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Maternal exposure to di-(2-ethylhexyl) phthalate exposure deregulates blood pressure, adiposity, cholesterol metabolism and social interaction in mouse offspring

Abstract

Long-term exposure to di-(2-ethylhexyl) phthalate (DEHP) is highly associated with carcinogenicity, fetotoxicity, psychological disorders and metabolic diseases, but the detrimental effects and mechanisms are not fully understood. We investigated the effect of exposing mouse mothers to DEHP, and the underlying mechanism, on blood pressure, obesity and cholesterol metabolism as well as psychological and learning behaviors in offspring. Tail-cuff plethysmography was used for blood pressure measurement; Western blot used was for phosphorylation and expression of protein; hematoxylin and eosin staining, Nissl staining and Golgi staining were used for histological examination. The serum levels of cholesterol, triglycerides and glucose were measured by blood biochemical analysis. Hepatic cholesterol and triglyceride levels were assessed by colorimetric assay kits. Offspring behaviors were evaluated by open-field activity, elevated plus maze, social preference test and Morris water maze. Maternal DEHP exposure deregulated the phosphorylation of endothelial nitric oxide synthase and upregulated angiotensin type 1 receptor in offspring, which led to increased blood pressure. It led to obesity in offspring by increasing the size of adipocytes in white adipose tissue and number of adipocytes in brown adipose tissue. It increased the serum level of cholesterol in offspring by decreasing the hepatic capacity for cholesterol clearance. The impaired social interaction ability induced by maternal DEHP exposure might be due to abnormal neuronal development. Collectively, our findings provide new evidence that maternal exposure to DEHP has a lasting effect on the physiological functions of the vascular system, adipose tissue and nerve system in offspring.

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Acknowledgments

The authors thank Laura Smales for help in language editing. This study was supported by grants from the National Science Council (101-2628-B-010-001-MY2, 101-2811-B-010-039, 102-2628-B-010-001-MY3 and 103-2628-B-010-040-MY3), Yen Tjing Ling Medical Foundation (CI-104-13) and Ministry of Education, Aim for the Top University Plan, Taiwan.

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The authors declare no conflict of interest.

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Correspondence to Tzong-Shyuan Lee.

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Kuan-I Lee and Chin-Wei Chiang have contributed equally to this work.

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Lee, KI., Chiang, CW., Lin, HC. et al. Maternal exposure to di-(2-ethylhexyl) phthalate exposure deregulates blood pressure, adiposity, cholesterol metabolism and social interaction in mouse offspring. Arch Toxicol 90, 1211–1224 (2016). https://doi.org/10.1007/s00204-015-1539-0

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Keywords

  • Di-(2-ethylhexyl) phthalate
  • Blood pressure
  • Adiposity
  • Cholesterol metabolism
  • Social interaction
  • Offspring