Zhang Sen, Chen Huan, Zhang Jingni, Li Jun, Hou Hongwei, Hu Qingyuan
China National Tobacco Quality Supervision & Test Center, Zhengzhou 450001, PR China.
China National Tobacco Quality Supervision & Test Center, Zhengzhou 450001, PR China.
Environ Int. 2020 Oct;143:105943. doi: 10.1016/j.envint.2020.105943. Epub 2020 Jul 10.
Aldehydes are common air pollutants with carcinogenicity. Genotoxicity of single aldehyde has been studied well, but the combined genotoxicity is rarely known. Here, we evaluated the combined genotoxicity of formaldehyde and acrolein on BEAS-2B cells in terms of DNA strands breakage, chromosome damage and gene mutation below subcytotoxic concentrations covering smoking-related concentrations. Meanwhile, the molecular mechanism was investigated further based on oxidative stress, DNA-protein crosslinks (DPCs), cell cycle and DNA damage-repair pathway. Co-exposure to formaldehyde and acrolein mixtures showed significantly synergistic interaction on DNA strands breakage and chromosome damage in a concentration/time-dependent manner, while antagonism was shown on the late genotoxic endpoints (e.g. cytoplasmic block micronucleus (CBMN) and HPRT gene mutation). Moreover, formaldehyde synergistically potentiated acrolein-induced S-phase arrest, inhibition of DNA repair and up-regulation of genes related to cell stress, which conversely strengtherned mixture-induced DNA/chromosome damage and finally resulted in antagonism on late genotoxic events. Additionally, formaldehyde-induced DNA damage mainly resulted from the direct covalent bonding (e.g. DPCs), while acrolein-induced DNA damage mainly generated from oxidative damage (e.g. oxidative stress), which dominated the synergistic DNA strand breakage induced by mixtures. Summarily, aldehyde mixtures (formaldehyde and acrolein) induced multiplex combined genotoxicity on BEAS-2B cells even at smoking-related concentrations, which was dependent on genotoxic endpoints and closely related to that formaldehyde potentiated acrolein-induced cell stress, S-phase arrest and inhibition of DNA repair. So prolonged exposure to aldehyde mixtures may have a more serious risk to respiratory system in animal and human than the expectation based on the toxicity of single aldehyde even at environmentally relevant concentrations.
醛类是常见的具有致癌性的空气污染物。单一醛类的遗传毒性已得到充分研究，但联合遗传毒性却鲜为人知。在此，我们在低于细胞毒性浓度（涵盖与吸烟相关的浓度）的条件下，从DNA链断裂、染色体损伤和基因突变方面评估了甲醛和丙烯醛对BEAS - 2B细胞的联合遗传毒性。同时，基于氧化应激、DNA - 蛋白质交联（DPC）、细胞周期和DNA损伤修复途径进一步研究了分子机制。甲醛和丙烯醛混合物共同暴露对DNA链断裂和染色体损伤呈现出显著的协同相互作用，且呈浓度/时间依赖性，而在后期遗传毒性终点（如细胞质阻滞微核（CBMN）和HPRT基因突变）上则表现出拮抗作用。此外，甲醛协同增强了丙烯醛诱导的S期阻滞、DNA修复抑制以及与细胞应激相关基因的上调，这反过来又加强了混合物诱导的DNA/染色体损伤，最终导致对后期遗传毒性事件的拮抗作用。另外，甲醛诱导的DNA损伤主要源于直接共价键合（如DPC），而丙烯醛诱导的DNA损伤主要由氧化损伤（如氧化应激）产生，这主导了混合物诱导的协同DNA链断裂。综上所述，醛类混合物（甲醛和丙烯醛）即使在与吸烟相关的浓度下也会对BEAS - 2B细胞诱导多重联合遗传毒性，这取决于遗传毒性终点，并且与甲醛增强丙烯醛诱导的细胞应激、S期阻滞和DNA修复抑制密切相关。因此，即使在环境相关浓度下，长期暴露于醛类混合物对动物和人类呼吸系统可能具有比基于单一醛类毒性预期更为严重的风险。
