Associations of prenatal co-exposure to phthalate metabolites and bisphenols with neural tube defects

Neural tube defects (NTDs) are one of the most common birth defects. Phthalates and bisphenols are ubiquitous endocrine-disrupting chemicals (EDCs), which can disrupt the endocrine system by altering hormone levels. However, there is no study on the associations between co-exposure to phthalate metabolites and bisphenols and risk of fetal NTDs. A case–control study was conducted among 286 participants in China from 2005 to 2016. Liquid chromatography–tandem mass spectrometry was used to detect the levels of 25 EDCs in placenta. Logistic regression and multipollutant models were used to evaluate the single and co-exposure effects of EDCs on NTD risk, with maternal age, gestational weeks at placenta collection, pre-pregnancy body mass index, history of birth defects, folate supplementation during pregnancy, and smoking status as covariates. This study also assessed whether gestational exposure to mono-(2-ethylhexyl) phthalate (MEHP) in pregnant mice induces NTDs in offspring. Individual exposure to high levels of MEHP, mono-octyl phthalate, and mono-cyclohexyl phthalate was associated with increased NTD risk [odds ratio (OR) = 2.89, 95% confidence interval (CI): 1.13, 7.43; OR = 3.00, 95% CI: 1.15, 7.85; OR = 2.78, 95% CI: 1.08, 7.18]. Multipollutant models showed a positive correlation between the EDCs mixture levels and NTD risk, with MEHP and bisphenol Z as the main contributors. In animal experiments, NTD rates increased with MEHP dosage, showing a statistically significant trend. This is the first study to evaluate the single and co-exposure effects of phthalate metabolites during pregnancy on NTD risk. Our findings suggest that exposure to phthalate metabolites and bisphenols during pregnancy may increase the risk of NTDs, and policies regarding phthalates and bisphenols exposure in the environment should be strengthened.