Role of estrogen receptors in thyroid toxicity induced by mono (2-ethylhexyl) phthalate via endoplasmic reticulum stress: An in vitro mechanistic investigation.

Mono(2-ethylhexyl) phthalate (MEHP) can influence the expression of estrogen receptors (ERs) and induce thyroid injury. The expression of ERs can be related to thyroid disease and abnormal expression of ERs has been associated with activation of endoplasmic reticulum stress. This study aimed to clarify the role of ERs in MEHP-induced thyroid damage via endoplasmic reticulum stress. We exposed Nthy-ori 3-1 cells to different doses of MEHP. We found that after the exposure, the cell viability and the expression levels of thyroid hormone metabolism-related proteins decreased, while the apoptosis level and the expression levels of ERs (ERα and GPR30) increased. Three endoplasmic reticulum stress-related signaling pathways were activated by MEHP. After ERα and GPR30 were knocked down, these three pathways were inhibited and the thyroid toxicity was alleviated. Taken together, our results indicate that MEHP can induce thyroid toxicity by upregulating the expression of ERs, further activating endoplasmic reticulum stress.

Di(2-ethylhexyl) phthalate induced thyroid toxicity via endoplasmic reticulum stress: In vivo and in vitro study.

Di(2-ethylhexyl) phthalate (DEHP) could induce thyroid injury but the mechanism was unclear. This study combined in vivo and in vitro experiments to clarify the mechanism. In vivo, the offspring of Sprague Dawley rats were gavaged with different doses of DEHP (5, 50, and 250 mg/[kg⋅d]) from in utero to 12 weeks-old. Transcriptome sequencing was used to detect the mRNA expression profile of the offspring's thyroids. Differentially expressed genes were identified, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In vitro, Nthy-ori 3-1 cells were exposed to DEHP's metabolite mono (2-ethylhexyl) phthalate (MEHP) to verify the pathway we found by KEGG analysis. The results indicated that DEHP could disorder the thyroid hormones. Compared with the offspring in control group, the mRNA levels of 656 genes were upregulated in the offspring exposed to 50 mg/(kg⋅d) DEHP. The upregulated genes were enriched in the pathway of "protein processing in the endoplasmic reticulum (ER)." It indicated that the ER stress might play significant role in the thyroid toxicity induced by DEHP. In vitro, the mitochondrial membrane potential (ΔΨm) level of cells was decreased while the reactive oxygen species level was increased after MEHP exposure. MEHP increased the intracellular Ca2+ level and induced ER stress. After ER stress was inhibited by the 4-phenylbutyric acid, the thyroid toxicity caused by MEHP was alleviated. Taken together, our results indicated that DEHP could induce thyroid toxicity by activating ER stress.