Associations of urinary benzothiazole and its derivatives with hypertension and underlying metabolic perturbations

As high-production-volume chemicals, benzothiazole and its derivatives (BTHDs) are produced and utilized extensively with ubiquitous human exposure, yet their potential cardiometabolic health effects remain an area of limited understanding. The current case-control study explored the associations of urinary BTHDs with hypertension risk and explored related metabolic perturbations in 287 newly diagnosed hypertension cases and 287 matched controls. Results showed that benzothiazole (BTH; mean 2.14 μg/g creatinine) had the highest mean urinary concentration in all participants, followed by 2-methylthio-benzothiazole (0.75 μg/g creatinine) and 2-hydroxy-benzothiazole (2-OH-BTH; 0.53 μg/g creatinine). A positive relationship was observed between urinary concentrations of BTH and 2-OH-BTH and hypertension risk. When comparing the highest to the lowest exposure quartiles, the adjusted odds ratios were 1.93 (95% CI: 1.33-2.53; p = 0.019) for BTH and 2.01 (95% CI: 1.38-2.64; p = 0.020) for 2-OH-BTH. Co-exposure to BTHDs was also positively associated with hypertension risk. Metabolomic analysis identified 176 differentially expressed metabolites in human urine between cases and controls. Mediation analysis demonstrated that disturbances in alpha-linolenic acid and linoleic acid metabolism and the urea cycle significantly mediated the BTH/2-OH-BTH exposure related hypertension risk. Our study provides novel epidemiological evidence linking BTHD exposure to hypertension, and offers insights into the underlying metabolic mechanisms.