No abstract

Endemic (Balkan) nephropathy (EN),environmental mutagen ͉ p53 mutation ͉ urothelial cancer ͉ DNA adduct

Sodium-ion batteries are emerging as candidates for large-scale energy storage due to their low cost and the wide variety of cathode materials available. As battery size and adoption in critical applications increases, safety concerns are resurfacing due to the inherent flammability of organic electrolytes currently in use in both lithium and sodium battery chemistries. Development of solid-state batteries with ionic electrolytes eliminates this concern, while also allowing novel device architectures and potentially improving cycle life. Here we report the computation-assisted discovery and synthesis of a high-performance solid-state electrolyte material: Na10SnP2S12, with room temperature ionic conductivity of 0.4 mS cm−1 rivalling the conductivity of the best sodium sulfide solid electrolytes to date. We also computationally investigate the variants of this compound where tin is substituted by germanium or silicon and find that the latter may achieve even higher conductivity.

Several recently discovered human DNA polymerases are associated with translesion synthesis past DNA adducts. These include human DNA polymerase kappa (pol kappa), a homologue of Escherichia coli pol IV, which enhances the frequency of spontaneous mutation. Using a truncated form of pol kappa (pol kappa Delta C), translesion synthesis past dG-(+)- or dG-(-)-anti-N(2)-BPDE (7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene) adducts was explored. Site-specifically-modified oligodeoxynucleotides containing a single stereoisomeric dG-N(2)-BPDE lesion were used as DNA templates for primer extension reactions catalyzed by pol kappa Delta C. Primer extension was retarded one base prior to the dG-N(2)-BPDE lesion; when incubated for longer times or with higher concentration of enzyme, full primer extension was observed. Quantitative analysis of fully extended products showed preferential incorporation of dCMP, the correct base, opposite all four stereoisomeric dG-N(2)-BPDE lesions. (+)-trans-dG-N(2)-BPDE, a major BPDE-DNA adduct, promoted small amounts of dTMP, dAMP, and dGMP misincorporation opposite the lesion (total 2.7% of the starting primers) and deletions (1.1%). Although (+)-cis-dG-N(2)-BPDE was most effective in blocking translesion synthesis, its miscoding properties were similar to other dG-N(2)-BPDE isomers. Steady-state kinetic data indicate that dCMP is efficiently inserted opposite all dG-N(2)-BPDE adducts and extended past these lesions. The relative frequency of translesion synthesis (F(ins) x F(ext)) of dC.dG-N(2)-BPDE pairs was 2-6 orders of magnitude higher than that of other mismatched pairs. Pol kappa may play an important role in translesion synthesis by incorporating preferentially the correct base opposite dG-N(2)-BPDE. Its relatively low contribution to mutagenicity suggests that other newly discovered DNA polymerase(s) may be involved in mutagenic events attributed to dG-N(2)-BPDE adducts in human cells.

ABSTRACT:Ingestion of herbal remedies containing aristolochic acids (AAs) is associated with the development of a syndrome, designated aristolochic acid nephropathy (AAN), which is characterized by chronic renal failure, tubulointerstitial fibrosis, and urothelial cancer. To distinguish the component(s) of AA responsible for these varied toxic effects, we administered 2.5 mg/kg/day of AA-I or AA-II for 9 days, either i.p. or p.o., to male C3H/He mice. Tissues were then collected and subjected to biochemical and histopathologic examination. Genotoxicity was assessed by determining quantitatively the level of aristolactam-DNA adducts in various tissues using 32 P-postlabeling/polyacrylamide gel electrophoresis and an internal standard. In the primary target tissues, represented by the renal cortex, medulla, and bladder, we found similar levels of DNA adducts derived from AA-I and AA-II. However, in nontarget tissues, the liver, stomach, intestine, and lung, the levels of aristolactam-DNA adducts derived from AA-I were significantly higher than those derived from AA-II. Histopathologic analysis revealed tubular cell necrosis and interstitial fibrosis in the renal cortex of AA-I-treated mice but only minimal changes in the renal cortex of mice treated with AA-II. We conclude that AA-I and AA-II have similar genotoxic and carcinogenic potential, and, although both compounds are cytotoxic, AA-I is solely responsible for the nephrotoxicity associated with AAN.