Benz[a]anthracene (BaA), a hazardous polycyclic aromatic hydrocarbon classified by the EPA, is a probable reproductive toxicant. Epidemiological studies suggest that BaA exposure may be a risk factor for recurrent miscarriage (RM). However, the underlying mechanisms are not well understood. This study identified DEC1 as a key gene through RNA-seq and single-cell RNA sequencing analysis. DEC1 expression was found to be downregulated in villous tissues from women with RM and in primary extravillous trophoblasts (EVTs) exposed to BaA. BaA suppressed DEC1 expression by promoting abnormal methylation patterns. Further analysis revealed that ARHGAP5 is a direct target of DEC1 in EVTs, where DEC1 inhibits trophoblast invasion by directly regulating ARHGAP5 transcription. Additionally, BaA destabilized matrix metalloproteinase 2 (MMP2) by activating the aryl hydrocarbon receptor (AhR) and promoting E3 ubiquitin ligase MID1-mediated degradation. In a mouse model, BaA induced miscarriage by modulating the DEC1/ARHGAP5 and MID1/MMP2 axes. Notably, BaA-induced miscarriage in mice was prevented by DEC1 overexpression or MID1 knockdown. These findings indicate that BaA exposure leads to miscarriage by suppressing the DEC1/ARHGAP5 pathway and enhancing the MID1/MMP2 pathway in human EVTs.
Qinghui Han,Shuguang Wang,Dawei Chen,Di Gan,Tao Wang
Tendon injuries are common clinical issues resulted from tissue overuse and age-related degeneration. Previous sutdies have suggested that exosomes secreted by mesenchymal stem cells (MSCs) contribute to tissue injury repair. Here, we provide evidence for a critical role of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes in reducing tendon injury by activating the RhoA signaling. Treatment of primary injured tenocytes with hucMSC exosomes increases cell proliferation and invasion, which correlates with increased RhoA activity. RhoA mediates the effects of hucMSC exosomes, as treatment of primary injured tenocytes with the RhoA inhibitor, CCG-1423, abolishes the effects of hucMSC exosomes on cell proliferation and invasion. Mechanistically, we observe that hucMSC exosomes induce the expression of a microRNA, miR-27b-3p, which targets and suppresses ARHGAP5, a negative regulator of RhoA. Consistent with this observation, ARHGAP5 overexpression suppresses the effects of hucMSC exosomes on cell proliferation and invasion, while knockdown of ARHGAP5 rescues these effects. Finally, we demonstrate the functional significance of our findings in vivo using an Achilles tendon injury model and show that treatment with exosomes reduces tendon injury in rats, which correlates with increased RhoA activity and reduced ARHGAP5 expression. Taken together, our findings highlight a critical role of hucMSC exosomes in reducing tendon injury via miR-27b-3p-mediated suppression of ARHGAP5, resulting in RhoA activation, and leading to increased cell proliferation and invasion of primary injured tenocytes.
危险品化学品经营许可证（带存储）