Paternal DEHP exposure impairs placental angiogenesis via inhibition of the zygotic Col1α1/Col1α2-Integrin α2β1 axis

The plasticizer DEHP is ubiquitous in the environment, and its unavoidable daily low-dose chronic exposure can impair male sperm. Paternal sperm damage is associated with abnormal placental development in offspring. However, the underlying mechanisms remain unknown. This study innovatively explored the effects and potential mechanisms of paternal DEHP exposure on placenta development in offspring. The results showed that 90-day exposure to environmental doses of DEHP, male mice exhibited sperm damage, accompanied by a significant reduction in the vascular sinus area within the labyrinthine layer of GD17 placentas, indicating that DEHP-induced sperm damage impairs placental angiogenesis in offspring. Transcriptomic revealed the mechanism of placental angiogenesis obstruction, we found that in both fertilized zygotes and GD17 placentas, the mRNA and protein expression of the angiogenesis-associated type I collagen genes Col1α1 were significantly decreased. Furthermore, the expression of binding partner integrin α2β1 was decreased, leading to inhibition of downstream PI3K-AKT signaling pathway activity. To verify that reduced expression of Col1α1 and Col1α2 inhibits placental angiogenesis, the study knocked down Col1α1 and Col1α2 in Human Umbilical Vein Endothelial Cells (HUVEC), and confirmed the inhibitory effect on angiogenesis and related signaling pathways. In summary, this study demonstrates that paternal DEHP exposure may induce downregulation of Col1α1 and Col1α2, which are important angiogenic genes in the fertilized zygotes and placenta, leading to a reduction in placental sinus area. This study clarifies the association between paternal subchronic exposure to environmental doses of DEHP and abnormal placental vascular development in offspring, challenging the traditional "maternal dominance" paradigm in placental development research. The study provides an important scientific basis for comprehensively assessing the reproductive health risks of environmental pollutants and for formulating precise prevention and control strategies.