Interfering effects of monoester phthalates on Nthy-ori 3–1 cells through purine metabolism and repairing effects of potassium iodide

As an environmental pollutant, di(2-ethylhexyl) phthalate (DEHP) is often present in people's lives, and its exposure can induce thyroid disease. Although DEHP is thyrotoxic, the toxic effects of its metabolites, mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), on the thyroid glands are unclear. This study employed a case-control design (case group: 111 papillary thyroid carcinoma patients; control group: 111 healthy individuals) to analyze the combined exposure effects of multiple environmental endocrine disruptors using the weighted quantile sum (WQS) model and the quantile-based g calculation (Qgcomp) model. WQS analysis identified that MEHHP and iodine were the primary drivers of thyroid cancer risk (OR = 2.68, 95 % CI: 1.74–3.61), with iodine accounting for 49 % of the weight and MEHHP for 18 %. This study used human normal thyroid follicular epithelial cells (Nthy-ori 3–1) for in vitro experiments. After 21 days of exposure to the 95th percentile concentration of MEHHP (31.7 ng/ml) and the median concentration of iodine (149.0 ng/ml) in human urine, MEHHP significantly induced apoptosis compared to the control group (21.87 ± 0.21 % vs. 4.48 ± 0.38 %, P < 0.0001), while co-exposure with KI reversed this effect (5.74 ± 0.36 %). Untargeted metabolomics analysis showed that the differential metabolites from MEHHP exposure were predominantly enriched in the purine metabolic pathway compared to controls ( P < 0.05), with significant reductions in nucleotides such as ATP, ADP, and AMP (fold change <0.5), and an abnormal increase in hypoxanthine (fold change >2); KI intervention restored the levels of nucleotides and other metabolites. This study first revealed that MEHHP induces thyroid cell damage by interfering with purine metabolism, and iodine exhibits antagonistic effects at both the population and cellular levels, providing metabolomics-based evidence for the prevention and treatment of combined toxicity from environmental pollutants. • This study reveals the thyroid toxicity effect of MEHHP, a key secondary metabolite of DEHP. • MEHHP exposure triggers thyroid cell apoptosis through disruption of purine metabolism pathways. • KI administration demonstrates potential therapeutic effects by counteracting MEHHP-induced thyroid dysfunction. • Metabolomic analysis establishes novel associations between MEHHP exposure and thyroid functional impairment.