Biotransformation pathway maps in WikiPathways enable direct visualization of drug metabolism related expression changes.

In recent decades, our knowledge of the genetics and functional genomics of drug-metabolizing enzymes has increased and a wealth of data on drug-related 'omics' has become available. Despite the availability of large amounts of biological information on xenobiotic biotransformation, the number of available biotransformation pathway maps that can easily be used for visualization of multiple omics data is limited. Here, we created integrated biotransformation pathway maps suitable for multiple omics analysis using PathVisio. The ease of visualizing data on these maps was demonstrated by using published microarray data from human hepatocyte-like cell models, exemplifying - where a sufficient capacity for metabolizing chemicals is a prerequisite for a suited model - how the biotransformation pathway maps can be used for model selection

Prevalence of at-risk genotypes for genotoxic effects decreases with age in a randomly selected population in Flanders: a cross sectional study

Background: We hypothesized that in Flanders (Belgium), the prevalence of at-risk genotypes for genotoxic effects decreases with age due to morbidity and mortality resulting from chronic diseases. Rather than polymorphisms in single genes, the interaction of multiple genetic polymorphisms in low penetrance genes involved in genotoxic effects might be of relevance. Methods: Genotyping was performed on 399 randomly selected adults (aged 50-65) and on 442 randomly selected adolescents. Based on their involvement in processes relevant to genotoxicity, 28 low penetrance polymorphisms affecting the phenotype in 19 genes were selected (xenobiotic metabolism, oxidative stress defense and DNA repair, respectively 13, 6 and 9 polymorphisms). Polymorphisms which, based on available literature, could not clearly be categorized a priori as leading to an 'increased risk' or a 'protective effect' were excluded. Results: The mean number of risk alleles for all investigated polymorphisms was found to be lower in the 'elderly' (17.0 +/- 2.9) than the 'adolescent' (17.6 +/- 3.1) subpopulation (P = 0.002). These results were not affected by gender nor smoking. The prevalence of a high (> 17 = median) number of risk alleles was less frequent in the 'elderly' (40.6%) than the 'adolescent' (51.4%) subpopulation (P = 0.002). In particular for phase II enzymes, the mean number of risk alleles was lower in the 'elderly' (4.3 +/- 1.6) than the 'adolescent' age group (4.8 +/- 1.9) P 4 = median) number of risk alleles was less frequent in the 'elderly' (41.3%) than the adolescent subpopulation (56.3%, P 8 = median) number of risk alleles for DNA repair enzyme-coding genes was lower in the 'elderly' (37,3%) than the 'adolescent' subpopulation (45.6%, P = 0.017). Conclusions: These observations are consistent with the hypothesis that, in Flanders, the prevalence of at-risk alleles in genes involved in genotoxic effects decreases with age, suggesting that persons carrying a higher number of at risk alleles (especially in phase II xenobiotic-metabolizing or DNA repair genes) are at a higher risk of morbidity and mortality from chronic diseases. Our findings also suggest that, regarding risk of disease associated with low penetrance polymorphisms, multiple polymorphisms should be taken into account, rather than single ones

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10-11 to 5.0 × 10-21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10-6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation

Principles in toxicological risk analysis

Principles in toxicological risk analysis. Kleinjans JC. Department of Health Risk Analysis and Toxicology, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands. [email protected] Toxicological risk analysis comprises a process of hazard identification, dose-response assessment and exposure assessment, providing as an output the estimation of the incidence and severity of adverse effects likely to occur in a human population in relation to actual or eventual exposure to hazardous compounds. Within this respect, toxicological risk analysis represents a scientific activity, which uses data from toxicological research, and serves as a basis for risk management which is the decision-making process which is performed by regulators and politicians, considering also non-scientific aspects such as socioeconomic and political factors. The predominant step in hazard identification is the answer to the question whether a compound must be classified as a genotoxic carcinogen, epigenetic carcinogen or non-carcinogen. Additional important aspects concern the questions how to extrapolate from high to low dose, as well as how to deal with exposures to complex mixtures of carcinogens. Also, the question is addressed whether it is required in toxicological risk analysis to consider susceptible subgroups in the population, for instance on the basis of specific genetic predisposition

Ecogenotoxicology: the evolving field

The occurrence of chemical contaminants with DNA-damaging capacity in the environment represents a threat to human health as well as to the health of the ecosystem. This mini-review describes studies that were aimed to monitor at field conditions, the presence of such environmental toxicants and their DNA-damaging effects in aquatic and terrestrial species, as well as in birds. It is obvious that these studies, in particular are abundantly performed in fish and aquatic invertebrates, have brought forward new information on the levels and genotoxic effects of these compounds which complements data coming from monitoring the abiotic fractions of the ecosystem, thereby demonstrating that the ecogenotoxicological approach is fruitful. However, in order to assess the genotoxic impact on the health of the ecosystem, a second generation type of field studies is required focusing on adverse effects on biodiversity and on survival potency. For this, the application of DNA microarray-based technologies provides new opportunities