Plasticizer-related toxicogenomic signatures in gestational diabetes: Mendelian randomization, placental single-cell...

Plasticizer exposure has been associated with gestational diabetes mellitus (GDM), but the placental toxicogenomic mechanisms that may connect environmental chemical signals to maternal dysglycaemia remain unresolved. We integrated plastic-associated compound target annotation, placental bulk transcriptomics, cis-eQTL-based Mendelian randomization (MR), Bayesian colocalization, machine-learning prioritization, pathway analysis, placental single-cell transcriptomics and trophoblast validation. Candidate targets were intersected with GDM-related placental expression signals and tested against FinnGen GDM summary statistics using blood-derived cis-eQTL instruments. Among expression-supported targets, 15 genes showed nominal MR associations with GDM and 11 loci showed colocalization support. LASSO regression and random forest prioritization converged on AKT1, CLEC7A and CTSS. Expression-direction checks showed concordance between bulk placental expression and MR direction for AKT1 and CTSS, whereas CLEC7A showed a discordant genetic direction and was therefore interpreted cautiously. Functional analyses placed these genes in immune, redox and metabolic pathways, while single-cell data localized them to trophoblast and immune-related placental compartments. In HTR-8/SVneo trophoblast cells, di-(2-ethylhexyl) phthalate (DEHP) exposure altered CLEC7A expression, providing targeted evidence that CLEC7A is phthalate-responsive at the mRNA level under the tested conditions. The two-dose design did not support a formal concentration-response conclusion. The findings define a toxicogenomic hypothesis in which plasticizer-related stress intersects with placental immunometabolic regulation in GDM. The study does not establish direct exposure causality, but it prioritizes testable placental targets for exposure-resolved toxicological and epidemiological validation.