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

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.

SUBMITTER: Zhao S

PROVIDER: S-EPMC9356100 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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

Zhao Shuai S Hong Yun Y Liang Yue-Yue YY Li Xiao-Lu XL Shen Jiang-Chuan JC Sun Cong-Cong CC Chu Ling-Luo LL Hu Jie J Wang Hua H Xu De-Xiang DX Zhang Shi-Chen SC Xu Dou-Dou DD Xu Tao T Zhao Ling-Li LL

Redox biology 20220720

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<sup>+</sup> ...[more]

PMID: 35926314

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Project description:IntroductionThe advanced maternal age (AMA) pregnancies escalate rapidly, which are frequently linked to higher risks of adverse outcomes. Advanced maternal age (AMA) placenta exhibited premature aging, presumably resulting in trophoblast dysfunction, inadequate placentation. However, the precise reasons and mechanisms of trophoblast aging in AMA placenta remain unclear, posing a significant limitation to provide effective guidance for prenatal healthcare in clinical settings. Notably, the organism shows heightened vulnerability to oxidative damage as it ages. YAP (Yes-associated protein) was reported to play a critical role in regulation of aging and resisting oxidative damage, yet these roles had not been elucidated in the placenta. Therefore, this study explored the relationship between trophoblast cell aging and oxidative injury and YAP in AMA pregnancy, which not only provided an insight into the mechanisms of trophoblast cell aging, but also provide valuable directions for healthcare during AMA pregnancy.MethodsIn this study, human term placentas were collected from AMA and normal pregnancies for the analysis of aging, oxidative damage and YAP level. HTR8/SVneo cells were manipulated with (hydrogen peroxide) H2O2 to explore the effects of oxidative damage on trophoblast cell senescence and YAP levels. YAP expression in HTR8/SVneo cells was manipulated to investigate its role in trophoblastic senescence and oxidative damage.ResultsCompared with the control group, the AMA placenta exhibits increased aging biomarkers, which is coupled with an elevation in oxidative damage within placental trophoblast cells and a notable decline in YAP levels. Cellular experiments demonstrated that oxidative damage from H2O2 triggered trophoblast cell senescence and resulted in a reduction of YAP levels. Furthermore, employing molecular modification to silence YAP expression in these cells led to an induction of aging. Conversely, overexpressing YAP ameliorated both trophoblast cell aging and the associated DNA oxidative damage that arised from H2O2.ConclusionThe decline of YAP in AMA pregnancy should be responsible for the increased oxidative injury and premature placenta aging, indicating that YAP plays a significant role in combating oxidative damage and delaying aging, thereby providing a new guidance for prenatal care in AMA pregnancies. Maintaining YAP levels or implementing anti-oxidative stress interventions could potentially mitigate the incidence of complications involved AMA pregnancy.

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

Publications

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

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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