In mice, prenatal exposure to low doses of bisphenol A has been shown to affect neurogenesis and neuronal migration in cortex, resulting in disturbance of both neuronal positioning and the network formation between thalamus and cortex in the offspring brain. In the present study we investigated whether prenatal exposure to bisphenol A disturbs the neurodevelopment of the cerebellum. Two different model systems were used; offspring from two strains of mice from mothers receiving bisphenol A in the drinking water before mating, during gestation and lactation, and chicken embryos exposed to bisphenol A (in the egg) on embryonic day 16 for 24h before preparation of cerebellar granule cell cultures. In the cerebellum, tight regulation of the level of transcription factor Pax6 is critical for correct development of granule neurons. During the development, the Pax6 level in granule neurons is high when these cells are located in the external granule layer and during their migration to the internal granule layer, and it is then reduced. We report that bisphenol A induced an increase in the thickness of the external granule layer and also an increase in the total cerebellar Pax6 level in 11 days old mice offspring. In cultured chicken cerebellar granule neurons from bisphenol A injected eggs the Pax6 level was increased day 6 in vitro. Together, these findings indicate that bisphenol A may affect the granule neurons in the developing cerebellum and thereby may disturb the correct development of the cerebellum.

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In this study the role of mitochondrial secretory PLA2-IIA in glutamate-induced cell death in cultured cerebellar granule neurons has been investigated. Inhibition of secretory PLA2-IIA blocked glutamate-induced cell death. Since PLA2 may generate reactive oxygen species (ROS), we have investigated ROS production, detected as dihydrorhodamine 123 oxidation and nitrotyrosine modifications of proteins, following glutamate treatment in the absence or presence of an inhibitor of secretory PLA2-IIA. There was an increased generation of ROS in both glutamate- and buffer-treated neurons compared to untreated neurons. Scavenging with dihydrorhodamine 123 reduced glutamate-induced death (60%), showing that ROS detected in glutamate-treated neurons were associated with cell death. However, ROS detected in buffer-treated neurons were not associated with toxicity. Glutamate treatment led to ROS production predominantly in peripheral mitochondria, whereas buffer treatment led to ROS production in somal mitochondria. Inhibition of secretory PLA2-IIA (i) reduced the generation of ROS after glutamate treatment, (ii) reduced the ROS production in peripheral mitochondria in glutamate-treated neurons, consistent with the fact that calcium entry through glutamate (NMDA) receptors has a privileged access to peripheral mitochondria, and (iii) did not reduce the generation of ROS after buffer treatment. In conclusion, activation of NMDA receptors induces ROS, which is critical for neuronal death, due to secretory PLA2-IIA associated with peripheral mitochondria.

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