Maternal 6PPD-Quinone Exposure is Associated with Infant Neurodevelopmental Delay: Epidemiological Evidence and Mechanistic Insights from a Birth Cohort Study

Tire-derived p-phenylenediamines (PPDs) and their quinone derivatives (PPD-Qs) have emerged as potential neurotoxicants, yet the associations of prenatal exposure with offspring neurodevelopment remain underexplored. Therefore, we conducted a nested case-control study within a prospective birth cohort (n = 1,317) and measured ten urinary PPDs/PPD-Qs at 6–16 weeks of gestation. In the primary adjusted model, higher urinary concentrations of 6PPD-quinone (6PPD-Q) and N,N′-di(o-tolyl)-p-phenylenediamine (DTPD) were associated with higher odds of neurodevelopmental delay. Quantile g-computation further indicated that a simultaneous one-quartile increase in all components of the PPDs/PPD-Qs mixture was associated with higher odds of neurodevelopmental delay (odds ratio = 1.33, 95% confidence interval: 1.03–1.72). Random forest analysis identified 6PPD-Q as having the highest variable importance among the measured PPDs/PPD-Qs. Network toxicology analysis implicated dopaminergic, serotonergic, and glutamatergic neurotransmission pathways as potentially relevant to 6PPD-Q-associated neurodevelopmental toxicity. In bEnd.3 mouse brain microvascular endothelial cells, 6PPD-Q exposure induced transcriptomic alterations involving xenobiotic metabolism, inflammatory signaling, and neurotransmission-related pathways. These changes were accompanied by decreased mRNA expression of the blood–brain barrier tight junction–related genes ZO-1 and occludin. Collectively, these epidemiological associations and complementary mechanistic findings support the biological plausibility of 6PPD-Q-associated developmental neurotoxicity and warrant further investigation and independent replication.