We investigated the association of urinary bladder cancer with genetic polymorphisms in the xeroderma pigmentosum complementation group C ( XPC ), group D ( XPD ) and group G ( XPG ), X-ray repair cross-complementing group 1 ( XRCC1 ) and group 3 ( XRCC3 ), Nijmegen breakage syndrome 1 ( NBS1 ), cyclin D1, methylene-tetrahydrofolate reductase ( MTHFR ), NAD(P)H dehydrogenase quinone 1 ( NQO1 ), H-ras and glutathione S -transferase theta 1 ( GSTT1 ) genes. Bladder cancer patients from the different hospitals in Stockholm County Council area and matching controls were genotyped for different polymorphisms. The frequency of the variant allele for A/C polymorphism in exon 15 of the XPC gene was significantly higher in the bladder cancer cases than in the controls (OR 1.49, 95% CI 1.16–1.92, P = 0.001). The variant allele homozygote genotype for the T/C polymorphism in exon 1 of the H-ra s gene was associated with a decreased risk for bladder cancer (OR 0.12, 95% CI 0.02–0.67, P = 0.006). The variant allele genotypes for the single nucleotide polymorphisms (SNPs) in DNA repair genes, XPG and NBS1 , showed a marginal association with the occurrence of bladder cancer (OR 0.38, 95% CI 0.15–0.94, P = 0.03 and OR 1.64, 95% CI 0.92–2.90, P = 0.09, respectively). We also report a positive correlation between the null homozygote of GSTT1 with the risk of bladder cancer (OR 2.54, 95% CI 1.32–4.98, P = 0.003). For other polymorphisms included in this study, NBS1 Glu185Gln, XPD Lys751Gln, XPG Asp1104His, XRCC1 Arg399Gln, XRCC3 Thr241Met, cyclin D1 Pro242Pro, MTHFR Ala222Val and Glu429Ala, NQO1 Arg139Trp and Pro187Ser, no significant differences for genotype distributions and allele frequencies between the bladder cancer cases and the controls were observed in the present study.

We analysed the associations between genetic polymorphisms in genes coding for DNA repair enzymes XPD (exon 23 A → C, K751Q), XPG (exon 15 G → C, D1104H), XPC (exon 15 A → C, K939Q), XRCC1 (exon 10 G → A, R399Q) and XRCC3 (exon 7 C → T, T241 M) and the levels of chromosomal aberrations (CAs) and single-strand breaks (SSBs) in peripheral lymphocytes in a central European population. We also measured the irradiation-specific DNA repair rates and the repair rates of 8-oxoguanines in these individuals. An elevated frequency of CAs was observed in individuals with the XPD exon 23 A allele (AA and AC) genotypes (F = 3.6, P = 0.028, ANOVA). In multifactorial analysis of variance, the XPD exon 23 polymorphism appeared as a major factor influencing CAs (F = 4.2, P = 0.017). SSBs in DNA, on the other hand, were modulated by XPD (F = 4.3, P = 0.023), XPG (F = 4.3, P = 0.024) and XRCC1 genotypes (F = 3.0, P = 0.064). Irradiation-specific DNA repair rates (reflecting mainly base excision repair activity) were affected by XRCC1 (F = 5.9, P = 0.010) and XPC polymorphisms (F = 4.2, P = 0.046, MANOVA). Our results from this study suggest that markers of genotoxicity are associated with polymorphisms in genes encoding DNA repair enzymes.

The astrocyte marker, glial fibrillary acidic protein (GFAP), has essential functions in the brain, but may trigger astroglial scarring when expressed in excess. Docosahexaenoic acid (DHA) is an n‐3 fatty acid that is protective during brain development. However, the effect of DHA on GFAP levels of developing brain remains unexplored. Here, we detected that treating developing rats with DHA‐enriched fish‐oil caused dose‐dependent GFAP augmentation. We investigated the mechanism promoting GFAP, hypothesizing the participation of fatty acid‐binding protein‐7 (FABP7), known to bind DHA. We identified that DHA stimulated FABP7 expression in astrocytes, and FABP7‐silencing suppressed DHA‐induced GFAP, indicating FABP7‐mediated GFAP increase. Further investigation proved FABP7 expression to be phosphatidylinositide 3‐kinases (PI3K)/AKT and nuclear receptor peroxisome proliferator‐activated receptor‐gamma (PPARγ)‐dependent. We found that PI3K/AKT activated PPARγ that triggered FABP7 expression via PPARγ‐responsive elements within its gene. Towards identifying FABP7‐downstream pathways, we considered our previous report that demonstrated cyclin‐dependent kinase‐5 (CDK5)‐PPARγ‐protein–protein complex to suppress GFAP. We found that the DHA‐induced FABP7 underwent protein‐protein interaction with PPARγ, which impeded CDK5‐PPARγ formation. Hence, it appeared that enhanced FABP7‐PPARγ in lieu of CDK5‐PPARγ resulted in increased GFAP. PI3K/AKT not only stimulated formation of FABP7‐PPARγ protein‐protein complex, but also up‐regulated a FABP7‐independent MAP‐kinase‐phosphatase‐3 pathway that inactivated CDK5 and hence attenuated CDK5‐PPARγ. Overall, our data reveal that via the proximal PI3K/AKT, DHA induces FABP7‐PPARγ, through genomic and non‐genomic mechanisms, and MAP‐kinase‐phosphatase‐3 that converged at attenuated CDK5‐PPARγ and therefore, enhanced GFAP. Accordingly, our study demonstrates a DHA‐mediated astroglial hyperactivation, pointing toward a probable injurious role of DHA in brain development. image