Dibutyl phthalate causes heart damage by disrupting Ca2+ transfer from endoplasmic reticulum to mitochondria and triggering subsequent pyroptosis

• Published in: The Science of the total environment Vol. 892; p. 164620
• Main Authors: Li, Bo, Huo, Siming, Du, Jiayu, Zhang, Xuliang, Zhang, Jian, Wang, Qi, Song, Miao, Li, Yanfei
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 20-09-2023
• Subjects: Dibutyl phthalate; Endoplasmic reticulum stress; Heart damage; Mitochondrial Ca2+ overload; Pyroptosis; GSDMD; IP3R1; Pyroptosis; H&E; Dibutyl phthalate; GRP78; VDAC-1; PERK; IL-1β; ER; GRP75; Endoplasmic reticulum stress; ASC; MMP; DBP; Heart damage; UPR; IRE1; MAM; mtROS; ATF6; Mitochondrial Ca2+ overload
• ISSN: 0048-9697; 1879-1026
• DOI: 10.1016/j.scitotenv.2023.164620

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.
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•DBP induces ER stress and mitochondrial damage in cardiomyocytes.•DBP promotes MAM formation and ER-to-mitochondria Ca2+ transfer in cardiomyocytes.•DBP induces NLRP3 inflammasome-mediated pyroptosis in cardiomyocytes.•Released mtROS is the inducer of DBP-induced pyroptosis in cardiomyocytes.