Exposure to multiple neonicotinoid insecticides, oxidative stress, and gestational diabetes mellitus: Association and potential mediation analyses

As the most extensively used insecticides worldwide, neonicotinoid insecticides (NNIs) have received a growing global concern over their adverse health effects. This study aimed to assess the associations of urinary concentrations of NNIs in early pregnancy with gestational diabetes mellitus (GDM), and the mediation roles of oxidative DNA damage, RNA damage, and lipid peroxidation in the associations. With a prospective nested case-control study, 519 GDM cases and 519 controls were matched on infant's sex and maternal age. Urinary biomarkers of NNIs exposure and oxidative stress were measured in early pregnancy. We estimated the associations of single and the mixture of NNIs and their metabolites with GDM by conditional logistic regression and quantile g-computation models, respectively. The mediating roles of oxidative stress were evaluated by structural equation model. The odds of GDM significantly increased by 15%, 18%, 26%, 42%, 49%, and 13% in each unit increment of ln-transformed concentrations of urinary imidacloprid (IMI), imidacloprid-olefin (IMI-olefin), desnitro-imidacloprid (DN-IMI), thiamethoxam (THM), clothianidin, and desmethyl-clothianidin, respectively. Exposure to the mixture of NNIs was associated with increased odds of GDM (adjusted OR: 1.76; 95%CI: 1.45, 2.13). Advanced maternal age enhanced the associations of 5-hydroxy-IMI, DN-IMI, and IMI-olefin with GDM (P < 0.05) and being overweight/obese before pregnancy strengthened the effects of IMI, IMI-olefin, and THM on GDM (P < 0.05). In the association of NNIs exposure and GDM, the proportions mediated by oxidative DNA damage, RNA damage, and overall oxidative stress were 9.8%, 11.8%, and 14.5%, respectively (P < 0.05). Exposure to NNIs in individual and in mixture were associated with GDM, and maternal age and pre-pregnancy BMI may modify the association. The possible mechanism underlying the association between NNIs and GDM may involve oxidative damage to nucleic acids.