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ISSN 2052-1472 (online)

Reproduction Abstracts (2014) 1 P235 | DOI: 10.1530/repabs.1.P235

Tamoxifen inducible Cre systems: adverse effects of low dose tamoxifen treatments on the male reproductive tract

Saloni H Patel, Laura Milne, Richard Sharpe & Lee B Smith

University of Edinburgh, Edinburgh, UK.

Introduction: Tamoxifen inducible Cre systems have been used to study development specific roles of genes in the testis as they allow tight temporal control of genetic manipulation. However, tamoxifen is an anti-estrogen that competitively binds estrogen receptors. Despite the antagonistic properties of tamoxifen, it also acts as a weak estrogen agonist, hence exerting estrogenic effects in a tissue and cell specific manner. Given the duality of tamoxifen function and the importance of estrogen signalling in male reproduction, here we utilise an inducible nestin-Cre reporter to examine testicular impacts of tamoxifen in inducing transgene expression.

Materials and methods: Inducible nestin-Cre recombinase reporter mice were treated with tamoxifen at low and high doses. Standard techniques used to analyse testicular structure and function.

Results and discussion: A high dose of 3 mg tamoxifen at day 21 causes a significant impact on testis function and seminal vesicle atrophy. Surprisingly, even low doses of tamoxifen (250 μg, 500 μg, and 1 mg) administered at day 16 show a long-term effect on the testis in adulthood. At day 47, a significant decrease in testis and seminal vesicle weight is observed in all three low dose groups. This is partly due to a decline in spermatogenesis as indicated by a significant decrease in seminiferous tubule diameter. Additionally, Leydig cell maturation is also perturbed in all treatment groups. These findings demonstrate that tamoxifen administration during postnatal development cause persistent changes in adult testis function. Therefore, tamoxifen inducible gene targeting during postnatal development may not be an appropriate tool in the study of male reproduction.

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