Hidekazu Fujimaki

Humans are exposed to nanoparticles (NPs; diameter < 100 nm) from ambient air and certain workplaces. There are two main types of NPs; combustion-derived NPs (e.g., particulate matters, diesel exhaust particles, welding fumes) and manufactured or engineered NPs (e.g., titanium dioxide, carbon black, carbon nanotubes, silver, zinc oxide, copper oxide). Recently, there have been increasing reports indicating that inhaled NPs can reach the brain and may be associated with neurodegeneration. It is necessary to evaluate the potential toxic effects of NPs on brain because most of the neurobehavioral disorders may be of environmental origin. This review highlights studies on both combustion-derived NP- and manufactured or engineered NP-induced neuroinflammation, oxidative stress, and gene expression, as well as the possible mechanism of these effects in animal models and in humans.

To investigate the relationship between sensitivity to toluene exposure and genetic background, male congenic mice, C57BL/10 (H-2(b)) and B10.BR/Sg (H-2(k)) were exposed to 0, 5, and 50 ppm toluene for 6 h per day, 5 days per week for 6 weeks. Groups of mice were injected with ovalbumin (OVA) intraperitoneally before starting exposure schedule and these mice were then challenged with aerosolized OVA as a booster. Following 24 h of the last exposure, the spleens were collected. We examined spleen cell proliferation using DNA synthesis and T-helper 1/2-related transcription factor genes in spleen of two congenic mice using real-time reverse transcriptase-polymerase chain reaction. Although lipopolysaccharide-induced (LPS-induced) cell proliferation was significantly increased in 50 ppm toluene-exposed, nonimmunized B10.BR mice but not in C57BL/10 mice, exposure to 50 ppm toluene significantly decreased LPS-induced cell proliferation in immunized B10.BR mice. The expression of transcription factor forkhead box P3, signal transducers and activators of transcription (STAT)5 and STAT6 mRNAs was significantly increased in spleen from 5 ppm toluene-exposed, OVA-immunized B10.BR mice, but not in those of C57BL/10 mice. Although there may be other differences unrelated to H-2 locus between the congenic mice of the same background, the findings of the present study strongly suggest a possible role of H-2 locus in the toluene-induced immune disturbance.

The aim of the present study was to investigate the effect of low-level concentrations, under the occupational acceptable limits, of toluene exposure and peptidoglycan (PGN) stimulation on Th1/Th2 immunity in infant mice. Pregnant BALB/c mice and their offspring were exposed to low-level toluene inhalation (0, 5, and 50 ppm) for 4 wk (from the late prenatal stage to early postnatal stage) in a whole-body exposure chamber. Some of the pregnant mice and their offspring were stimulated with PGN during toluene exposure. We measured total immunoglobulins of different subclasses in plasma, and production and expression level of cytokines in the lung and spleen, and transcription factors related to Th1/Th2 immunity in the spleen of infant (3 wk old) mice. Exposure of mice to 5 or 50 ppm toluene resulted in increased immunoglobulin (Ig) G1 and decreased IgG2a and IgE antibodies in the plasma; significantly decreased T-bet, GATA-3, and Foxp3 mRNA in the spleen; and a tendency toward decreased interferon (IFN)-gamma mRNA in spleen. Exposure of mice to low-level toluene together with PGN stimulation resulted in decreased IgG1 as well as IgG2a antibodies in the plasma and Foxp3 mRNA in spleen as compared with control or PGN-treated mice. These findings suggest that low-level toluene exposure and PGN stimulation from the late prenatal to early postnatal stage suppressed the splenic parameter related to Th1/Th2 immunity in infant mice.

To investigate the role of CD4⁺ T cells in neurotrophin production following toluene exposure, male C3H mice were exposed to filtered air (control) or 9 ppm of toluene in a nose-only exposure chamber for 30 min on 3 consecutive days followed by weekly sessions for 4 weeks. All the mice were immunized with ovalbumin and some groups of mice were treated with anti-CD4 antibody. BDNF content in BAL fluid and NGF content in plasma were significantly increased in toluene-exposed mice. However, treatment with anti-CD4 mAb completely abrogated these effects. These findings suggest that the CD4⁺ T cells may be involved in the toluene-induced modulation of neurotrophin production.