Elsevier

Redox Biology

Volume 55, September 2022, 102414
Redox Biology

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

https://doi.org/10.1016/j.redox.2022.102414Get rights and content
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Highlights

  • DEHP reduces placental NAD + by compartmental regulation.

  • DEHP inhibits ATP production by disrupting mitochondrial structure quantity and function.

  • Limited NAD+ and ATP together inhibit DNA damage repair activity of PARP1.

  • Appropriate NAM can alleviate DNA and mitochondria damage to some extent.

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.

Graphical abstract

DEHP decreases the overall NAD+ level of the placenta and reduces the NAD+ level in the placental cell nucleus by participating in the regulation of NAD+ regionalization. By destroying the placental cell mitochondrial structure, reducing the number of mitochondria, hindering the way of electron transfer in the respiratory chain, DEHP reduces ATP production. Under the combined action of NAD+ and ATP depletion, inhibition of PARP1 activity leads to the accumulation of DNA damage and ultimately to the reduction of the placental trophoblast area. The partially damaging effects of DEHP on DNA and mitochondrial structures can be alleviated by moderate supplementation of NAD+ precursor NAM.

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Keywords

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

Data availability

Data will be made available on request.

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1

These authors contributed equally to this work.