Trihalomethane Exposurein Relation to DepressiveSymptoms in Postmenopausal Women and Underlying Mechanisms from Anorgan-on-a-chip Model

Trihalomethanes (THMs) are suspected neurotoxicants, yet their relationships with depression remain unclear. This study examined the associations between blood THM concentrations and depressive symptoms, assessed by the Patient Health Questionnaire-9 (PHQ-9), in 2,130 postmenopausal U.S. women. Blood concentrations of bromodichloromethane (BDCM), dibromochloromethane (DBCM), and brominated trihalomethanes (Br-THMs) showed positive dose-response associations with depressive symptoms (PHQ-9 >= 5; all P for trend <0.05). Compared with the lowest exposure category, participants in the highest category of BDCM (T3), DBCM (>= 75th percentile), and Br-THMs (Q4) had increased odds ratios (ORs) for depressive symptoms of 1.38 (95% confidence interval: 1.04-1.82), 1.62 (1.25-2.09), and 1.46 (1.02-2.09), respectively. Further mechanistic experiments in a human neuroimmune organ-on-a-chip model (SH-SY5Y cells cocultured with THP-1 cells) showed that environmentally relevant exposure (0.001 mM BDCM and 0.0005 mM DBCM) increased interleukin-1 beta (IL-1 beta) levels and reduced 5-hydroxytryptamine (5-HT) levels. Low-dose BDCM exposure (0.001 mM) also induced neuronal cytoskeletal changes in SH-SY5Y cells, as reflected by changes in mean fluorescence intensity and skeletonized area. Together, our findings suggest that exposure to Br-THMs may be associated with depressive symptoms in postmenopausal women, potentially via IL-1 beta-mediated neuroinflammation and neurotransmitter imbalance.