Cadmium exposure induces mitochondrial pathway apoptosis in swine myocardium through xenobiotic receptors-mediated CYP450s activation.

Cadmium (Cd) pollution has become an important public and environmental health issue. Xenobiotic receptors (XRs, aryl hydrocarbon receptor, AHR; constitutive androstane receptor, CAR; pregnane X receptor, PXR) modulate downstream cytochrome P450 enzymes (CYP450s) expression to metabolize xenobiotics and environmental contaminants. However, the underlying mechanisms of cardiotoxicity induced by Cd(II) in swine and the roles of XRs and CYP450s remain poorly understood. In this study, the cardiotoxicity of Cd(II) was investigated by establishing a Cd(II)-exposed swine model (CdCl 2 , 20 mg Cd/Kg diet). Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) assay and transmission electron microscope were used to observe the apoptosis. Antioxidant capacity was evaluated by free radicals contents and antioxidant enzymes activities. RT-PCR and western blot were used to measure the expression of XRs, CYP450s and apoptosis-related genes. Our results revealed that Cd(II) exposure activated the XRs and increased the CYP450s expression, contributing to the production of reactive oxygen species (ROS). Cd(II) exposure restrained the antioxidant capacity, causing oxidative stress. Moreover, mitogen-activated protein kinase (MAPK) pathway including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38 mitogen-activated protein kinase (P38) was activated, triggering the mitochondrial apoptotic pathway. In brief, we concluded that Cd(II) caused mitochondrial pathway apoptosis in swine myocardium via the oxidative stress-MAPK pathway, and XRs-mediated CYP450s expression might participate in this process through promoting the ROS. [Display omitted] • Cd(II) exposure activated xenobiotic receptors (XRs) pathway. • Cd(II) exposure upregulated the expression of cytochromes P450 enzymes (CYP450s). • Cd(II) exposure caused oxidative stress in swine myocardium. • Cd(II) exposure activated mitogen-activated protein kinase (MAPK) pathway. • Cd(II) exposure induced apoptosis via mitochondrial pathway in swine myocardium. [ABSTRACT FROM AUTHOR]