Genotoxic stress from environmental pollutants plays a critical role in cytotoxicity. The most abundant nitro-polycyclic aromatic hydrocarbon in environmental pollutants, 1-nitropyrene (1-NP), is generated during fossil fuel, diesel, and biomass combustion under sunlight. Macrophages, the key regulators of the innate immune system, provide the first line of defense against pathogens. The toxic effects of 1-NP on macrophages remain unclear. Through a lactate dehydrogenase assay, we measured the cytotoxicity induced by 1-NP. Our results revealed that 1-NP induced genotoxicity also named DNA damage, including micronucleus formation and DNA strand breaks, in a concentration-dependent manner. Furthermore, 1-NP induced p53 phosphorylation and nuclear accumulation; mitochondrial cytochrome c release; caspase-3 and -9 activation and cleavage; and poly (ADP-ribose) polymerase-1 (PARP-1) cleavage in a concentration-dependent manner. Pretreatment with the PARP inhibitor, 3-aminobenzamide, significantly reduced cytotoxicity, genotoxicity, and PARP-1 cleavage induced by 1-NP. Pretreatment with the caspase-3 inhibitor, z-DEVD-fmk, significantly reduced cytotoxicity, genotoxicity, PARP-1 cleavage, and caspase 3 activation induced by 1-NP. Pretreatment with the p53 inhibitor, pifithrin-α, significantly reduced cytotoxicity, genotoxicity, PARP-1 cleavage, caspase 3 activation, and p53 phosphorylation induced by 1-NP. We propose that cytotoxicity and genotoxicity induced by 1-NP by PARP-1 cleavage via caspase-3 and -9 activation through cytochrome c release from mitochondria and its upstream p53-dependent pathway in macrophages.

来自环境污染物的遗传毒性应激在细胞毒性中起关键作用。1-硝基py（1-NP）是环境污染物中含量最高的硝基-多环芳烃，是在阳光下化石燃料，柴油和生物质燃烧过程中产生的。巨噬细胞是先天免疫系统的关键调节剂，为抵抗病原体提供了第一道防线。1-NP对巨噬细胞的毒性作用仍不清楚。通过乳酸脱氢酶测定，我们测量了由1-NP诱导的细胞毒性。我们的结果表明，1-NP诱导的遗传毒性也以浓度依赖的方式称为DNA损伤，包括微核形成和DNA链断裂。此外，1-NP诱导p53磷酸化和核积累。线粒体细胞色素c释放; caspase-3和-9的激活和切割; 聚（ADP-核糖）聚合酶-1（PARP-1）的切割以浓度依赖性方式进行。用PARP抑制剂3-氨基苯甲酰胺进行的预处理可以显着降低1-NP诱导的细胞毒性，遗传毒性和PARP-1裂解。用caspase-3抑制剂z-DEVD-fmk进行预处理可显着降低1-NP诱导的细胞毒性，遗传毒性，PARP-1裂解和caspase 3活化。用p53抑制剂pifithrin-α进行预处理可显着降低1-NP诱导的细胞毒性，遗传毒性，PARP-1裂解，caspase 3活化和p53磷酸化。我们建议1-NP通过PARP-1裂解通过胱天蛋白酶3和-9激活通过细胞色素c诱导的细胞毒性和遗传毒性 巨噬细胞中线粒体及其上游p53依赖途径的释放。