Association of radiation risk in the second and third generations with polymorphisms in the genes CYP1A1, CYP2E1, GSTP1 and changes in the thyroid.

BACKGROUND: To study the association of radiation risk in the 2nd -3rd generations with polymorphisms in the genes CYP1A1, CYP2E1, GSTP1 and changes in the thyroid. METHODS: 5 polymorphic gene variants (rs1048943, rs4646421, rs2070676, rs3813867, rs1695) were studied in 399 people living in the East Kazakhstan region in this research. 248 people of the 2nd - 3rd generation lived in the territory with radiation exposure in Abai, Borodulikha areas, and 151 people the comparison group lived in Kurchum district without radiation exposure comparable in sex and age with control group. RESULTS: The results show that there is a significant association of rs1048943 in exposed and unexposed groups (p < 0.003), and the absence of association of rs4646421, rs2070676, rs3813867, rs1695 in the studied groups. The mean value of thyroxine in carriers of the AG + GG genotype of rs4646421 is significantly lower than in AA genotype carriers (p = 0.04); no significant changes were found in genotypes' distribution with thyroid-stimulating hormone and anti-thyroid peroxidase indicators. Significant changes were in levels of anti-thyroid peroxidase between exposed and unexposed groups (p = 0.007). The thyroxine - thyroid-stimulating hormone levels were not significantly different in exposed and unexposed groups (p > 0.3). CONCLUSIONS: This study demonstrated the association of rs1048943 polymorphism with living in the radiation zone in the 2nd and 3rd generations for the first time. Thyroxine levels decrease was identified in the 2nd and 3rd generation residents of the exposed area, as well as a significant increase of anti-thyroid peroxidase occurs in individuals of the 2nd and 3rd generation living in areas with radiation exposure.

Novel cytochrome P450 1 (CYP1) genes in tree shrews are expressed and encode functional drug-metabolizing enzymes.

Tree shrews (Tupaia belangeri) are a non-rodent primate-like species sometimes used for biomedical research involving hepatitis virus infections and toxicology. Genome analysis has indicated similarities between tree shrews and humans in the numbers of cytochromes P450 (P450 or CYP), which constitute a family of important drug-metabolizing enzymes; however, P450s have not been fully investigated in tree shrews. In this study, we identified CYP1A1, CYP1A2, CYP1B1, and CYP1D1 cDNAs from tree shrew liver and compared their characteristics with dog, pig, and human CYP1As. The deduced amino acid sequences of tree shrew CYP1s were highly identical (82-87 %) to human CYP1s. In tree shrews, CYP1A1 and CYP1A2 mRNAs were preferentially expressed in liver, whereas CYP1D1 mRNA was preferentially expressed in kidney and lung. In contrast, CYP1B1 mRNA was expressed in various tissues, with the most abundant expression in spleen. Among the tree shrew CYP1 mRNAs, CYP1A2 mRNA was most abundant in liver, and CYP1B1 mRNA was most abundant in kidney, small intestine, and lung. All tree shrew CYP1 proteins heterologously expressed in Escherichia coli catalyzed caffeine and estradiol in a similar manner to tree shrew liver microsomes and human, dog, and pig CYP1 proteins. These results suggest that tree shrew CYP1A1, CYP1A2, CYP1B1, and CYP1D1 genes, different form human pseudogene CYP1D1P, are expressed in liver, small intestine, lung, and/or kidney and encode functional drug-metabolizing enzymes important in toxicology.

Untangling mechanisms of crude oil toxicity: Linking gene expression, morphology and PAHs at two developmental stages in a cold-water fish.

Early life stages of fish are highly sensitive to crude oil exposure and thus, short term exposures during critical developmental periods could have detrimental consequences for juvenile survival. Here we administered crude oil to Atlantic haddock (Melanogrammus aeglefinus) in short term (3-day) exposures at two developmental time periods: before first heartbeat, from gastrulation to cardiac cone stage (early), and from first heartbeat to one day before hatching (late). A frequent sampling regime enabled us to determine immediate PAH uptake, metabolite formation and gene expression changes. In general, the embryotoxic consequences of an oil exposure were more severe in the early exposure animals. Oil droplets on the eggshell resulted in severe cardiac and craniofacial abnormalities in the highest treatments. Gene expression changes of Cytochrome 1 a, b, c and d (cyp1a, b, c, d), Bone morphogenetic protein 10 (bmp10), ABC transporter b1 (abcb1) and Rh-associated G-protein (rhag) were linked to PAH uptake, occurrence of metabolites of phenanthrene and developmental and functional abnormalities. We detected circulation-independent, oil-induced gene expression changes and separated phenotypes linked to proliferation, growth and disruption of formation events at early and late developmental stages. Changes in bmp10 expression suggest a direct oil-induced effect on calcium homeostasis. Localized expression of rhag propose an impact on osmoregulation. Severe eye abnormalities were linked to possible inappropriate overexpression of cyp1b in the eyes. This study gives an increased knowledge about developmentally dependent effects of crude oil toxicity. Thus, our findings provide more knowledge and detail to new and several existing adverse outcome pathways of crude oil toxicity.