Transplacental Exposure to the DNA Demethylating Agent, 5-AZA-CdR, Affects the Sexual Behavior of CD-1 Male Mice

Abstract

Intrauterine exposure to 5-AZA-2′-deoxycytidine (5-AZA-CdR) alters gene expression causing malformations, abnormal post-natal growth and altered reproductive capacity. To elucidate whether the phenomenon observed in 5-AZA-CdR in utero exposed male mice was a behavioral alteration, at gestation day (GD) 10, CD-1 pregnant mice were administered 1 mg/kg i.p. of 5-AZA-CdR or saline solution. After parturition, the number and sex of pups were recorded. While litter size was not affected, the ratio of male to female offspring was altered in treated mice. To determine whether the phenotypic observation of male gender corresponded to the appropriate genotype, presence of Sry gene in 5-AZA-CdR F1 males was determined. At 3 months of age, the male sexual behavior test outlined by Chubb was conducted. Presence of vaginal plug and pregnancy were determined in the natural breeding phase. Mount latency and number of mounts per mouse were assessed in the behavioral test phase. In utero exposed male mice resulted in diminished mating behavior (as measured by vaginal plug presence, mount latency and number of mounts) and reduced sexual interest while exposed to a receptive female. While normal presence of Sry gene was observed, mating behavior was altered in exposed males suggesting that the reproductive alteration could be attributed to a behavioral phenomenon.