5-aza-2'-deoxycytidine induces alterations in murine spermatogenesis and pregnancy outcome.
Because of the ability of cytidine analogues, such as 5-aza-2'-deoxycytidine, to incorporate into DNA and lead to decreases in DNA methylation, there has recently been renewed interest in using these drugs in anticancer therapy. To determine the effects of paternal 5-aza-2'-deoxycytidine treatment on spermatogenesis and progeny outcome in the mouse and whether effects are modulated by decreased levels of the predominant DNA methyltransferase, DNMT1, adult Dnmt1(+/+) and Dnmt1-deficient (Dnmt1(c/+)) male mice were treated with 5-aza-2'-deoxycytidine for 7 weeks, which resulted in dose-dependent decreases in testicular weight, an increase in histological abnormalities, and a decline in sperm counts, with no apparent effect on androgen status. Testes of Dnmt1(c/+) mice, however, were less severely affected by 5-aza-2'-deoxycytidine than were those of wild-type mice. The exposure of Dnmt1(+/+) male mice to even low doses of 5-aza-2'-deoxycytidine followed by mating elicited significantly reduced pregnancy rates and elevated preimplantation loss in females. Dnmt1 deficiency, however, protected against such drug-induced decreases in pregnancy rate but not preimplantation loss. Altered DNA methylation or DNMT1 activity may explain such adverse effects, because treatment resulted in dose-dependent decreases in the global methylation of sperm DNA. Thus, in the mouse, paternal administration of 5-aza-2'-deoxycytidine interferes with normal male germ cell development and results in reduced fertility, whereas lowering DNMT1 levels appears to partially protect the seminiferous epithelium from deleterious drug effects.
Departments of Pediatrics, McGill University, and McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada.
Tamara L J
TL
Kelly
En
E
Li
Jacquetta M
JM
Trasler
D000818:Animals; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001769:Blood / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency* / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011247:Pregnancy; D011256:Pregnancy Outcome; D012669:Seminal Vesicles / Q000187:drug effects; D013076:Sperm Count; D013091:Spermatogenesis / Q000187:drug effects*; D013094:Spermatozoa / Q000502:physiology; D013737:Testis / Q000187:drug effects / Q000473:pathology
D004791:Enzyme Inhibitors; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; D001374:Azacitidine