Black carbon and psychosocial stress synergistically impair cardiovascular function via hippocampal glucocorticoid receptor methylation

• Air pollution-stress joint exposure synergistically impairs cardiovascular health. • Joint exposure causes dysfunction of the HPA axis through epigenetic pathways. • DNMT3b-mediated hypermethylation of NR3C1 gene results in hippocampal GR suppression. • Hippocampal GR suppression and GC over-secretion mediate the pathogenic synergy. Black carbon (BC), a key toxic constituent of ambient PM 2.5 , and psychosocial stress, heightened by socioeconomic instability, both impair cardiovascular health. While epidemiological studies suggest that psychosocial stress could amplify the cardiovascular risks associated with air pollution, experimental evidence on the acute effects and mechanisms of joint exposure to BC and psychosocial stress is still lacking. In this study, a psychosocial stress model of male Sprague Dawley rats was exposed to different doses of BC by intratracheal instillation, followed by measurement of the hippocampal glucocorticoid receptor (GR) methylation, DNA methyltransferase (DNMT) and GR expressions hypothalamic–pituitary–adrenal (HPA) axis-associated glucocorticoid secretion and cardiovascular indicators. Rats were additionally treated with a DNMT inhibitor (SGI-1027) to further validate the upstream regulatory role of hippocampal GR methylation. The results demonstrated that joint exposure to BC and psychosocial stress induces hypermethylation of the hippocampal GR-encoding gene NR3C1 via upregulation of DNMT3b, leading to decreased GR expression. This, in turn, weakens the negative feedback on the HPA axis, thereby contributing to the sustained elevation of stress hormones including corticosterone. Consequently, joint exposure induces more apparent acute cardiovascular dysfunction, including reduced ejection fraction, elevated blood pressure, increased myocardial enzymes (e.g., CK, CK-MB) and oxidative stress (e.g., MDA) compared to separate exposures. This study demonstrated that acute joint exposure to air pollution and psychosocial stress impairs cardiovascular function via hippocampal GR epigenetic reprogramming and HPA-axis dysregulation, and established a novel paradigm for investigating “environmental-psychological-biological” interactions.