Compartmentalized regulation of NAD+ by Di (2-ethyl-hexyl) phthalate induces DNA damage in placental trophoblast

Shuai Zhao; Yun Hong; Yue-Yue Liang; Xiao-Lu Li; Jiang-Chuan Shen; Cong-Cong Sun; Ling-Luo Chu; Jie Hu; Hua Wang; De-Xiang Xu; Shi-Chen Zhang; Dou-Dou Xu; Tao Xu; Ling-Li Zhao

doi:10.1016/j.redox.2022.102414

Compartmentalized regulation of NAD⁺ by Di (2-ethyl-hexyl) phthalate induces DNA damage in placental trophoblast

Redox Biol. 2022 Sep:55:102414. doi: 10.1016/j.redox.2022.102414. Epub 2022 Jul 20.

Authors

Shuai Zhao¹, Yun Hong¹, Yue-Yue Liang¹, Xiao-Lu Li¹, Jiang-Chuan Shen², Cong-Cong Sun³, Ling-Luo Chu⁴, Jie Hu⁵, Hua Wang⁵, De-Xiang Xu⁵, Shi-Chen Zhang⁶, Dou-Dou Xu⁷, Tao Xu⁸, Ling-Li Zhao⁹

Affiliations

¹ Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Department of Toxicology, Anhui Provincial Key Laboratory of Population Health and Aristogenics, MOE Key Laboratory of Population Health Across Life Cycle, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230032, China; School of Biology, Food and Environment, Hefei University, Hefei, 230601, China.
² Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, 47405, USA.
³ Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Department of Toxicology, Anhui Provincial Key Laboratory of Population Health and Aristogenics, MOE Key Laboratory of Population Health Across Life Cycle, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230032, China; Key Laboratory of the Public Health Safety, Ministry of Education, Department of Environmental Health, School of Public Health / Center for Water and Health, School of Public Health, Fudan University, Shanghai, 200032, China.
⁴ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, 02138, USA.
⁵ Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Department of Toxicology, Anhui Provincial Key Laboratory of Population Health and Aristogenics, MOE Key Laboratory of Population Health Across Life Cycle, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230032, China.
⁶ Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Department of Toxicology, Anhui Provincial Key Laboratory of Population Health and Aristogenics, MOE Key Laboratory of Population Health Across Life Cycle, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230032, China; School of Public Health and Health Management, Anhui Medical College, No 632 Furong Road, Hefei, Anhui, 230601, China.
⁷ Department of Pediatrics, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China.
⁸ Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Department of Toxicology, Anhui Provincial Key Laboratory of Population Health and Aristogenics, MOE Key Laboratory of Population Health Across Life Cycle, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230032, China; School of Biology, Food and Environment, Hefei University, Hefei, 230601, China. Electronic address: xutao@hfuu.edu.cn.
⁹ Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Department of Toxicology, Anhui Provincial Key Laboratory of Population Health and Aristogenics, MOE Key Laboratory of Population Health Across Life Cycle, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230032, China. Electronic address: zhaolingli@ahmu.edu.cn.

Abstract

Di (2-ethyl-hexyl) phthalate (DEHP) is a wildly used plasticizer. Maternal exposure to DEHP during pregnancy blocks the placental cell cycle at the G2/M phase by reducing the efficiency of the DNA repair pathways and affects the health of offsprings. However, the mechanism by which DEHP inhibits the repair of DNA damage remains unclear. In this study, we demonstrated that DEHP inhibits DNA damage repair by reducing the activity of the DNA repair factor recruitment molecule PARP1. NAD⁺ and ATP are two substrates necessary for PARP1 activity. DEHP abated NAD⁺ in the nucleus by reducing the level of NAD⁺ synthase NMNAT1 and elevated NAD⁺ in the mitochondrial by promoting synthesis. Furthermore, DEHP destroyed the mitochondrial respiratory chain, affected the structure and quantity of mitochondria, and decreased ATP production. Therefore, DEHP inhibits PARP1 activity by reducing the amount of NAD⁺ and ATP, which hinders the DNA damage repair pathways. The supplement of NAD⁺ precursor NAM can partially rescue the DNA and mitochondria damage. It provides a new idea for the prevention of health problems of offsprings caused by DEHP injury to the placenta.

Keywords: ATP; DNA damage; Di (2-ethyl-hexyl) phthalate; Nicotinamide adenine dinucleotide; Placental development.