Journal
JOURNAL OF HAZARDOUS MATERIALS
Volume 421, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jhazmat.2021.126815
Keywords
Placental development; Di (2-ethyl-hexyl) phthalate; Fetal growth restriction; DNA double-strand break; Progesterone
Categories
Funding
- National Natural Science Foundation of China, China [82073593]
- Scientific Research Projects in Colleges and Universities of Anhui Education Department, China [KJ2019A0281, KJ2020A0666]
- Innovation and Entrepreneurship Training Program for College Students of Anhui Province, China [S201910366036, 201911059051]
- Domestic Visiting and Training Project for Excellent Young Key Teachers of Colleges and Universities, China [gxgnfx2020115]
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DEHP inhibits placental cell proliferation through two main mechanisms: suppressing classical DSB repair pathways, leading to cell cycle arrest at G2/M phase; and stimulating an elevated level of progesterone, blocking the cell cycle at metaphase by disrupting chromosome arrangement. These two events facilitate micronuclei formation and ultimately result in cell proliferation inhibition.
Di (2-ethyl-hexyl) phthalate (DEHP) is a widely used plasticizer. Maternal DEHP exposure inhibits cell proliferation and reduces placentas size, which associates with fetal growth restriction and adulthood diseases. However, the mechanism of placental cell proliferation inhibition by DEHP remains elusive. This study investigated the effect of DEHP on placental cell proliferation from cell cycle arrest. Utilizing in vitro and in vivo experiments, we investigated cell cycle arrest, DNA double-strand break (DSB) repair, genotoxic stress response, and micronuclei formation. Most DEHP metabolizes to mono (2-Ethylhexyl) phthalate (MEHP) and distributes to organs quickly, so MEHP and DEHP were used in cultured cell and animal experiments, respectively. Here, a double blocking mode for the proliferation inhibition of the placental cell was revealed. One is that the classical DSB repair pathways were suppressed, which arrested the cell cycle at the G2/M phase. The other is that DEHP stimulated an elevated level of progesterone, which blocked the cell cycle at metaphase by disrupting chromosome arrangement. These two sets of events facilitated micronuclei formation and resulted in cell proliferation inhibition. This findings provide a novel mechanistic understanding for DEHP to inhibit placental cell proliferation.
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