Systemic administration of 3-nitropropionic acid (3-NPA) leads to a shortage of cellular ATP and induces striatum-specific lesions that resemble Huntington's disease. Gender differences, in terms of vulnerability of striatum to 3-NPA, have been shown in male rats. The goal of the present study was to determine whether changes in sex hormone levels during the critical period of sexual differentiation (E17-P4) influence striatal vulnerability to 3-NPA. An androgen receptor antagonist, flutamide, or an aromatase-inhibitor, fadrozole hydrochloride, which block conversion of testosterone to estradiol, were administered to embryonic rats during E17-E20 or E18-E20, respectively, with subsequent 3-NPA (20mg/(kg day) for 2 days) treatment during adulthood (8-9 weeks old). Motor behavior and histological changes (IgG exudation due to blood-brain barrier dysfunction and glial fibrillary acidic protein immunoreactivity) were assessed. Treatment with flutamide significantly decreased the 3-NPA-induced motor behavior in male rats, while administration of fadrozole hydrochloride increased atypical motor behavior in female rats. IgG exudation, as well as decreased glial fibrillary acidic protein reactivity, was observed in animals with motor defects. Flutamide decreased testosterone levels in male rats, while fadrozole hydrochloride increased testosterone levels in female rats. These results suggest that prenatal modulation of sexual hormonal levels greatly influences vulnerability to 3-NPA during adulthood and directly correlates to serum testosterone levels.