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There is growing concern that prenatal exposure to excessive glucocorticoids may have deleterious effects on the development of various organs, including the nervous system. This study aimed at evaluating whether prenatal exposure to high levels of glucocorticoids might produce long-term effects on neuronal cell survival. Pregnant rats were injected i.p. with 0.1 mg͞kg dexamethasone (DEX) from day 14 postconception, and cerebellar granule cells (CGC) were prepared from 1-week-old rats from DEX-treated and control dams. After 7 days in culture, cells were exposed to H 2O2, methylmercury, or colchicine at concentrations known to induce apoptotic cell death. After exposure to H 2O2 or methylmercury, both inducing oxidative stress, the number of apoptotic cells was significantly higher in DEX-than in control-CGC. Because mitochondria play a key role in apoptosis, mitochondrial function was investigated, and a decrease in the threshold level of Ca 2؉ necessary for induction of mitochondrial permeability transition, in Ca 2؉ accumulation rate, and in oxygen consumption was detected in DEX-CGC. Moreover, the activity of the antioxidant enzyme catalase was significantly decreased in DEX-CGC. A similar decrease in catalase activity was observed in cerebellar homogenate from newborn and 40-day-old DEX-rats. In conclusion, these results indicate that prenatal exposure to high levels of glucocorticoids induces long-lasting changes in CGC rendering them more sensitive to oxidative stress. With the increasing use of multiple doses of glucocorticoids in preterm infants, the possibility that prenatal exposure to excess glucocorticoids may lead to long-term neurological consequences becomes a relevant issue.

In the present study the neurotoxic effects of a low dosage (0.5 mg/kg per day) of methylmercury (MeHg) on the developing nervous system were investigated. Pregnant rats were treated with MeHg from day 7 of pregnancy to day 7 of lactation. Locomotor activity (locomotion, rearing, and motility) and spatial learning ability were tested in the offspring at 6 months of age. The expression of tyrosine hydroxylase (TH) was examined by immunohistochemistry and in situ hybridization. A significant decrease in spontaneous motility and rearing was observed only in the MeHg-treated male rats. After administration of a low dose of d-amphetamine (0.5 mg/kg) no differences could be observed between control and MeHg-treated male rats, suggesting that changes in dopaminergic transmission were involved. However, no change in TH messenger RNA expression was observed. No changes in spatial learning acquisition or memory were shown in MeHg-treated rats. Taken together, these findings show that during development a very low dosage of MeHg exerts neurotoxic effects detectable in adulthood, and that susceptibility is gender-dependent.

Oxidative stress has been implicated in various neurodegenerative diseases. There is substantial evidence indicating that gonadal hormones can affect neuronal cell survival via both a genomic as well as a non-genomic mode of action. In the present study, the potential protective activity of testosterone on neuronal cells was investigated by using an in vitro/ex vivo model. Cerebellar granule cells (CGC) were prepared from 7-day-old rats which had been treated with a single dose of oil or testosterone propionate on postnatal day 3. After 7 days in culture, cells were exposed to oxidative challenges, including hydrogen peroxide and the nitric oxide donor S-nitrosocysteine (SNOC), which can induce CGC death via apoptosis. Colchicine, which causes apoptosis via a different mechanism, was also used. The cells were monitored for apoptotic morphology by propidium iodide and TUNEL staining. Additionally, the presence of chromatin fragmentation was determined. CGC obtained from testosterone-treated rats were found to be more resistant to hydrogen peroxide and nitric oxide toxicity, as shown by a 75 and 45% decrease in apoptotic cells, respectively. In contrast, the susceptibility to colchicine was not modified. As CGC from testosterone-treated pups were selectively protected from oxidative stress, different components of the antioxidant defence systems were analysed. A twofold increase in the activity of catalase and superoxide dismutase was found in the CGC prepared from testosterone-treated rats. These results suggest that in vivo treatment with androgens render CGC less vulnerable to oxidative stress-induced apoptosis by potentiating antioxidant defences.