Oxidative stress in the testis induced by tamoxifen and its effects on early embryo development in isogenic mice

Abstract

-Oxidative stress induced by tamoxifen (TAM) in male testis and its effects on fertility and early embryo development were investigated. TAM was orally administered for 4 weeks repeatedly to two isogenic male mice strains, inbred strain of C57BL/6J (B6) mice and hybrid strain of C57BL/6J x CBA F1 (B6CBAF1) mice. Oxidative stress in mice testis was measured based on the level of lipid peroxidation (LPO). The LPO level was significantly increased in inbred strain of B6 mice (p < 0.05), but not hybrid strain of B6CBAF1 mice. Paternal exposure to TAM led to a significant decrease in the fertilization rate in B6 mice (p < 0.05), but not their B6CBAF1 counterparts. Interestingly, TAM had no impact on the cell number and apoptosis status in blastocysts. These results indicate that susceptibility to TAMinduced oxidative stress in the testis differs between isogenic mice strains, and genetic variations play an important role in promoting differential degrees of toxic response. Key words: Tamoxifen, Oxidative stress, Male fertility, Early embryonic development, IsogenicityCorrespondence: Dong Il Jin (E-mail: dijin@cnu.ac.kr) Original ArticleThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.37, No.4, 675-679, 2012 Vol. 37 No. 4 675 MATERIALS AND METHODS AnimalsInbred C57BL/6J (B6) and hybrid C57BL/6J X CBA (B6CBAF1) mice were used. Mice were bred and maintained at a temperature of 22-23°C, relative humidity of 50-55% and a 14 hr light:10 hr dark cycle. Animals were fed sterilized mouse pellets and allowed access to water ad libitum. All animal care and use procedures were approved by the Institutional Animal Care and Use Committee of Chungnam National University. TAM treatmentMale mice aged 4 weeks (n = 6 per group) were administered 0.4 mg/kg/day tamoxifen citrate (Sigma Co., Saint Louis, MO, USA), which dose level was reported to reduce the fertility of adult male rat (Saberwal et al., 2002), orally for 4 weeks. The drug was suspended uniformly in saline via sonication. Saline was used as the vehicle control. Lipid peroxidation (LPO) assay in testisMice were sacrificed 24 hr after the final treatment in the morning between 09:00 and 11:00 am to minimize the circadian cycle effects. Testes were removed, immediately immersed in liquid nitrogen and stored at -80°C. Testes were sliced into sections and homogenized in cold 50 mM phosphate buffer (pH 7.0) containing 0.1 mM EDTA. Homogenates were centrifuged at 600 g for 10 min at 0°C, and the supernatant fractions used for LPO assay and protein determination. In the LPO assay, the malondialdehyde (MDA) level was measured as described by Ohkawa et al. (1979). A 100 μl aliquot of tissue extract was added to 50 μl of 8.1% sodium dodecyl sulfate (SDS), mixed by vortexing, and incubated for 10 min at room temperature. Next, 375 μl of 20% acetic acid (pH 3.5) and 375 μl of thiobarbituric acid (0.6%) were added and the mixture placed in a boiling water bath for 60 min. Samples were allowed to cool down to room temperature. A 250 μl aliquot of distilled water...

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