Chromatin buds (CHB), broken eggs, or budding cell nuclei are structures similar to micronuclei (MN) in shape, structure, and size, which are linked to the main nuclei of cells by a thread or stalks of chromatin. They have been observed in numerous cell types and there are reports of their existence relating them with MN or with genotoxic events. However, there is no systematic study reporting their frequency and no experiment has been done to ascertain whether they are really induced by genotoxins. Furthermore, they have been discarded as genotoxic events with the argument that they are not formed in dividing cells. Studies are presented here that indicate that CHB can be considered as genotoxic events and that their origin is comparable to that of MN. Bromodeoxyuridine (BrdU) was used to label proliferating lymphocytes, which were later identified by means of an immunohistochemical method, using the H2O2-DAB stain. The results show that CHB are consistently formed where MN are seen. CHB were induced by the clastogen mitomycin C (MMC) as well as by the aneuploidogen colcemid, with frequencies similar to MN in both cases, and to multinucleated cells in the case of colcemid. CHB occur in lymphocytes of smokers with frequencies similar to those of MN, and we found that the infection with Taenia solium metacestodes induced a comparable increase of both MN and CHB frequency in lymphocytes from pigs.
Background The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances. Results We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10−10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations. Conclusion Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.
Exposure to organochlorine pesticides was studied in a group of mother-infant pairs living in a rural area where agriculture is the main economic activity. Fumigation in this zone is performed with airplanes, thus affecting the inhabited areas around them, including schools. Heparinized venous blood of mothers and umbilical cords was used to evaluate the olive tail moment in the comet assay, and micronuclei, chromatin buds, and nucleoplasmic bridges in peripheral blood lymphocytes. Cord blood samples were taken at the moment of birth only from natural and normal parturitions. Determinations of hexachlorobenzene, aldrin, heptachlor epoxide, oxichlordane, t and c-chlordane, cis-nonachlor, mirex, alpha and beta-endosulfan, alpha, beta and gamma hexachlorocyclohexane, and p'p'-DDT, p'p'-DDE were conducted to establish the differential distribution of the toxicants between compartments, i.e., mother and umbilical cord. Significantly higher pesticide levels were found in umbilical cord plasma than in mothers' plasma for almost all compounds tested, except DDE and oxychlordane. Significantly higher olive tail moments were found in umbilical cords than in mothers, whereas micronuclei frequencies were higher in mothers than in umbilical cords. However, neither the levels of micronuclei nor the olive tail moment were correlated with pesticide levels. Given that no other exposure to toxic compounds has been identified in this region, the lack of correlation between genotoxicity biomarkers and pesticide levels may be due to the variability of the exposure and to endogenous processes related to lipid mobility during pregnancy, the metabolism of the compounds, and individual susceptibilities.
Genotoxicity in cells may occur in different ways, direct interaction, production of electrophilic metabolites, and secondary genotoxicity via oxidative stress. Chloroform, dichloromethane, and toluene are primarily metabolized in liver by CYP2E1, producing reactive electrophilic metabolites, and may also produce oxidative stress via the uncoupled CYP2E1 catalytic cycle. Additionally, GSTT1 also participates in dichloromethane activation. Despite the oxidative metabolism of these compounds and the production of oxidative adducts, their genotoxicity in the bone marrow micronucleus test is unclear. The objective of this work was to analyze whether the oxidative metabolism induced by the coexposure to these compounds would account for increased micronucleus frequency. We used an approach including the analysis of phase I, phase II, and antioxidant enzymes, oxidative stress biomarkers, and micronuclei in bone marrow (MNPCE) and hepatocytes (MNHEP). Rats were administered different doses of an artificial mixture of CLF/DCM/TOL, under two regimes. After one administration MNPCE frequency increased in correlation with induced GSTT1 activity and no oxidative stress occurred. Conversely, after three-day treatments oxidative stress was observed, without genotoxicity. The effects observed indicate that MNPCE by the coexposure to these VOCs could be increased via inducing the activity of metabolism enzymes.
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