Maternal CuO NPs exposure induces vascular damage in offspring via ferroptosis and cuproptosis: the regulatory role of GSH.

Abstract

With extensive applications in industrial, agricultural, and biomedical fields, copper oxide nanoparticles (CuO NPs) have attracted increasing concerns over their environmental exposure and potential health risks. Maternal nanoparticles exposure affects fetal development and leads to long-term health consequences in offspring. However, the developmental vascular toxicity and underlying mechanisms of CuO NPs on offspring remain unclear. In this study, pregnant rats were exposed to CuO NPs from gestation to lactation. CuO NPs induced histopathological damage and collagen deposition in the offspring aorta, indicating vascular structural damage. Moreover, alterations associated with ferroptosis and cuproptosis were observed in the offspring aorta. In vitro, CuO NPs induced oxidative stress and promoted the ubiquitination-dependent degradation of xCT in HUVECs, accompanied with intracellular glutathione (GSH) depletion. GSH depletion was associated with impaired GPX4-mediated antioxidant defense, increased DLAT aggregation, and loss of Fe-S cluster proteins. These findings supported the involvement of ferroptosis and cuproptosis related responses and suggested a potential interaction between these two processes. Furthermore, Fer-1, TTM, and GSH alleviated CuO NPs-induced alterations, whereas erastin, elesclomol, and BSO exacerbated these processes, further supporting an association between ferroptosis and cuproptosis. These findings suggested that vascular injury in offspring was associated with maternal CuO NPs exposure, accompanied by ferroptosis and cuproptosis related alterations, while GSH might serve as an important regulatory factor in their interaction. This study provides critical insights into the vascular toxicity risks in offspring after maternal nanoparticles exposure and highlights the potential role of GSH in nanoparticle-induced developmental cardiovascular injury.