Endocrine Abstracts (2006) 11 P432

Androgen-dependent Sertoli cell proliferation as a target for endocrine disruptors relevant to human male reproductive health

H Scott, N Hallmark, PTK Saunders, G Verhoeven, K De Gendt, G Hutchison & RM Sharpe

Human Reproductive Sciences Unit, Edinburgh, United Kingdom.

Smoking by women during pregnancy can result in a 30–48% reduction in sperm count and testis size in the exposed offspring in adulthood, probably because of a decrease in the number of Sertoli cells. Until recently Sertoli cell proliferation was thought to be androgen independent because fetal Sertoli cells do not express the androgen receptor, but new evidence suggests that androgens may play the lead role in regulating Sertoli cell proliferation in fetal (Tan et al. 2005) and early neonatal life (Atanassova et al. 2005). We hypothesize that a unifying mechanism via which fetal exposure to environmental chemicals could affect sperm count in adulthood, is through interference with androgen production/action. To test this hypothesis, we have compared the effects of exposing fetal male rats from E13.5 onwards to 7,12-diemethyl benz[a]anthracene (DMBA) or it’s metabolite DMBA-DHD (as candidate molecules present in cigarette smoke), or n-dibutyl phthalate (DBP; a plasticizer shown to lower fetal testosterone levels), on Sertoli cell number, proliferation, apoptosis and functional development, using a combination of in vitro and in vivo studies. We have also used the AR antagonist, Flutamide, and tissue from mice, in which ablation of androgen action has been induced by transgenesis (ARKOs).

Any effects that androgens do have on Sertoli cell proliferation/number must be indirect, so our studies are also directed at identifying the pathways via which any such effects could be mediated, such as local production of Insulin-Like Growth Factor 1 (IGF1) which has already been shown to increase Sertoli cell proliferation. We have demonstrated that fetal exposure to DMBA, DBP or Flutamide reduces expression of IGF1 mRNA, although preliminary results have so far shown no change in Sertoli cell number in treated animals and Sertoli cell proliferation indices are still under investigation.

Tan KA, et al. Endocrinology 146:2674–83 2005

Atanassova NN, et al. J Endocrinol 184:107–17 2005

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