Brain Influences of Phthalates and Bisphenols in Adolescents

项目总结

Project Summary This proposal will leverage unprecedented data from a Dutch birth cohort to examine the influence of phthalate and bisphenol exposures in multiple potentially susceptible periods on executive function and behavior in adolescents. Substantial literature has investigated the negative impact of prenatal exposures to phthalates and bisphenols on developmental programming of cognition and behavior. Yet few studies have examined exposures beyond early childhood. Further, the rigor of earlier studies is limited due to the lack of focus on mechanisms and failure to apply a life course approach. We propose to measure urinary levels of phthalates and bisphenols at ages 9–10 and 13–14 years in ≈ 1000 participants of Generation R, the largest neuroimaging study in the general pediatric population enrolled prenatally with follow-up through adolescence. We will evaluate executive function and behavior in children at age 16–18 years and measure sex hormones. Available data on measures of chemicals during the prenatal period and at 5–6 years, thyroid function in both mother and child, brain magnetic resonance imaging at ages 9–10 and 13–14 years, and feasibility of follow-up during adolescence provide an exceptional opportunity to parse out neurotoxic effects of pre- and postnatal exposures and identify the mechanisms. The large sample size will allow assessing sex as a biological variable. Specific aims are 1) to determine the impact of prenatal, childhood, and early adolescent phthalate and bisphenol exposures on executive function and behavior in adolescents and 2) to examine potential mechanisms underlying adverse influences of phthalates and bisphenols including thyroid and sex hormone disruption as well as brain structural abnormalities and white matter integrity. We hypothesize that chemical exposures during childhood and adolescence are associated with impaired executive function and behavioral problems, independent of prenatal exposure. Perturbations of thyroid and sex hormones are hypothesized to partly explain this association. We expect to observe the impact of childhood and early adolescence exposures on parietal lobe, attention networks, and prefrontal and limbic tracts, independent of the global effect of prenatal chemical exposures. This proposal is grounded on evidence showing that significant growth and maturation of the adolescent brain occurs in response to hormonal changes. Our preliminary data show anti- androgenic effects of di-2-ethylhexylphthalate in adolescents and thyroid disruption by prenatal phthalate and bisphenol exposures. Because of similarities in exposure levels in this Dutch cohort and the US samples, findings of this study will be applicable to the US context. Understanding the neurotoxicity of phthalates and bisphenols during adolescence has high implications because the plasticity of the adolescent brain makes this period a time of considerable opportunity for intervention. If the adolescent brain is found to be affected by chemicals then guidance in regulations of chemical exposures beyond the prenatal period might be indicated.