Q126959183
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DNA methylation is the most studied epigenetic mechanism that regulates gene expression, and it can serve as a useful biomarker of prior environmental exposure and future health outcomes. This study focused on DNA methylation profiles in a human cohort, comprising 125 nonsmoking city policemen (sampled twice), living and working in three localities (Prague, Ostrava and Ceske Budejovice) of the Czech Republic, who spent the majority of their working time outdoors. The main characterization of the localities, differing by major sources of air pollution, was defined by the stationary air pollution monitoring of PM2.5, B[a]P and NO2. DNA methylation was analyzed by a genome-wide microarray method. No season-specific DNA methylation pattern was discovered; however, we identified 13,643 differentially methylated CpG loci (DML) for a comparison between the Prague and Ostrava groups. The most significant DML was cg10123377 (log2FC = -1.92, p = 8.30 × 10-4) and loci annotated to RPTOR (total 20 CpG loci). We also found two hypomethylated loci annotated to the DNA repair gene XRCC5. Groups of DML annotated to the same gene were linked to diabetes mellitus (KCNQ1), respiratory diseases (PTPRN2), the dopaminergic system of the brain and neurodegenerative diseases (NR4A2). The most significant possibly affected pathway was Axon guidance, with 86 potentially deregulated genes near DML. The cluster of gene sets that could be affected by DNA methylation in the Ostrava groups mainly includes the neuronal functions and biological processes of cell junctions and adhesion assembly. The study demonstrates that the differences in the type of air pollution between localities can affect a unique change in DNA methylation profiles across the human genome.
- MeSH
- celogenomová asociační studie MeSH
- dospělí MeSH
- látky znečišťující vzduch škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- metylace DNA účinky léků MeSH
- policie * MeSH
- vystavení vlivu životního prostředí škodlivé účinky MeSH
- znečištění ovzduší škodlivé účinky MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- MeSH
- biologické markery MeSH
- diabetes mellitus 2. typu * MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- exprese genu MeSH
- hematotestikulární bariéra MeSH
- modely nemocí na zvířatech * MeSH
- mužská infertilita * genetika MeSH
- myši MeSH
- protaminy MeSH
- protein obsahující valosin MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Diabetes is a chronic metabolic disorder characterized by hyperglycemia and associated with many health complications due to the long-term damage and dysfunction of various organs. A consequential complication of diabetes in men is reproductive dysfunction, reduced fertility, and poor reproductive outcomes. However, the molecular mechanisms responsible for diabetic environment-induced sperm damage and overall decreased reproductive outcomes are not fully established. We evaluated the effects of type 2 diabetes exposure on the reproductive system and the reproductive outcomes of males and their male offspring, using a mouse model. We demonstrate that paternal exposure to type 2 diabetes mediates intergenerational and transgenerational effects on the reproductive health of the offspring, especially on sperm quality, and on metabolic characteristics. Given the transgenerational impairment of reproductive and metabolic parameters through two generations, these changes likely take the form of inherited epigenetic marks through the germline. Our results emphasize the importance of improving metabolic health not only in women of reproductive age, but also in potential fathers, in order to reduce the negative impacts of diabetes on subsequent generations.
- MeSH
- diabetes mellitus 2. typu krev chemicky indukované genetika MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- experimentální diabetes mellitus MeSH
- fenotyp * MeSH
- infertilita krev chemicky indukované genetika MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- paternální dědičnost účinky léků genetika MeSH
- spermie účinky léků fyziologie MeSH
- streptozocin toxicita MeSH
- těhotenství MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
DNA damage can impair normal cellular functions and result in various pathophysiological processes including cardiovascular diseases and cancer. We compared the genotoxic potential of diverse DNA damaging agents, and focused on their effects on the DNA damage response (DDR) and cell fate in human lung cells BEAS-2B. Polycyclic aromatic hydrocarbons [PAHs; benzo[a]pyrene (B[a]P), 1-nitropyrene (1-NP)] induced DNA strand breaks and oxidative damage to DNA; anticancer drugs doxorubicin (DOX) and 5-bromo-2'-deoxyuridine (BrdU) were less effective. DOX triggered the most robust p53 signaling indicating activation of DDR, followed by cell cycle arrest in the G2/M phase, induction of apoptosis and senescence, possibly due to the severe and irreparable DNA lesions. BrdU not only activated p53, but also increased the percentage of G1-phased cells and caused a massive accumulation of senescent cells. In contrast, regardless the activation of p53, both PAHs did not substantially affect the cell cycle distribution or senescence. Finally, a small fraction of cells accumulated only in the G2/M phase and exhibited increased cell death after the prolonged incubation with B[a]P. Overall, we characterized differential responses to diverse DNA damaging agents resulting in specific cell fate and highlighted the key role of DNA lesion type and the p53 signaling persistence.
The biological effects induced by complete engine emissions in a 3D model of the human airway (MucilAirTM) and in human bronchial epithelial cells (BEAS-2B) grown at the air-liquid interface were compared. The cells were exposed for one or five days to emissions generated by a Euro 5 direct injection spark ignition engine. The general condition of the cells was assessed by the measurement of transepithelial electrical resistance and mucin production. The cytotoxic effects were evaluated by adenylate kinase (AK) and lactate dehydrogenase (LDH) activity. Phosphorylation of histone H2AX was used to detect double-stranded DNA breaks. The expression of the selected 370 relevant genes was analyzed using next-generation sequencing. The exposure had minimal effects on integrity and AK leakage in both cell models. LDH activity and mucin production in BEAS-2B cells significantly increased after longer exposures; DNA breaks were also detected. The exposure affected CYP1A1 and HSPA5 expression in MucilAirTM. There were no effects of this kind observed in BEAS-2B cells; in this system gene expression was rather affected by the time of treatment. The type of cell model was the most important factor modulating gene expression. In summary, the biological effects of complete emissions exposure were weak. In the specific conditions used in this study, the effects observed in BEAS-2B cells were induced by the exposure protocol rather than by emissions and thus this cell line seems to be less suitable for analyses of longer treatment than the 3D model.
- MeSH
- biologické markery MeSH
- biologické modely * MeSH
- elektrická impedance MeSH
- epitelové buňky účinky léků metabolismus MeSH
- exprese genu MeSH
- lidé MeSH
- muciny biosyntéza MeSH
- respirační sliznice účinky léků metabolismus MeSH
- výfukové emise vozidel toxicita MeSH
- vystavení vlivu životního prostředí škodlivé účinky MeSH
- zlomy DNA MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Pro detekci molekulárních změn vyvolaných diabetes mellitus jsme použili panel protilátek proti vybraným proteinům testes a spermií. Detegovali jsme změny v morfologii a histologii varlat a změny v expresi důležitých proteinů, které jsou zapojeny do spermatogeneze a mezibuněčné komunikace. Monoklonální protilátky proti intra -akrozomálním proteinům prokázaly zhoršenou kvalitu spermií u diabetických pacientů i spermií diabetických myší. Panel vybraných protilátek lze použít k testování změn v testes a kvalitě spermií vyvolaných diabetem. Tyto výsledky jasně dokumentují vliv diabetického prostředí na morfologii a histologii varlat a kvalitu spermií.
We used a panel of antibodies against selected testicular and sperm proteins to detect molecular changes induced by diabetes mellitus. We detected changes in morphology and histology of the testes, and changes in the expression and distribution of proteins involved in spermatogenesis and intercellular communication. Monoclonal antibodies against intra -acrosomal proteins demonstrated the impaired quality of sperms from diabetic patients as well as sperms from diabetic mice. In conclusion, the panel of selected antibodies can be used to test diabetes -induced changes in the testes and sperm quality. These results clearly document the effect of the diabetic environment on the morphology and histology of the testes, and sperm quality.
