Increased apoptosis and abnormal visual behavior by histone modifications with exposure to para-xylene in developing Xenopus

• Para-xylene (PX) is neurotoxic and causes an increase in the abnormality rate.
• PX induces an increase of apoptotic cells, which is rescued by d-glucuronolactone (DGA).
• DGA rescues PX exposure-induced deficits in visually guided avoidance behavior.
• DGA represses the increase in acetylation of H3K9 (H3K9ac) and dimethylation of H4K12 (H4K12me2) in PX-treated animals.
• DGA may be used as a detoxicant to ameliorate the neurotoxicity induced by PX.

Xylene and its derivatives are raw materials widely used in industry and known to be toxic to animals. However, the mechanism underlying the neurotoxicity of para-xylene (PX) to the central nervous system (CNS) in vivo is less clear. Here, we exposed Xenopus laevis tadpoles to sub-lethal concentrations of PX during the critical period of brain development to determine the effects of PX on Xenopus development and visual behavior. We found that the abnormality rate was significantly increased with exposure to increasing concentrations of PX. In particular, the number of apoptotic cells in the optic tectum was dramatically increased with exposure to PX at 2 mM. Long-term PX exposure also resulted in significant deficits in visually guided avoidance behavior. Strikingly, co-incubation with PX and d-glucuronolactone (GA) decreased the number of apoptotic cells and rescued the avoidance behavior. Furthermore, we found that the acetylation of H4K12 (H4K12ac) and the dimethylation of H3K9 (H3K9me2) in the optic tectum were significantly increased in PX-treated animals, and these effects were suppressed by GA treatment. In particular, the increase in apoptotic cells in PX-treated brains was also inhibited by GA treatment. These effects indicate that epigenetic regulation plays a key role in PX-induced apoptosis and animal behavior. In an effort to characterize the neurotoxic effects of PX on brain development and behavior, these results suggest that the neurotoxicity of PX requires further evaluation regarding the safety of commercial and industrial uses.

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