Acute Dosing and XXXX -Deficiency Promote Cellular Sensitivity to DNA Methylating Agents.

@entity1 @entity7045 @entity10842 @entity5 @entity876 @entity7044 @entity10843
UNASSIGNED: Risk assessment of @entity1 exposure to chemicals is crucial for understanding whether such agents can cause @entity5 . The current emphasis on avoidance of animal testing has placed greater importance on in  vitro tests for the identification of genotoxicants. Selection of an appropriate in  vitro dosing regime is imperative in determining the genotoxic effects of test chemicals. Here, the issue of dosing approaches was addressed by comparing acute and chronic dosing, uniquely using low-dose experiments. Acute 24   h exposures were compared with equivalent dosing every 24   h over 5-day, fractionated treatment periods. The in  vitro micronucleus assay was used to measure clastogenicity induced by @entity10842 ( @entity10843 ) and @entity7044 ( @entity7045 ) in @entity1 lymphoblastoid cell line, TK6. Quantitative real-time (qRT) PCR was used to measure mRNA level induction of DNA repair enzymes. Lowest observed genotoxic effect levels (LOGELs) for @entity10843 were obtained at 0.7     g/ml for the acute study and 1.0     g/ml for the chronic study. For acute @entity7045 dosing, a LOGEL was observed at 0.46     g/ml, yet genotoxicity was completely removed following the chronic study. Interestingly, acute @entity7045 dosing demonstrated a statistically significant decrease at 0.009     g/ml. Levels of selected DNA repair enzymes did not change significantly following doses tested. However, @entity876 deficiency (using the TK6-isogenic cell line, NH32) increased sensitivity to @entity10843 during chronic dosing, causing this LOGEL to equate to the acute treatment LOGEL. In the context of the present data for 2 alkylating agents, chronic dosing could be a valuable in  vitro supplement to acute dosing and could contribute to reduction of unnecessary in  vivo follow-up tests.
