Abstract Mitochondrial quality control (MQC) is implicated in cell death induced by heavy metal pollutants. Dynamin-related protein 1 (Drp1) regulates mitochondrial fission, which is an important part of MQC. Retinoblastoma (RB) protein can regulate MQC in a transcription-independent manner. Necroptosis plays a critical role in hepatic pathologies such as inflammatory, infectious, and xenobiotics-induced injury and diseases. We aimed to explore the role and mechanism of Drp1 interaction with RB in hepatocyte’s necroptosis caused by cadmium (Cd). CdCl 2 was employed to expose to Institute of Cancer Research (ICR) mice and human hepatic L02 cells. CdCl 2 exposure induced necroptosis and hepatic injury both in vivo and in vitro. Moreover, Drp1 and RB protein were up-regulated and translocated to mitochondria in CdCl 2 -exposed hepatocytes. Inhibition of Drp1 with siRNA (si DNM1L ) or inhibitors not only suppressed the RB expression and its mitochondrial translocation, but also alleviated MQC disorder, necroptosis, and hepatotoxicity caused by CdCl 2 . Moreover, blocking Drp1 with metformin rescued necroptosis and hepatic injury triggered by CdCl 2 . RB was proved to directly interact with Drp1 at mitochondria to form a complex which then bound to receptor interaction protein kinase (RIPK3) and enhanced the formation of necrosome after CdCl 2 exposure. In summary, we found a new molecular mechanism of regulated cell death that Drp1 interacted with RB and promoted them mitochondrial translocation to mediate necroptosis and hepatic injury in hepatocytes induced by Cd-exposure. The mitochondrial Drp1-RB axis would be a novel target for the protection cells from xenobiotics triggering hepatic injury and diseases involved in necroptosis.
Phthalic acid esters (PAEs) are widely used as plasticizers in industrial process and consumer products. Nowadays, PAEs are ubiquitous in the environment and are reported to be associated with cardiorespiratory diseases. However, studies about the association between indoor airborne PAEs exposure and cardiorespiratory health were limited, and the potential biological mechanism remains under-recognized. A randomized crossover trial was conducted on 57 healthy young adults in Beijing. Repeated health measurements were performed under real and sham indoor air purification with a washout interval of at least 2 weeks. The concentration of indoor airborne PAEs were determined by gas chromatography-orbit ion trap mass spectrometry. Health indicators including blood pressure, lung function, airway inflammation, and circulating biomarkers reflecting blood coagulation and systematic oxidative stress were measured. Linear mixed-effect model was used to examine the between-treatment differences in health indicators, and three models including single-constituent, constituent-fine particulate matter (PM2.5) joint, and single-constituent residual model were used to estimate the association between indoor airborne PAEs and health indicators. The indoor airborne PAEs were reduced effectively under real air purification. The total indoor airborne di-2-ethylhexyl phthalate (DEHP), bis (4-Methyl-2-pentyl) phthalate (DMPP), diphenyl phthalate (DPP), and diethyl phthalate (DEP) were identified to be most significantly associated with the increase of blood pressure and airway inflammation, and decrease of lung function. A doubling increase in DEHP, DMPP, DPP, DEP was associated with the increase of 17.2% (95% CI: 3.9%, 32.2%), 11.7% (95% CI: 3.5%, 20.6%), 7.0% (95% CI: 2.4%, 11.8%), 6.0% (95% CI: 1.8%, 10.4%) in FeNO, respectively, in single-constituent residual model. Significant associations between specific total indoor airborne PAEs and increased levels of health biomarkers including oxidized low-density lipoprotein (ox-LDL), 8-isoprostane (8-isoPGF2α), and soluble P-selectin (sP-selectin) were observed. Indoor airborne PAEs may cause adverse cardiorespiratory health effects in young healthy adults, and indoor air purification could ameliorate the adverse cardiorespiratory effects.
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