White matter microstructural integrity mediates associations between prenatal endocrine-disrupting chemicals exposure and intelligence in adolescents.

Per- and polyfluoroalkyl substances (PFAS) and phthalic acid esters (PAEs) are well-known endocrine-disrupting chemicals (EDCs) that potentially affect child neurodevelopment. We aimed to investigate the effects of prenatal exposure to PFAS and PAEs on macro- and micro-structural brain development and intelligence in adolescents using multimodal neuroimaging techniques. We employed structural magnetic resonance imaging (MRI) and various diffusion MRI techniques, including diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and neurite orientation dispersion and density imaging (NODDI), to assess the gray-matter macrostructure and white-matter microstructural integrity and complexity. Participants were drawn from a birth cohort of 52 mother-child pairs in central Taiwan recruited in 2001, and the adolescent intelligence quotient (IQ) scores were assessed using the Wechsler Intelligence Scale. Nine PFAS concentrations of cord blood and maternal serum samples were obtained from the children's mothers during the third trimester of pregnancy (27-40 weeks) using a liquid chromatography system coupled to a triple-quadrupole mass spectrometer, while maternal urinary phthalates were used to evaluate PAEs exposure. Our results showed significant associations between prenatal exposure to PFAS and phthalates with changes in specific fronto-parietal regions of the adolescent male brain, including reduced cortical thickness in the inferior frontal gyrus and right superior parietal cortex, which are involved in language, memory, and executive function. A dose-response association was observed, with higher levels of PFAS and PAE exposure modulating altered white-matter fiber integrity in the superior cerebellar peduncle and inferior cerebellar peduncle of the male and female adolescent brains. In addition, higher levels of prenatal exposure to EDCs were associated with lower IQ scores in adolescents. Mediation analyses further revealed that white-matter microstructure of inter-hemispheric and cerebellar fibers mediated the association between prenatal EDC exposure and adolescent IQ scores in female adolescents. Our multimodal human neuroimaging findings suggest that prenatal exposure to EDCs may have long-lasting effects on neuroanatomical development, neural fiber connectivity, and intelligence in adolescents, and highlight the importance of using advanced diffusion imaging techniques, including DKI and NODDI, to detect neurodevelopmental changes and their brain-behavioral consequences with the risks associated with these environmental exposures.