Individual and co-exposure to perchlorate, nitrate, and thiocyanate and insulin resistance in the U.S population: A dominant role of perchlorate

Insulin resistance significantly contributes to diabetes; it can be influenced not only by lifestyle but also by environmental contaminants. Emerging evidence suggests that perchlorate, nitrate, and thiocyanate-widely dispersed sodium/iodide symporter (NIS)-inhibiting pollutants- might influence insulin resistance; however, their direct associations remain insufficiently investigated. Using NHANES data, this study investigated whether urinary levels of these chemicals correlate with insulin resistance, addressing a critical gap in understanding environmental contributors to diabetes risk. We analyzed 2011-2020 NHANES data from 3047 U.S. adults (≥20 years). Insulin resistance was assessed via HOMA-IR, with values > 2.6 being used to define insulin resistance. Weighted multivariable regression models showed that the highest tertile of perchlorate exposure demonstrated positive associations with HOMA-IR (β=0.13, [95 % CI: 0.03, 0.23]) and insulin resistance (OR=1.96, [95 % CI: 1.20, 3.22]) in fully adjusted models. (RCS) Analyses revealed an inverted U-shaped nonlinear dose-response relationship between nitrate exposure and both HOMA-IR and insulin resistance. Stratified analyses identified pronounced effects among obese individuals (BMI≥30 kg/m²), with perchlorate showing the strongest association (HOMA-IR β=0.45, [95 % CI: 0.31, 0.59]; insulin resistance OR=3.47, [95 % CI: 1.93, 6.23]). Similar patterns emerged for those with large waist circumference (≥100 cm). Weighted quantile sum regression indicated a significant positive trend mixture effect (HOMA-IR β=0.06, [95 % CI: 0.02, 0.12]), with perchlorate contributing most substantially (weight=0.74). However, BKMR further captured the complex joint effects of the chemical mixture, demonstrating component-specific and nonlinear exposure-response relationships, with perchlorate emerging as the primary contributor to the mixture-related metabolic effects. In conclusion, this study identified a positive association between higher perchlorate exposure and insulin resistance, with obesity markedly potentiating this association, underscoring the need to consider environmental chemical exposures in diabetes prevention strategies.