Sex- and trimester-specific impact of gestational co-exposure to organophosphate esters and phthalates on insulin action among preschoolers: Findings from the Ma’anshan birth cohort

• First epidemiological study of prenatal co-exposure to OPEs and PAEs and child insulin. • Co-exposure to OPEs and PAEs was associated with increased insulin resistance. • Co-exposure to OPEs and PAEs was associated with decreased insulin action index. • The second trimester appears to be the sensitive window for the effects of co-exposure. • Girls show greater susceptibility in insulin action due to co-exposure compared to boys. Prenatal exposure to organophosphate esters (OPEs) and phthalic acid esters (PAEs) is ubiquitous among pregnant individuals. However, research exploring the relationship between prenatal co-exposure to OPEs and PAEs and childhood insulin function remains limited. In this study, utilizing data from 2,246 maternal-fetal dyads in the Ma’anshan Birth Cohort, associations between co-exposure to OPEs and PAEs and insulin action were analyzed. Repeated measures of tris (2-chloroethyl) phosphate, six OPE metabolites, and seven PAE metabolites were collected from maternal urine. Homeostasis model assessment of insulin resistance (HOMA-IR) and the insulin action index (IAI) served as outcome measures. After adjusting for potential confounders, the effects of repeated exposure on insulin action were evaluated using generalized estimating equations, while mixture effects were assessed through BayesianKernel Machine Regression and Quantile-Based G-Computation. The average age of the children at the time of the study was 5.33 years. Repeated measures analysis revealed that prenatal exposure to MEP was positively associated with increased HOMA-IR ( β , 0.027; 95 % CI : 0.002, 0.053), while IAI was inversely correlated with rising MEP levels ( β , 0.025; 95 % CI : −0.046, −0.004) and MEHHP exposure ( β , −0.128; 95 % CI : −0.218, −0.037). Mixed exposure modeling further indicated that co-exposure to OPEs and PAEs was positively linked to HOMA-IR ( β , 0.058; 95 % CI : 0.001, 0.114) and negatively correlated with IAI ( β , −0.054; 95 % CI : −0.097, −0.010), with stronger effects observed during the second trimester. Notably, the association was more pronounced in female children compared to males. This study provides the first epidemiological evidence highlighting the pregnancy- and sex-specific links between prenatal co-exposure to OPEs and PAEs and childhood insulin action.