铅、镉联合暴露通过引起氧化应激和干扰DNA修复基因表达诱导遗传损伤OA

[Background]Lead smelting workers are exposed to mixed heavy metals such as lead(Pb)and cadmium(Cd).However,the specific associations and molecular mechanisms by which their combined exposure induces genetic damage remain unclear. [Objective]To clarify the association between combined Pb-Cd exposure and genetic damage and to explore the possible biological mechanisms through occupational epidemiological investi-gations and animal experiments. [Methods](1)Population study:A cross-sectional study was conducted on 374 lead smelting workers in northern China.Inductively coupled plasma mass spectrometry(ICP-MS)was used to detect urinary levels of 8 metals including Pb and Cd,and graphite furnace atomic ab-sorption spectroscopy(GFAAS)was used to quantify blood levels of Pb and Cd.The cytokinesis-block micronucleus assay(CBMN)was used to assess genetic damage.Poisson regression was used to analyze the association between metal exposure and micronucleus rates.(2)In vivo experiment:Thirty SD rats were randomly assigned to five groups:control(pure water),Pb(300 mg·L-1 lead acetate),Cd(50 mg·L-1 cadmium chloride),combined exposure(Pb+Cd),and resveratrol intervention(Pb+Cd+50 mg·L-1 resveratrol).After 8 weeks of ad libitum drinking water exposure,liver pathology,oxidative stress indicators[reactive oxygen species(ROS),reduced glutathione(GSH),oxidized glutathione(GSSG),malondialdehyde(MDA),catalase(CAT),and superoxide dismutase(SOD)],genetic damage(Comet assay and γ-H2AX)were evaluated.Furthermore,cell cycle distribution,apoptosis rates,and mRNA expression of DNA damage response(DDR),DNA repair,and apoptosis-related genes were measured. [Results](1)The geometric mean(GM,95%CI)of urinary Pb and Cd were 14.69(13.14,16.51)µg·L-1 and 2.11(1.90,2.33)µg·L-1,respectively;the blood Pb and Cd levels were 117.10(105.59,129.87)µg·L-1 and 4.55(4.23,4.89)µg·L-1,respectively among the 374 workers.The mean micronucleus rate was(1.64±0.081)‰,with significantly higher rates in males(1.65±0.083)‰ than females(1.53±0.334)‰(U=4.166,P=0.041).All Pb and Cd biomarkers were positively correlated with micronucleus rate(FR>1,P<0.05),with a significant interaction effect observed between Pb and Cd(FR>1,P<0.05).(2)In rats,co-exposure to Pb and Cd caused liver tissue damage and inflammatory infiltration.Significant increases were observed in lymphocyte ROS;GSSG and MDA in lung tissue increased,while GSH and CAT activity decreased.Comet assay indicators and γ-H2AX levels were significantly elevated.Co-exposure induced S-phase arrest and increased apoptosis.mRNA levels of DDR(ATM,ATR,Chk2,and P53)and pro-apoptotic genes(Bax and Caspase-3)were upregulat-ed,while the anti-apoptotic gene Bcl-2 and DNA repair genes(BRCA1,BRCA2,RAD51,RAD52,and CtIP)were downregulated.Two-way ANOVA confirmed synergistic effects on GSSG,Comet assay indicators,and ATR/Chk2 mRNA expression. [Conclusion]Occupational co-exposure to Pb and Cd synergistically induces genetic damage.This damage is mediated by oxidative stress and DNA damage,which activates the DDR pathway and inhibits the expression of DNA repair genes,ultimately leading to cell cycle arrest and apoptosis.