Chemical dosimetry of ethyl nitrosourea in the mouse testis.
[3H-Et]Nitrosourea was administered to male (101 X C3H) mice by i.p. injection at exposure levels of 10 mg/kg or 100 mg/kg. At intervals from 1 h to 6 days following treatment, the ratio of O6-ethylguanine to N7-ethylguanine in testis DNA averaged 1.13 following the 100 mg/kg exposure and 0.72 following the 10 mg/kg exposure. The amount of O6-ethylguanine recovered after the 100 mg/kg exposure was 40% greater than predicted from a linear extrapolation of the amount of O6-ethylguanine recovered after the 10 mg/kg exposure. We suggest that the high (100 mg/kg) exposure to ethyl nitrosourea results in depletion of the O6-alkylguanine acceptor protein within the testis and permits O6-ethylguanine to persist at higher levels than would be predicted from lower exposure data. W.L. Russell et al. (1982), W.L. Russell (1984) have found that specific-locus mutation frequencies induced in mouse spermatogonial stem cells are 5.8-fold greater after a single 100 mg/kg exposure to ethyl nitrosourea than after 10 weekly exposures to 10 mg/kg. The finding that the corresponding ratio for O6-ethylguanine formed in the testis is only 1.4 may be interpreted in a number of possible ways. If O6-ethylguanine is an important lesion for producing specific-locus mutations, then its formation in the stem cells must be at least 4-fold greater than that for the whole testis as the ENU exposure goes from 10 to 100 mg/kg: alternatively, the rate of repair of this lesion by the stem cells must decrease at least 4-fold relative to the average testicular cell. Other explanations for the difference in mutation response of the stem cells to acute vs. chronic ethyl nitrosourea-exposures include the possibility that other DNA lesions may be responsible for many of the mutations or that two hits on the DNA may be required to produce an effect.
D000477:Alkylating Agents; D000478:Alkylation; D000818:Animals; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005038:Ethylnitrosourea / Q000378:metabolism / Q000633:toxicity*; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D051379:Mice; D013093:Spermatogonia / Q000187:drug effects; D013737:Testis / Q000187:drug effects*; D013997:Time Factors
D000477:Alkylating Agents; C022007:7-ethylguanine; C007673:6-ethylguanine; D006147:Guanine; D004247:DNA; D005038:Ethylnitrosourea