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Although it is established that in utero exposure to antiandrogenic compounds such as flutamide induces hypospermatogenesis in adult male rat offspring, the cellular and molecular mechanisms remain to be investigated. By using adult rats exposed in utero to flutamide (0.4, 2, 10 mg/kg.d) as a model, we show that the hypospermatogenesis could be related to a chronic apoptotic cell death process associated with a long-term increase in caspase-3 and -6 expression and activation in germ cells. The number of apoptotic (terminal deoxynucleotidyl transferase-mediated deoxyuridine positive) adult germ cells was dependent on the dose of flutamide. The apoptotic germ cell death process could be related to an increased expression and activation of effector caspases-3 and -6. Procaspases-3 and -6 were immunodetected in germ cells from both untreated or flutamide-treated rats, whereas cleaved active caspase-3 was detected exclusively in germ cells from adult rat exposed in utero to flutamide. Exposure to the antiandrogen increased in a dose-dependent manner as caspase-3 and -6 mRNA (in RT-PCR approaches) as well as procaspase-3 and -6 protein (in Western blotting analyses) levels in the adult rat testis. Flutamide also activates procaspases. Indeed, whereas cleaved active caspase-3 and -6 proteins were absent in control animals, they were detected in adult rat testes exposed in utero to flutamide. Our results show that whereas the apoptotic germ cell death process associated with the increased caspase expression and activation in adult rat germ cells was chronic and nonreversible when exposure to flutamide occurred in utero, it was transient when such an exposure occurred during adulthood. Indeed, although an increase in caspase-3 and -6 mRNA and procaspase-3 and -6 protein levels was observed in germ cells after 3 d of exposure to flutamide, 1-2 wk after the cessation of the antiandrogen exposure, the caspase mRNA and procaspase protein levels were back to control. Active cleaved caspase-3 and -6 protein appeared following the exposure to the antiandrogen, whereas they disappeared at cessation of exposure to flutamide. In summary, the present findings indicate that in utero exposure to the antiandrogen induced in the adult rat testes a chronic apoptotic germ cell death associated with a long-term increase in the expression and activation in germ cells of caspases-3 and -6, two key components in the death machinery.

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Aims:The aim of the present study was to investigate hyperhomocysteinemia in Tunisian bipolar I patients according to 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. Methods:The subjects consisted of 92 patients with bipolar I disorder diagnosed according to DSM-IV, and 170 controls. Plasma total homocysteine, folate and vitamin B12 were measured. MTHFR C677T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism.Results: Compared with controls, patients had a significantly higher homocysteine level (16.4 Ϯ 9.8 vs 9.6 Ϯ 4.5 mmol/L; P < 0.001) and a significantly lower folate level (3.2 Ϯ 0.9 vs 6.5 Ϯ 3.2 mg/L; P < 0.001). C677T MTHFR polymorphism genotype frequencies were in Hardy-Weinberg equilibrium. After adjustment for MTHFR C677T genotypes, hypofolatemia, hypovitamin B12 and for potential confounding factors, the odds ratio (OR) of hyperhomocysteinemia associated with bipolar disorder remained significant (OR, 5.53; 95% confidence interval: 1.92-15.86; P = 0.001). In patients, there was no significant change in hyperhomocysteinemia, hypofolatemia and hypovitamin B12 with regard to the clinical and therapeutic characteristics, whereas the highest prevalence of hyperhomocysteinemia was found in depressive patients and when illness duration was >12 years. Hypofolatemia was seen in all patients on lithium and in the majority of patients on carbamazepine, and the highest prevalence of hypovitamin B12 was noted in patients taking carbamazepine. Conclusion:Hyperhomocysteinemia was more frequent in bipolar I patients independent of C677T polymorphism. Patients had reduced levels of folate, which modulates homocysteine metabolism. Indeed, this finding indicates that folate supplementation may be appropriate for bipolar patients with hyperhomocysteinemia.