-
Julian Laubenthal,
Olga Zlobinskaya,
Krzysztof Poterlowicz,
Adolf Baumgartner,
Michal R Gdula,
Eleni Fthenou,
Maria Keramarou,
Sarah J Hepworth,
Jos C S Kleinjans,
Frederik-Jan van Schooten,
Gunnar Brunborg,
Roger W Godschalk,
Thomas E Schmid,
Diana Anderson
[show abstract]
[hide abstract]
ABSTRACT: The relevance of preconceptional and prenatal toxicant exposures for genomic stability in offspring is difficult to analyze in human populations, because gestational exposures usually cannot be separated from preconceptional exposures. To analyze the roles of exposures during gestation and conception on genomic stability in the offspring, stability was assessed via the Comet assay and highly sensitive, semiautomated confocal laser scans of γH2AX foci in cord, maternal, and paternal blood as well as spermatozoa from 39 families in Crete, Greece, and the United Kingdom. With use of multivariate linear regression analysis with backward selection, preconceptional paternal smoking (% tail DNA: P>0.032; γH2AX foci: P>0.018) and gestational maternal (% tail DNA: P>0.033) smoking were found to statistically significantly predict DNA damage in the cord blood of F1 offspring. Maternal passive smoke exposure was not identified as a predictor of DNA damage in cord blood, indicating that the effect of paternal smoking may be transmitted via the spermatozoal genome. Taken together, these studies reveal a role for cigarette smoke in the induction of DNA alterations in human F1 offspring via exposures of the fetus in utero or the paternal germline. Moreover, the identification of transgenerational DNA alterations in the unexposed F1 offspring of smoking-exposed fathers supports the claim that cigarette smoke is a human germ cell mutagen.-Laubenthal, J., Zlobinskaya, O., Poterlowicz, K., Baumgartner, A., Gdula, M. R., Fthenou, E., Keramarou, M., Hepworth, S. J., Kleinjans, J. C. S., van Schooten, F.-J., Brunborg, G., Godschalk, R. W., Schmid, T. E., Anderson, D. Cigarette smoke-induced transgenerational alterations in genome stability in cord blood of human F1 offspring.
The FASEB Journal 06/2012; 26(10):3946-56. · 5.71 Impact Factor
-
Deepak Gurbani,
Vandna Kukshal, Julian Laubenthal,
Ashutosh Kumar,
Alok Pandey,
Sarita Tripathi,
Ashish Arora,
Swatantra K Jain,
Ravishankar Ramachandran,
Diana Anderson,
Alok Dhawan
[show abstract]
[hide abstract]
ABSTRACT: The inhibition of human topoisomerase IIα (Hu-TopoIIα), a major enzyme involved in maintaining DNA topology, repair, and chromosome condensation/decondensation results in loss of genomic integrity. In the present study, the inhibition of ATPase domain of Hu-TopoIIα as a possible mechanism of genotoxicity of 1,4-benzoquinone (BQ), hydroquinone (HQ), naphthoquinone (1,2-NQ and 1,4-NQ), and 9,10-phenanthroquinone (9,10-PQ) was investigated. In silico modeling predicted that 1,4-BQ, 1,2-NQ, 1,4-NQ, and 9,10-PQ could interact with Ser-148, Ser-149, Asn-150, and Asn-91 residues of the ATPase domain of Hu-TopoIIα. Biochemical inhibition assays with the purified ATPase domain of Hu-TopoIIα revealed that 1,4-BQ is the most potent inhibitor followed by 1,4-NQ > 1,2-NQ > 9,10-PQ > HQ. Ligand-binding studies using isothermal titration calorimetry revealed that 1,4-BQ, HQ, 1,4-NQ, 1,2-NQ, and 9,10-PQ enter into four sequentially binding site models inside the domain. 1,4-BQ exhibited the strongest binding, followed by 1,4-NQ > 1,2-NQ > 9,10-PQ > HQ, as revealed by their average K(d) values. The cellular fate of such inhibition was further evidenced by an increase in the number of Hu-TopoIIα-DNA cleavage complexes in the human lung epithelial cells (BEAS-2B) using trapped in agarose DNA immunostaining (TARDIS) assay, which utilizes antibody specific for Hu-TopoIIα. Furthermore, the increase in γ-H2A.X levels quantitated by flow cytometry and visualized by immunofluorescence microscopy illustrated that accumulation of DNA double-strand breaks inside the cells can be attributed to the inhibition of Hu-TopoIIα. These findings collectively suggest that 1,4-BQ, 1,2-NQ, 1,4-NQ, and 9,10-PQ inhibit the ATPase domain and potentially result in Hu-TopoIIα-mediated clastogenic and leukemogenic events.
Toxicological Sciences 01/2012; 126(2):372-90. · 4.65 Impact Factor
-
Joost O Linschooten, Julian Laubenthal,
Eduardo Cemeli,
Adolf Baumgartner,
Diana Anderson,
Ville E Sipinen,
Gunnar Brunborg,
Guido R M M Haenen,
Eleni Fthenou,
Jacob J Briedé,
Frederik J van Schooten,
Roger W L Godschalk
[show abstract]
[hide abstract]
ABSTRACT: Although DNA damage in human spermatozoa is associated with adverse health effects, its origin is not fully understood. Therefore, we assessed biomarkers in ejaculates that retrospectively reflect processes that occurred in the epididymis or testis. Smoking increased the amount of DNA strand breaks (P<0.01), and enhanced the presence of vitamin C radicals in seminal plasma. In vitro, vitamin C protected mature spermatozoa against DNA damage, but this protection appeared to be insufficient in vivo. CAT and DDIT4 expression in spermatozoa were higher in smokers than in nonsmokers, but were not related to DNA damage. CAT and DDIT4 expression were inversely related with sperm count (P=0.039 and 0.024 resp.), but no effect was observed for SOD2 expression. These data indicate that spermatozoa of smokers encounter higher levels of oxidative stress. Expression of antioxidant enzymes and seminal vitamin C were insufficient to provide full protection of spermatozoa against DNA damage.
Reproductive Toxicology 05/2011; 32(1):106-11. · 3.23 Impact Factor
-
Deepak Gurbani,
Vandna Kukshal, Julian Laubenthal,
Ashutosh Kumar,
Alok Pandey,
Sarita Tripathi,
Ashish Arora,
Swatantra K. Jain,
Ravishankar Ramachandran,
Diana Anderson,
Alok Dhawan
Toxicological Sciences 01/2011; · 4.65 Impact Factor
-
Jelena Katic,
Eduardo Cemeli,
Adolf Baumgartner, Julian Laubenthal,
Irene Bassano,
Solvor B Stølevik,
Berit Granum,
Ellen Namork,
Unni C Nygaard,
Martinus Løvik,
Danitsja van Leeuwen,
Kim Vande Loock,
Diana Anderson,
Aleksandra Fucić,
Ilse Decordier
[show abstract]
[hide abstract]
ABSTRACT: Complex exposure to xenobiotics is one of the reasons for the reported increase of respiratory diseases, cancer and immunological disturbances. Among such xenobiotics there are food mutagens whose effects on human health in the low level and/or chronic exposure still remains unknown. In the present manuscript, the compounds ethanol (EtOH), 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4'-tetrachlorobiphenyl (PCB 153), benzo[a]pyrene (BaP), 2-amino-3-methylimidazol[4,5-f]quinoline (IQ), 2-amino-1-methyl-6-phenylimidazol[4,5-b]pyridine (PhIP), N-Nitrosodimethylamine (NDMA) and acrylamide (AA) were evaluated in an interlaboratory comparison in the in vitro cytokinesis-block micronucleus assay (CBMN) with objective of assessing the induction of micronuclei, buds and nucleoplasmic bridges in dose responses. Statistically significant increase in MNBN frequency in binucleated cells was recorded by both laboratories for the compound PhIP (2.5μM). The compounds PCB (250 microM) and AA (500 microM) induced statistically significant increase of MNBN although it was recorded by one of the two laboratories. Induction of buds and nucleoplasmic bridges was only observed for BaP (100 microM) and AA (500 microM) by one of the laboratories. Data generated in this study may assist in the interpretation of the mother/newborn biomonitoring study being carried out within project NewGeneris and will contribute to overall knowledge on the genotoxic potential of dietary/environmental toxicants.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 10/2010; 48(10):2612-23. · 2.99 Impact Factor
