title: Ethylation of DNA and protamine by ethyl methanesulfonate in the germ cells of male mice and the relevancy of these molecular targets to the induction of dominant lethals.
abstract: The molecular dosimetry of ethyl methanesulfonate (EMS) in the germ cells of male mice has been investigated. The mice were injected i.p. with 200 mg/kg of [3H]EMS and the ethylations per sperm head, per deoxynucleotide, and per unit of protamine were then determined over a 2-week period. The ethylations per sperm head closely paralleled the dominant-lethal frequency curve for EMS, reaching a maximum of 5 to 6.5 million ethylations per vas sperm head at 8 to 10 days after treatment. Ethylation of sperm DNA was greatest at 4 h after treatment, with 5.7 ethylations/10(5) deoxynucleotides, and gradually decreased to 2.2 ethylations/10(5) deoxynucleotides at 15 days after treatment. The ethylation of sperm DNA did not increase in the germ-cell stages most sensitive to EMS, and was not correlated with the dominant-lethal frequency curve for EMS. However, ethylation of sperm protamine did increase in the germ-cell stages most sensitive to EMS, and showed an excellent correlation with the incidence of dominant lethals produced by EMS in the germ cells. A model is presented to explain, at a molecular level, how dominant lethals may be induced in mouse germ cells by EMS. Ethylation of cysteine sulfhydryl groups contained in mouse-sperm protamine could block normal disulfide-bond formation, preventing proper chromatin condensation in the sperm nucleus. Stresses in the chromatin structure could then eventually lead to chromosome breakage, with resultant dominant lethality.
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005020:Ethyl Methanesulfonate / Q000494:pharmacology*; D005787:Gene Frequency; D005799:Genes, Dominant; D005804:Genes, Lethal; D008297:Male; D008698:Mesylates / Q000494:pharmacology*; D051379:Mice; D011479:Protamines / Q000378:metabolism*; D013077:Sperm Head / Q000187:drug effects* / Q000378:metabolism; D013094:Spermatozoa / Q000187:drug effects*
chemical_list: D008698:Mesylates; D011479:Protamines; D004247:DNA; D005020:Ethyl Methanesulfonate