Prenatal exposure to low doses of benzophenone-3 elicits disruption of cortical vasculature in fetuses through perturbations in Wnt/β-catenin signaling correlating with depression-like behavior in offspring mice

Benzophenone-3 (BP-3), commonly used in personal care products, is routinely detected in environmental and human matrices. Evidence delineates a correlation between gestational BP-3 exposure and emotional and social disorders in children and adolescents. However, sensitive target cells and the mode of action underlying the early responses to environmentally relevant level of BP-3 exposure remain unclear. In this study, 0.3 and 3 mg/kg of BP-3 were administered to pregnant mice. Compared with the control group, the cortical blood vessel development process manifested the highest susceptibility to BP-3 exposure using transcriptomic sequencing at embryonic day 14 (E14). Notably, the diminution in vascular density and tight junction proteins presence was observed in the fetal cortex at E14, concomitant with the suppressed transcriptional activity of genes essential to angiogenesis and barrier formation. Strikingly, the investigation revealed that BP-3 exposure impeded vascular sprouting in aortic ring explants and neuroendothelial migration, implicating the Wnt/β-catenin signaling pathway. Moreover, BP-3 exposure compromised perivascular neural stem cell differentiation. Cortical vascular injury correlated with the exhibition of depression-like behavior in four-week postnatal progeny. These insights underscore the cerebrovasculature as an early sensitive target for low doses of BP-3 exposure, fostering the development of biomarkers and the establishment of the adverse outcome pathway framework for BP-3 hazard evaluation.