Abstract
Dibutyl phthalate (DBP) is a typical plasticizer and is widely used in industrial manufacturing. DBP has been reported to be cardiotoxic, manifested by oxidative stress and inflammatory damage. However, the potential mechanism of heart damage caused by DBP remains unclear. By in vivo and in vitro experiments, first, this study demonstrated that DBP induced endoplasmic reticulum (ER) stress, mitochondrial damage, and pyroptosis in cardiomyocytes; second, it was confirmed that the ER stress increased mitochondrial-associated ER membrane (MAM), which led to mitochondrial damage by abnormalizing Ca2+ transfer within MAMs; finally, it was confirmed that mitochondrial reactive oxygen species (mtROS) production was increased after mitochondrial damage, which activated NLRP3 inflammasome and pyroptosis in cardiomyocytes. In summary, ER stress is the initiation of DBP cardiotoxicity, which leads to mitochondrial damage by disrupting Ca2+ transfer from ER to mitochondria. Subsequently, released mtROS promotes the activation of NLRP3 inflammasome and pyroptosis, eventually leading to heart damage.