Paternal subchronic exposure to environmental doses of DEHP causes placental retardation by reducing the expression of collagen-related genes Col1a1 and Col1a2 in fertilized zygotes and placentas of the offspring, inhibiting the integrin α2β1-PI3K-AKT pathway activity, and decreasing the vascular area of the placenta. This effect may result from the impairment of genetic information in paternal germ cells. • From the perspective of parental research to reveal that Paternal exposure to DEHP can induced impairment of placental vascular development through sperm damage. • Proposing the possibility of epigenetic transmission of “sperm-fertilized zygotes- placenta”. • The downregulation of Col1a1 and Col1a2 expression in both fertilized zygotes and placental tissues suppresses α2β1-PI3K-AKT signaling pathway activity in placental vascular endothelial cells. • Combining TEM sperm analysis, placental histopathology, transcriptomics, and HUVEC cell siRNA knock down to gain toxicity relationship. 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 Col1a1 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 Col1a1 and Col1a2 inhibits placental angiogenesis, the study knocked down Col1a1 and Col1a2 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 Col1a1 and Col1a2 , 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.
Li et al. (2026) studied this question.