Antiestrogens Inhibit Xenoestrogen-Induced Brain Aromatase Activity but Do Not Prevent Xenoestrogen-Induced Feminization in Japanese Medaka (Oryzias latipes)

In fish, exposure to estrogen or estrogen-mimicking chemicals (xenoestrogens) during a critical period of development can irreversibly invert sex differentiation. In medaka, a male-to-female reversal upon exposure to a xenoestrogen is accompanied by an increase in brain aromatase expression and activity. However, whether this increase is the direct cause of sex reversal is unknown. In this study we further examined the role brain aromatase plays in genesis of developmental abnormalities in response to endocrine-disrupting chemicals (EDCs). Further, the effects of a mixture of apparent antagonistic environmentally relevant EDCs on development were examined to determine if their combined actions could lessen each other’s impacts. To this end, hatchling medaka were subjected in a 2-week flow-through immersion exposure to an estrogen mimic [dichlorodiphenyltrichloroethane (o,p′-DDT)] and to pharmaceutical [fadrozole (FAD)] and environmental aromatase inhibitors [tributyltin (TBT)] alone and in combination. Brain aromatase expression and enzyme activity were measured on exposure days 5, 9, and 14 by real-time reverse-transcriptase polymerase chain reaction and tritiated water release assay, respectively. We recorded sex reversals at sexual maturity by examining the phenotypic and genotypic sex of d-rR–strain medaka. Results indicate that FAD and TBT inhibit aromatase activity in o,p′-DDT–treated fish but do not prevent feminization, indicating that increased brain aromatase activity is not critical to EDC-induced male-to-female sex inversion. The observation that estradiol biosynthesis inhibitors do not block the effect of the xenoestrogen suggests that in the environment, exposure to seemingly antagonistic EDCs does not necessarily lessen the harmful impacts of these compounds.