{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:26:20Z","timestamp":1791289580914,"version":"4.3.0"},"reference-count":64,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2006,6,30]],"date-time":"2006-06-30T00:00:00Z","timestamp":1151625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Human exposure to toxic metals is a concern of the highest priority, due to their vast array of biological effects, including carcinogenicity. The particulate (water insoluble) form of several heavy metals presents a higher carcinogenic potential than its soluble counterparts. Our previous work demonstrates that the particulate forms of different heavy metals, such as nickel oxide, cadmium sulfide and mercury sulfide, stimulate human L1 mobile element activity leading to genomic instability. We present data demonstrating that the soluble form of CdCl2 also stimulates L1 retrotransposition in a dose-dependent manner comparable to the insoluble carcinogenic form of this compound. Reproducible results demonstrated a 2 to 3 fold dose-dependent increase in L1 retrotransposition compared to control cells. Heavy metals may cause DNA breaks through the generation of reactive oxygen species. However, evaluation of DNA damage by comet assay revealed no differences between the negative controls and the CdS-treated cells. In addition, active L1 elements express a protein with endonuclease activity that can generate toxicity through the creation of double strand breaks. To determine the contribution of the L1 endonuclease to the toxicity observed in our metal treatment assays, we compared the wildtype L1 vector with an L1 endonuclease-mutant vector. The presence of an active L1 endonuclease did not contribute significantly to the toxicity observed in any of the CdCl2 or CdS doses evaluated. No correlation between the creation of DNA breaks and L1 activity was observed. Alternatively, heavy metals inhibit enzymatic reactions by displacement of cofactors such as Zn and Mg from enzymes. Concomitant treatment with Mg(Ac)2 and Zn(Ac)2 ppb suppresses the stimulatory effect on L1 activity induced by the 3.8 ppb CdS treatment. Overall, these results are consistent with our previous observations, suggesting that the mechanism of L1 stimulation by heavy metals is most likely due to an overall inhibition of DNA repair proteins or other enzymes caused by the displacement of Mg and Zn from cellular proteins.<\/jats:p>","DOI":"10.3390\/ijerph2006030015","type":"journal-article","created":{"date-parts":[[2008,10,25]],"date-time":"2008-10-25T13:52:15Z","timestamp":1224942735000},"page":"121-128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The L1 Retrotranspositional Stimulation by Particulate and Soluble Cadmium Exposure is Independent of the Generation of DNA Breaks"],"prefix":"10.3390","volume":"3","author":[{"given":"Shubha P.","family":"Kale","sequence":"first","affiliation":[{"name":"Dept. of Biology, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary C.","family":"Carmichael","sequence":"additional","affiliation":[{"name":"Dept. of Biology, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelley","family":"Harris","sequence":"additional","affiliation":[{"name":"Dept. of Biology, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid M.","family":"Roy-Engel","sequence":"additional","affiliation":[{"name":"Tulane Cancer Center SL-66, Dept. of Epidemiology, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2006,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"(1993). Meeting of the IARC working group on beryllium, cadmium, mercury and exposures in the glass manufacturing industry. Scand. J. Work Environ. Health, 19, (5), 360\u2013363.","DOI":"10.5271\/sjweh.1461"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0162-0134(00)00009-X","article-title":"Cadmium carcinogenesis in review","volume":"79","author":"Waalkes","year":"2000","journal-title":"J. Inorg. Biochem"},{"key":"ref_3","first-page":"367","article-title":"Carcinogenicity of cadmium chloride aerosols in W rats","volume":"70","author":"Takenaka","year":"1983","journal-title":"J. Natl. Cancer Inst"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1023\/A:1017978500031","article-title":"Molecular biology of nickel carcinogenesis","volume":"222","author":"Costa","year":"2001","journal-title":"Mol. Cell Biochem"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0300-483X(00)00144-X","article-title":"The inhibitory effect of zinc on cadmium-induced cell apoptosis and reactive oxygen species (ROS) production in cell cultures","volume":"145","year":"2000","journal-title":"Toxicology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/BF00756493","article-title":"Protective effect of magnesium on DNA strand breaks induced by nickel or cadmium","volume":"10","author":"Littlefield","year":"1994","journal-title":"Cell Biol. Toxicol"},{"key":"ref_7","first-page":"75","article-title":"Search for molecular mechanisms in the genotoxicity of nickel","volume":"19","author":"Sunderman","year":"1993","journal-title":"Scand. J. Work Environ. Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3109\/07357909509031921","article-title":"Possible role of oxidative damage in metal-induced carcinogenesis","volume":"13","author":"Kasprzak","year":"1995","journal-title":"Cancer Invest"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1006\/taap.2000.9014","article-title":"Effects of arsenic, cadmium, chromium, and lead on gene expression regulated by a battery of 13 different promoters in recombinant HepG2 cells","volume":"168","author":"Tully","year":"2000","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1006\/taap.1997.8125","article-title":"Cadmium, gene regulation, and cellular signalling in mammalian cells","volume":"144","author":"Beyersmann","year":"1997","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0378-4274(99)00273-8","article-title":"Interference by toxic metal compounds with isolated zinc finger DNA repair proteins","volume":"112\u2013113","author":"Asmuss","year":"2000","journal-title":"Toxicol. Lett"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0378-4274(98)00312-9","article-title":"Carcinogenicity of metal compounds: possible role of DNA repair inhibition","volume":"102\u2013103","author":"Hartwig","year":"1998","journal-title":"Toxicol. Lett"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1021\/tx049842s","article-title":"Co(II) and Cd(II) substitute for Zn(II) in the zinc finger derived from the DNA repair protein XPA, demonstrating a variety of potential mechanisms of toxicity","volume":"17","author":"Kopera","year":"2004","journal-title":"Chem. Res. Toxicol"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s007750050012","article-title":"Spectroscopic characterization of Co(II)-, Ni(II)-, and Cd(II)-substituted wild-type and non-native retroviral-type zinc finger peptides","volume":"5","author":"Chen","year":"2000","journal-title":"J. Biol. Inorg. Chem"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1093\/carcin\/21.11.2097","article-title":"Differential effects of toxic metal compounds on the activities of Fpg and XPA, two zinc finger proteins involved in DNA repair","volume":"21","author":"Asmuss","year":"2000","journal-title":"Carcinogenesis"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0162-0134(99)00240-8","article-title":"Inhibition of antimutagenic enzymes, 8-oxo-dGTPases, by carcinogenic metals. Recent developments","volume":"79","author":"Kasprzak","year":"2000","journal-title":"J. Inorg. Biochem"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/35057062","article-title":"Initial sequencing and analysis of the human genome","volume":"409","author":"Lander","year":"2001","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1002\/j.1460-2075.1984.tb02042.x","article-title":"Defining the beginning and end of KpnI family segments","volume":"3","author":"Grimaldi","year":"1984","journal-title":"Embo J"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5280","DOI":"10.1073\/pnas.0831042100","article-title":"Hot L1s account for the bulk of retrotransposition in the human population","volume":"100","author":"Brouha","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U. S. A"},{"key":"ref_20","first-page":"01","article-title":"Biology of Mammalian l1 retrotransposons","volume":"355","author":"Ostertag","year":"2001","journal-title":"Annu. Rev. Genet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1073\/pnas.92.5.1520","article-title":"Tightly regulated, developmentally specific expression of the first open reading frame from LINE-1 during mouse embryogenesis","volume":"92","author":"Trelogan","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"27753","DOI":"10.1074\/jbc.M312985200","article-title":"Cell type-specific expression of LINE-1 open reading frames 1 and 2 in fetal and adult human tissues","volume":"279","author":"Ergun","year":"2004","journal-title":"J. Biol. Chem"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/nature03663","article-title":"Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition","volume":"435","author":"Muotri","year":"2005","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/0378-1119(93)90064-A","article-title":"LINE-1: a human transposable element","volume":"135","author":"Singer","year":"1993","journal-title":"Gene"},{"key":"ref_25","first-page":"1385","article-title":"Unit-length line-1 transcripts in human teratocarcinoma cells","volume":"8","author":"Skowronski","year":"1988","journal-title":"Mol. Cell Biol"},{"key":"ref_26","first-page":"239","article-title":"Comparative expression of the LINE-1 p40 protein in human breast carcinomas and normal breast tissues","volume":"8","author":"Asch","year":"1996","journal-title":"Oncol. Res"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1002\/1097-0142(19940501)73:9<2333::AID-CNCR2820730915>3.0.CO;2-4","article-title":"Expression of LINE-1 retrotransposons in human breast cancer","volume":"73","author":"Bratthauer","year":"1994","journal-title":"Cancer"},{"key":"ref_28","first-page":"507","article-title":"Active LINE-1 retrotransposons in human testicular cancer","volume":"7","author":"Bratthauer","year":"1992","journal-title":"Oncogene"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8841","DOI":"10.1038\/sj.onc.1208137","article-title":"Distinctive pattern of LINE-1 methylation level in normal tissues and the association with carcinogenesis","volume":"23","author":"Chalitchagorn","year":"2004","journal-title":"Oncogene"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Roman-Gomez, J. (2005). Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense\/antisense transcription and marks the progression of chronic myeloid leukemia. Oncogene, epub.","DOI":"10.1038\/sj.onc.1208866"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1093\/nar\/28.2.411","article-title":"Members of the SRY family regulate the human LINE retrotransposons","volume":"28","author":"Tchenio","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/ng1269","article-title":"RNA truncation by premature polyadenylation attenuates human mobile element activity","volume":"35","author":"Deininger","year":"2003","journal-title":"Nat Genet"},{"key":"ref_33","first-page":"643","article-title":"Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer","volume":"52","author":"Miki","year":"1992","journal-title":"Cancer Res"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/333087a0","article-title":"Insertional mutagenesis of the myc locus by a LINE-1 sequence in a human breast carcinoma","volume":"333","author":"Morse","year":"1988","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/(SICI)1098-2264(199909)26:1<84::AID-GCC12>3.0.CO;2-Y","article-title":"De novo retrotransposition of unbiased sequences in a human breast cancer cell clone","volume":"26","author":"Sylla","year":"1999","journal-title":"Genes Chromosomes. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/0092-8674(93)90078-5","article-title":"Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition","volume":"72","author":"Luan","year":"1993","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1006\/jmbi.1994.0121","article-title":"Characterization of a non-long terminal repeat retrotransposon cDNA (L1Tc) from Trypanosoma cruzi: homology of the first ORF with the ape family of DNA repairs enzymes","volume":"247","author":"Martin","year":"1995","journal-title":"J. Mol. Biol"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/S0092-8674(00)81997-2","article-title":"Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition","volume":"87","author":"Feng","year":"1996","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/0888-7543(87)90003-6","article-title":"Origin of the human L1 elements: proposed progenitor genes deduced from a consensus DNA sequence","volume":"1","author":"Scott","year":"1987","journal-title":"Genomics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1126\/science.1722352","article-title":"Reverse transcriptase encoded by a human transposable element","volume":"254","author":"Mathias","year":"1991","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/ng898","article-title":"DNA repair mediated by endonuclease-independent LINE-1 retrotransposition","volume":"31","author":"Morrish","year":"2002","journal-title":"Nat. Genet"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/383644a0","article-title":"Capture of retrotransposon DNA at the sites of chromosomal double-strand breaks","volume":"383","author":"Moore","year":"1996","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1126\/science.283.5407.1530","article-title":"Exon shuffling by L1 retrotransposition","volume":"283","author":"Moran","year":"1999","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"84","DOI":"10.3390\/ijerph2005010014","article-title":"Heavy metals stimulate human LINE-1 retrotransposition","volume":"2","author":"Kale","year":"2005","journal-title":"Int. J. Env. Res. Public Health"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1289\/ehp.898173","article-title":"Perspectives on the mechanism of nickel carcinogenesis gained from models of in vitro carcinogenesis","volume":"81","author":"Costa","year":"1989","journal-title":"Environ. Health Perspect"},{"key":"ref_46","first-page":"1307","article-title":"Chromium-induced genotoxicity and apoptosis: relationship to chromium carcinogenesis (review)","volume":"5","author":"Singh","year":"1998","journal-title":"Oncol. Rep"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1093\/carcin\/23.1.47","article-title":"Effect of soluble and particulate nickel compounds on the formation and repair of stable benzo[a]pyrene DNA adducts in human lung cells","volume":"23","author":"Schwerdtle","year":"2002","journal-title":"Carcinogenesis"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1093\/carcin\/7.11.1903","article-title":"Apparent synergy in lung carcinogenesis: interactions between N-nitrosoheptamethyleneimine, particulate cadmium and crocidolite asbestos fibres in rats","volume":"7","author":"Harrison","year":"1986","journal-title":"Carcinogenesis"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0378-4274(01)00482-9","article-title":"Interactions by carcinogenic metal compounds with DNA repair processes: toxicological implications","volume":"127","author":"Hartwig","year":"2002","journal-title":"Toxicol. Lett"},{"key":"ref_50","first-page":"95","article-title":"Mechanisms of dissolution of nickel subsulfide in rat serum","volume":"16","author":"Kasprzak","year":"1977","journal-title":"Res. Commun. Chem. Pathol. Pharmacol"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1021\/tx00024a001","article-title":"The role of oxidative processes in metal carcinogenesis","volume":"4","author":"Klein","year":"1991","journal-title":"Chem. Res. Toxicol"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/path.950","article-title":"Heavy metals of relevance to human health induce genomic instability","volume":"195","author":"Coen","year":"2001","journal-title":"J. Pathol"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0300-483X(98)00003-1","article-title":"Evaluation of the direct genotoxic potential of cadmium in four different rodent cell lines","volume":"126","author":"Misra","year":"1998","journal-title":"Toxicology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.jmb.2005.09.050","article-title":"Nickel stimulates L1 retrotransposition by a post-transcriptional mechanism","volume":"354","author":"Kale","year":"2005","journal-title":"J Mol. Biol"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1093\/carcin\/19.4.617","article-title":"Disturbance of DNA damage recognition after UV-irradiation by nickel(II) and cadmium(II) in mammalian cells","volume":"19","author":"Hartmann","year":"1998","journal-title":"Carcinogenesis"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1289\/ehp.7038","article-title":"Inhibition of Ape1 nuclease activity by lead; iron; and cadmium","volume":"112","author":"McNeill","year":"2004","journal-title":"Environ. Health Perspect"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1093\/nar\/gki291","article-title":"Cadmium inhibits mismatch repair by blocking the ATPase activity of the MSH2-MSH6 complex","volume":"33","author":"Banerjee","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0921-8777(96)00052-3","article-title":"Cobalt(II) inhibits the incision and the polymerization step of nucleotide excision repair in human fibroblasts","volume":"383","author":"Kasten","year":"1997","journal-title":"Mutat. Res"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/S0026-895X(25)14380-0","article-title":"Correlations of DNA strand breaks and their repair with cell survival following acute exposure to mercury(II) and X-rays","volume":"24","author":"Cantoni","year":"1983","journal-title":"Mol. Pharmacol"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0026-895X(25)10355-6","article-title":"In vivo effects of mercury (II) on deoxyuridine triphosphate nucleotidohydrolase, DNA polymerase (alpha; beta), and uracil-DNA glycosylase activities in cultured human cells: relationship to DNA damage, DNA repair, and cytotoxicity","volume":"31","author":"Williams","year":"1987","journal-title":"Mol. Pharmacol"},{"key":"ref_61","first-page":"117","article-title":"Thiol involvement in the inhibition of DNA repairs by metals in mammalian cells","volume":"2","author":"Snyder","year":"1989","journal-title":"Mol. Toxicol"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/S1383-5742(97)00011-2","article-title":"Inhibition of poly (ADP-ribose) polymerase by arsenite","volume":"386","author":"Yager","year":"1997","journal-title":"Mutat. Res"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1093\/carcin\/18.2.399","article-title":"Interaction of arsenic(III) with nucleotide excision repair in UV-irradiated human fibroblasts","volume":"18","author":"Hartwig","year":"1997","journal-title":"Carcinogenesis"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1016\/j.jmb.2006.01.089","article-title":"The human LINE-1 retrotransposon creates DNA double-strand breaks","volume":"357","author":"Gasior","year":"2006","journal-title":"J. Mol. Biol"}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/3\/2\/121\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T22:25:00Z","timestamp":1760221500000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/3\/2\/121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,6,30]]},"references-count":64,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2006,6]]}},"alternative-id":["ijerph2006030015"],"URL":"https:\/\/doi.org\/10.3390\/ijerph2006030015","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,6,30]]}}}