Combined exposure to high-cholesterol diet and PM 2.5 : Brain injury and regulatory mechanism of HIF-1α in female mice

Abstract High-cholesterol diet (HCD) and fine particulate matter (PM2.5) are related to stroke. The comprehensive influence of two factors on stroke is not well known, especially for females. In this study, we investigated brain injury and behavioral changes in female mice exposed to HCD plus PM2.5 for three months and six months, respectively. We measured gene expression of some factors related to stroke and the blood-brain barrier (BBB) in different groups of mice and further explored molecular mechanisms of epigenetic regulation of hypoxia-inducible factor-1α (HIF-1α). The results showed that HCD and PM2.5 co-exposure altered brain-body weight ratio, induced brain pathology damage and behavioral abnormality and elevated inflammatory markers (IL-6 and TNF-α) in mice relative to exposure to PM2.5 or HCD alone. Six-month exposure caused more severe brain damage than that three-month exposure. Co-exposure significantly changed the expressions of HIF-1α and the key genes (VEGF/COX-2/MMP-9/ZO-1/Occludin) in the HIF-1α signaling pathway in the brains of mice compared to the single exposure. Interestingly, HIF-1α was epigenetic regulated by histone deacetylase 4 (HDAC4) and histone 3 lysine 9 acetylation (H3K9ac) by chromatin immunoprecipitation (ChIP) assay. It suggests that the HIF-1α pathway exerts a crucial regulatory role in brain injury and behavioral abnormality in female mice after six-month exposure to HCD plus PM2.5, which are potential mechanisms for HCD and PM2.5-triggering stroke risk in female individuals.