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While humans are exposed to a wide range of potentially neurotoxic environmental chemicals, assessing their overall impact on the central nervous system (CNS) remains challenging due to the difficulty in quantifying multi-class chemicals at low concentrations and direct access to the CNS. We leverage our unique collection of paired plasma and cerebrospinal fluid (CSF) samples from pregnant women in an urban pregnancy cohort to comprehensively profile environmental exposures and explore their potential associations with postpartum neuropsychiatric symptoms. We quantified and characterized the distribution of 143 potential neurotoxic chemicals in 25 paired CSF-plasma samples, collected prior to delivery, using a high-sensitivity targeted multiclass assay. The chemicals spanned 16 classes including pesticides, phthalates and PFAS. We report wide detection of these chemicals or analytes not only in plasma but also in CSF, with 16 and 18 detected in all CSF and plasma samples, respectively. Additionally, 51 and 57 analytes were detected in >50% CSF and plasma samples, respectively, with 31 commonly detected in both and 17 (mostly phthalates and pesticides) at higher concentrations in CSF. We also observed an indication of a prospective associations between exposure mixture and Edinburgh Postnatal Depression Scale (EPDS) at six weeks postpartum using Weighted Quantile Sum (WQS) regression analysis, however confidence interval included zero. Our exploratory "exposome-scale" study is among the first to report a prevalent detection of numerous multi-class environmental chemicals in CSF, suggesting their ability to cross the blood-CSF barrier, and their collective presence in CNS may play a role in maternal postpartum mental health.