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Transcriptome analysis revealed the mechanism of the metabolic toxicity and susceptibility of di-(2-ethylhexyl)phthalate on adolescent male ICR mice with type 2 diabetes mellitus

  • Molecular Toxicology
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Abstract

The prevalence of adolescent type 2 diabetes mellitus (A-T2DM) is increasing year by year. Di-(2-ethylhexyl)phthalate (DEHP), a widely used plasticizer, could exacerbate type 2 diabetes mellitus (T2DM). The study aimed to investigate the metabolic toxicity, susceptibility and mechanism of DEHP exposure to A-T2DM. DEHP was administered orally (0, 0.18, 1.8, 18, and 180 mg/kg/day) for 3 weeks to adolescent normal mice (A-normal mice) and established A-T2DM mice. The results of fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) levels showed that the susceptibility of A-T2DM mice to DEHP exposure was more significant than that of A-normal mice. DEHP, interfering with glucose and lipid metabolism of A-normal and A-T2DM mice, caused the body weight increase of A-normal mice and decrease of A-T2DM mice. Besides, DEHP could cause more injury of cardiovascular, hepatic and renal function to A-T2DM mice than A-normal mice. Hepatic transcriptome analysis revealed that DEHP exposure interfered with the biological feedback adjustment of endocrine and metabolic system in A-T2DM mice and then led to the development of T2DM. According to the transcriptome results, insulin signaling transduction pathway was applied and researched by immunoassay. It was discovered that DEHP reduced insulin sensitivity and disturbed insulin signaling transduction, glucose utilization, lipid synthesis and protein synthesis. Collectively, DEHP could disturb the endocrine and metabolic functions and increase the insulin resistance in adolescent mice. Moreover, the adolescent T2DM mice are more sensitive to DEHP-induced endocrine and metabolic toxicity than the healthy adolescent mice.

Highlights

  • DEHP could cause metabolic toxicity and insulin resistance to adolescent mice.

  • DEHP could exacerbate insulin resistance and metabolic disorders in adolescent T2DM mice.

  • Adolescent T2DM mice are more sensitive to DEHP than normal adolescent mice.

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Acknowledgements

The experiments were supported by Institute of Environmental health and Ecological Security, Jiangsu University, Zhenjiang, Jiangsu, China.

Funding

This work was supported financially by Specialized Research Fund for the Natural Science Foundation of China (81602889), China Postdoctoral Science Foundation (2017M611741), Postdoctoral Science Foundation of Jiangsu Province (1701108B), Research Foundation for Senior Talents of Jiangsu University (15JDG146), Graduate Innovative Projects in Jiangsu Province (KYCX17_1795), State Key Laboratory of Environmental Chemistry and Ecotoxicology Open Fund (KF 2018-02), Natural Science Foundation of Jiangsu province (BK20160497) and Collaborative Innovation Center for Water Treatment Technology and Materials.

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  1. Yangyang Ding and Kun Gao contributed to this article equally and are co-first authors.

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  1. School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang, Jiangsu, China

    Yangyang Ding, Kun Gao, Yongchao Liu, Guanghua Mao, Kun Chen, Xuchun Qiu, Weiwei Feng & Xiangyang Wu

  2. School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang, Jiangsu, China

    Ting Zhao & Liuqing Yang

  3. Institute of Environmental Health and Ecological Security, Jiangsu University, Zhenjiang, Jiangsu, China

    Kun Chen, Xuchun Qiu, Weiwei Feng & Xiangyang Wu

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Ding, Y., Gao, K., Liu, Y. et al. Transcriptome analysis revealed the mechanism of the metabolic toxicity and susceptibility of di-(2-ethylhexyl)phthalate on adolescent male ICR mice with type 2 diabetes mellitus. Arch Toxicol 93, 3183–3206 (2019). https://doi.org/10.1007/s00204-019-02590-8

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