Differential mRNA expression of neuroimmune markers in the hippocampus of infant mice following toluene exposure during brain developmental period

Abstract

Toluene, a volatile organic compound with a wide range of industrial applications, can exert neurotoxic and immunotoxic effects. However, the effects of toluene exposure on developmental immunotoxicity in the brain have not yet been characterized. To investigate the susceptible window to toluene exposure during development and the effects of fetal and neonatal toluene exposure on the neuroimmune markers, gestational day (GD) 14 pregnant mice, postnatal day (PND) 2 and PND 8 male offspring were exposed to filtered air (control; 0 ppm), or 5 or 50 ppm toluene for 6 h per day for five consecutive days. The neuroimmune markers in the hippocampus of PND 21 were examined using a real-time RT-PCR and immunohistochemical analysis. Mice exposed to 50 ppm toluene on PND 2-6 showed significantly increased levels of nerve growth factor (NGF) and tumor necrosis factor (TNF)-α mRNAs. In contrast, NGF and brain-derived neurotrophic factor (BDNF) and proinflammatory cytokines TNF-α, CCL3, NF-κB, toll-like receptor (TLR)-4, astrocyte marker glial fibrillary acidic protein (GFAP), and microglia marker ionized calcium binding adapter molecule (Iba)-1 mRNAs were increased significantly in mice exposed to 5 ppm toluene on PND 8-12. These results indicate that low-level toluene exposure during the late postnatal period (PND 8-12) might induce neuroinflammatory mediators via TLR4-dependent NF-κB pathway in the hippocampus of PND 21 male mice. Among the three developmental phases, PND 8-12 seems to be most sensitive to toluene exposure. This is the first study to show developmental phase- and dose-specific changes in neuroimmune markers in infant mice following toluene exposure.