Wistar Rats Woman Work autism spectrum disorder autistic base consumer product developmental neurotoxicity exposed human population fetal male neurobehavioral disorder neurodevelopment neurotoxic neurotoxicity novel postnatal prenatal prenatal exposure relating to nervous system response screening sex trait

项目摘要

Project Summary Prenatal chemical exposures are widely suspected to contribute to risk of neurodevelopmental disorders but direct evidence linking specific chemicals to adverse neural effects is sparse, and very little is known about the mechanisms by which they impact the developing brain. The pressing need to understand how prenatal chemical exposures contribute to disorders of neurodevelopment is the scientific premise for this proposal. Our preliminary data show that disruption of placental serotonin (5-HT) constitutes a potentially key and novel mechanism of neurodevelopmental disruption. The proposed studies will test the hypothesis that chemical exposures disrupt serotonergic communication between the placenta and developing forebrain resulting in ASD-related behavioral deficits and compromised synaptic organization and neurodevelopment. 5-HT, arising from the fetal placenta, has profound effects on the developing brain, particularly forebrain. Our preliminary data in rats shows that prenatal exposure to the chemical flame retardant (FR) mixture Firemaster® 550 (FM550) disrupts the placental 5-HT biosynthetic pathway and results in higher anxiety in males and hyperactivity in females later in life. We further show that FM550 components bioaccumulate in rat placenta and the brominated components transfer across the placenta into the fetus. An important aspect of this proposed work is a focus on sex differences, both in susceptibility and the exposure phenotype. We have found that FM550 components bioaccumulate to a greater degree in males, an outcome similar to what we have also seen for other FRs in humans, suggesting males are at greater risk of exposure- related consequences. This mirrors the male-biased incidence of many neurobehavioral disorders. FM550 contains two brominated FRs and a mixture of organophosphate ester FRs, the latter of which have large volume applications as plasticizers, so human exposure is widespread and predates the introduction of FM550. The potential toxicity of these replacement FRs is poorly characterized. Sex-specific disruption of placental 5-HT constitutes a potentially key and novel mechanism of neurodevelopmental disruption. Aim 1: Establish the toxicokinetics of FM550 components in gestating rats, and quantify the degree to which FM550 bioaccumulates in rats and humans of each sex. Aim 2: Elucidate the capacity of FM550 to disrupt placental 5-HT biosynthesis and serotonergic input on the developing forebrain. Aim 3: Understand the long term impact of developmental FM550 exposure on neural development and behavior. The long term goal of our work is to elucidate the impact of prenatal chemical exposures on brain development so that strategies can be devised to limit exposure to harmful compounds, and mitigate their harmful effects.

项目总结