Abstract
Aldehydes are common air pollutants and metabolites of the organism, which widely exist in many in vivo (e.g. Alzheimer's disease) and in vitro (e.g. cigarette smoke) situations. Individual aldehydes have been studied well alone, while their combined toxicity is still obscure. Here, we examined the combined apoptosis of aldehyde mixtures in BEAS-2B cells at smoking-related environmental/physiologically relevant concentrations, and the potential mechanism was investigated further based on the related signaling pathway. Co-exposure to aldehyde mixtures demonstrated significant synergistic interaction on apoptosis in a concentration-dependent manner, which differed from the expectation based on single aldehydes. Moreover, formaldehyde significantly potentiated the induction of death receptor-5, caspase 8/10, cleaved caspase 3/7/9, pro-apoptotic proteins (Bim, Bad and Bax), depolarization of MMP (mitochondrial membrane potential) and AIF (apoptosis-inducing factor) induced by acrolein, and synergistically decreased expressions of pro-survival proteins (Bcl-2 and Bcl-XL) and poly ADP-ribose polymerase. Therefore, aldehyde mixture-induced synergistic apoptosis was mediated both by TRAIL death receptor and mitochondrial pathway. Additionally, reactive oxygen species, Ca2+ levels, DNA damage, and phosphorylated MDM2 were all synergistically induced by aldehyde mixtures, while total p53, phosphorylated p53 and phosphorylated AKT (serine/threonine kinase) were inhibited. Antioxidants N-acetylcysteine suppressed the aldehyde mixture-induced ROS, DNA damage and apoptosis, and blocked the TRAIL death receptor and mitochondrial pathway, while it did not rescue the p53 and AKT pathway. Briefly, aldehyde mixtures induced synergistic apoptosis even at smoking-related environmental/physiologically relevant concentrations, which could be enhanced through ROS-mediated death receptor/mitochondrial pathway, and the down-regulation of phosphorylated AKT.