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/[kgÁd]) 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, Nthyori 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/(kgÁd) 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 Ca 2+ 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.

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Background:Di-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers.Many studies focus on the impact of continuous exposure to DEHP on humans and ecosystems.In this study, the bibliometric analysis of DEHP and its metabolites research was conducted to assess the research performances, hotspot issues, and trends in this field. Method:The data was retrieved from a web of science core collection online database.VOSviewer 1.6.18 was used to analyze. Result:A total of 4672 publications were retrieved from 1975 to 2022 October 21.The number of publications and citations increased annually in the last decades.China had the largest number of publications and the USA had the highest co-authorship score.The most productive and most frequently cited institutions were the Chinese Academy of Sciences and the Centers for Disease Control & Prevention(USA) , respectively.The journal with the most publications was Science of Total Environment and the most cited one was Environmental Health Perspectives.The most productive and cited author was Calafat AM(USA).The most cited reference was “Phthalates: Toxicology and exposure”.Four hotspot issues were as follows: influences of DEHP on the organisms and its possible mechanisms; assessment of DEHP exposure to the human and its metabolism; dynamics of DEHP in external environments; indoor exposure of DEHP and health outcomes.The research trends were DNOP, preterm birth, gut microbiota, microplastics, lycopene, hypertension, and thyroid hormones. Conclusion:This paper will be a useful resource for researchers to rapidly take the valuable information related to the authoritative scholars, publications, journals and institutions, hotspot issues, and trends in this research field.