Induction of mitochondrial apoptosis pathway mediated through caspase-8 and c-Jun N-terminal kinase by cadmium-activated Fas in rat cortical neurons

Abstract

Cadmium (Cd) is a toxic metal and an environmental pollutant, and can cause neurotoxicity by inducing apoptosis. Fas (CD95/Apo-1) is a cell surface receptor that triggers apoptosis upon ligand binding, mediated through the mitochondrial apoptotic pathway. However, the role and regulatory mechanism of Fas in Cd-induced neuronal apoptosis remains understudied. Here, we demonstrate that activation of caspase-8 and the JNK pathway are mechanisms underlying Cd-induced Fas-mediated activation of the mitochondrial apoptotic pathway in rat cerebral cortical neurons. In vitro, Cd induced apoptosis in primary cortical neurons by activating caspase-8, JNK, and the mitochondrial apoptotic pathway. Fas knockdown enhanced cell viability in the presence of Cd, and inhibited apoptosis by blocking Cd-activated Fas, caspase-8, and JNK. Fas knockdown also inhibited decrease of mitochondrial membrane potential (MMP), cleavage of caspase-9/3 and poly (ADP-ribose) polymerase 1 (PARP1), and impaired nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (Endo G). In vivo, Fas knockdown alleviated Cd-induced neuronal injury, and inhibited apoptosis, activation of caspase-8, JNK, and mitochondrial apoptotic pathways in rat cerebral cortical neurons. In summary, our results demonstrate that Cd-activated Fas relays apoptotic signals from the cell surface to the mitochondria via caspase-8 and JNK activation in rat cerebral cortical neurons, leading to aggravation of neuronal injury.

Involvement of caspase-3 in apoptosis of human lymphocytes exposed to cadmium chloride

“…59 Cadmium also increases ROS levels and activates caspase-8 to damage mitochondrial. 60,61 The dysfunction of mitochondria causes the release of apoptogenic factors including cytochrome c from mitochondria, resulting in the activation of caspase-3. 62 Assessment of apoptogenic factors such as cytochrome c, cytosolic calcium levels as well as the activity of other caspases can help to elucidate the exact mechanism(s) involved in the apoptosis of human lymphocytes treated with cadmium.

Figure 5.Possible mechanisms involved in cadmium-induced apoptosis in human lymphocytes.

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Mechanisms of Cadmium-Induced Testicular Injury: A Risk to Male Fertility

“…According to research, more apoptotic sperm was reported in the semen of infertile patients than in fertile donors [ 18 ]. The most significant characteristics of apoptosis are activation of caspase, chromatin condensation, DNA fragmentation, changes in phosphatidylserine location within the plasma membrane, and disturbance of mitochondrial membrane potential (MMP) [ 19 , 20 , 21 , 22 ].…”

Cadmium neurotoxicity and therapeutic strategies

“…Recent studies have demonstrated that Cd can activate the Fas/FasL‐mediated mitochondrial apoptotic pathway in PC12 cells and rat cerebral cortical neurons in vitro and in the rat cerebral cortex in vivo. [ 91,92 ]…”