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Recent studies have suggested that inhalation of diesel exhaust (DE), a major source of air pollution, results in pulmonary alterations; however, the effects of DE at low concentrations are poorly understood. Therefore, this study was conducted to elucidate the pulmonary effects of low-level exposure to DE and the potential role of a ceramide de novo biosynthesis inhibitor, fumonisin B1 (FB1) to ameliorate the DE-toxicity. Male C57BL/6 J mice underwent 1- or 7-day experiments (4 equal groups/experiment) and were assigned to the control, DE (0.1 mg/m 3 ), FB1 (6.75 mg/kg body weight SC at days 0, 3 and 6) or DE+FB1 groups. DE and/or FB1 treatment had no effect on the expression of Nos 2, a biomarker of oxidative stress. Ceramide production in the bronchial epithelial cells and Sphk 1 mRNA expression were induced in the lung after the 7-day DE exposure and were partially suppressed by the FB1 treatment. Additionally, the effects of DE on SP-A and SP-D mRNA expression were also suppressed by the FB1 treatment. These results suggest that ceramide and Sphk 1 may be sensitive biomarkers for low-level DE-induced pulmonary effects. Collectively, ceramide likely contributes to the DE-induced early stage of airway inflammation, which is considered a potential pulmonary target during low-level DE exposure. [ABSTRACT FROM AUTHOR]

Diesel exhaust particles are a major component of ambient particulate matter, and concern about the health effects of exposure to ambient particulate matter is growing. Previously, we found that in utero exposure to diesel exhaust affected locomotor activity and motor coordination, but there are also indications that such exposure may contribute to increased aggression in offspring. Therefore, the aim of the present study was to test the effects of prenatal diesel exhaust exposure on social isolation-induced territorial aggression. Pregnant mice were exposed to low concentrations of diesel exhaust (DE; mass concentration of 90 μg/m3: DE group: n = 15) or clean air (control group: n = 15) for 8 h/day during gestation. Basal locomotion of male offspring was measured at 10 weeks of age. Thereafter, male offspring were individually housed for 2 weeks and subsequently assessed for aggression using the resident−intruder test at 12 weeks of age, and blood and brain tissue were collected from the male offspring on the following day for measuring serum testosterone levels and neurochemical analysis. There were no significant differences in locomotion between control and DE-exposed mice. However, DE-exposed mice showed significantly greater social isolation-induced territorial aggressive behavior than control mice. Additionally, socially-isolated DE-exposed mice expressed significantly higher concentrations of serum testosterone levels than control mice. Neurochemical analysis revealed that dopamine levels in the prefrontal cortex and nucleus accumbens were higher in socially isolated DE-exposed mice. Serotonin levels in the nucleus accumbens, amygdala, and hypothalamus were also lower in the socially isolated DE-exposed mice than in control mice. Thus, even at low doses, prenatal exposure to DE increased aggression and serum testosterone levels, and caused neurochemical changes in male socially isolated mice. These results may have serious implications for pregnant women living in regions with high levels of traffic-related air pollution. [ABSTRACT FROM AUTHOR]

There is an emerging concern that particulate air pollution increases the risk of cranial nerve disease onset. Small nanoparticles, mainly derived from diesel exhaust particles reach the olfactory bulb by their nasal depositions. It has been reported that diesel exhaust inhalation causes inflammation of the olfactory bulb and other brain regions. However, these toxicological studies have not evaluated animal rearing environment. We hypothesized that rearing environment can change mice phenotypes and thus might alter toxicological study results. In this study, we exposed mice to diesel exhaust inhalation at 90 µg/m3, 8 hours/day, for 28 consecutive days after rearing in a standard cage or environmental enrichment conditions. Microarray analysis found that expression levels of 112 genes were changed by diesel exhaust inhalation. Functional analysis using Gene Ontology revealed that the dysregulated genes were involved in inflammation and immune response. This result was supported by pathway analysis. Quantitative RT-PCR analysis confirmed 10 genes. Interestingly, background gene expression of the olfactory bulb of mice reared in a standard cage environment was changed by diesel exhaust inhalation, whereas there was no significant effect of diesel exhaust exposure on gene expression levels of mice reared with environmental enrichment. The results indicate for the first time that the effect of diesel exhaust exposure on gene expression of the olfactory bulb was influenced by rearing environment. Rearing environment, such as environmental enrichment, may be an important contributive factor to causation in evaluating still undefined toxic environmental substances such as diesel exhaust. [ABSTRACT FROM AUTHOR]

We investigated whether pre- and postnatal low-dose exposure to diesel exhaust (DE) affects male reproductive function in mice. The DE concentration is less than that indicated as the environmental quality standard for suspended particulate matter (SPM) in Japan. ICR mice were exposed prenatally to low-dose diesel exhaust (0.17 mg of DE particles/m3) through the airway for 8 h/day in an exposure chamber from gestational day 2 until the examination. In the DE-exposed groups, normal sperm morphology in the epididymis was reduced ( p < 0.01), and seminiferous tubules showed degenerative changes in which the number of Sertoli cells was decreased ( p < 0.01). Those changes were observed at 6 and 12 weeks of age. Furthermore, ultrastructural studies revealed an increase in damaged mitochondria in Sertoli cells ( p < 0.001) and variform spermatozoa. These results indicate that pre- and postnatal exposure of low-dose DE is detrimental to Sertoli cell function and may cause abnormal spermatozoa. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have suggested that suspended particulate matter (SPM) causes detrimental health effects such as respiratory and cardiovascular diseases, and that diesel exhaust particles from automobiles is a major contributor to SPM. It has been reported that neonatal and adult exposure to diesel exhaust damages the central nervous system (CNS) and induces behavioral alteration. Recently, we have focused on the effects of prenatal exposure to diesel exhaust on the CNS. In this study, we examined the effects of prenatal exposure to low concentration of diesel exhaust on behaviour and the monoaminergic neuron system. Spontaneous locomotor activity (SLA) and monoamine levels in the CNS were assessed. Methods: Mice were exposed prenatally to a low concentration of diesel exhaust (171 μg DEP/m3) for 8 hours/day on gestational days 2-16. SLA was assessed for 3 days in 4-week-old mice by analysis of the release of temperature-associated infrared rays. At 5 weeks of age, the mice were sacrificed and the brains were used for analysis by high-performance liquid chromatography (HPLC). Results and Discussion: Mice exposed to a low concentration of diesel exhaust showed decreased SLA in the first 60 minutes of exposure. Over the entire test period, the mice exposed prenatally to diesel exhaust showed decreased daily SLA compared to that in control mice, and the SLA in each 3 hour period was decreased when the lights were turned on. Neurotransmitter levels, including dopamine and noradrenaline, were increased in the prefrontal cortex (PFC) in the exposure group compared to the control group. The metabolites of dopamine and noradrenaline also increased in the PFC. Neurotransmitter turnover, an index of neuronal activity, of dopamine and noradrenaline was decreased in various regions of the CNS, including the striatum, in the exposure group. The serum corticosterone level was not different between groups. The data suggest that decreased SLA in mice exposed prenatally to diesel exhaust is due to facilitated release of dopamine in the PFC. Conclusions: These results indicate that exposure of mice in utero to a low concentration of diesel exhaust decreases SLA and alters the neurochemical monoamine metabolism of several regions of the brain. [ABSTRACT FROM AUTHOR]

We recently showed that prenatal exposure to diesel exhaust (DE) disrupts spermatogenesis in mouse offspring. This study was undertaken to determine whether filtered DE in which 99.97% of diesel exhaust particles >0.3 μm in diameter were removed affects spermatogenesis in growing mice. After prenatal exposure to filtered DE for 2–16 days postcoitum, we examined daily sperm production (DSP), testicular histology, serum testosterone levels and mRNA expression of hormone synthesis process-related factors. In the filtered DE exposed group, DSP was markedly reduced at 12 weeks compared with the control group; clean air exposed group. Histological examination showed multinucleated giant cells and partial vacuolation in the seminiferous tubules of the exposed group. Testosterone was elevated significantly at 5 weeks. Moreover, luteinizing hormone receptor mRNA at 5 and 12 weeks, 17α-hydroxylase/C17-20-lyase and 17β-hydroxysteroid dehydrogenase mRNAs at 12 weeks were significantly elevated. These results suggest that filtered DE retains its toxic effects on the male reproductive system following prenatal exposure. [ABSTRACT FROM AUTHOR]

The effect of prenatal exposure to diesel exhaust (DE) was investigated. Twenty pregnant ICR mice were exposed to DE at the particle concentration of 1.0 mg/m3, from d 2 until d 16 postcoitum. Male offspring were kept alive until 12 wk of age, and then male reproductive organ weight, daily sperm production (DSP), serum testosterone level, and mRNA expression of sex steroid hormone synthesis process-related factors were measured. Serum testosterone levels of the exposed group were reduced significantly at 3 wk, whereas they were elevated significantly at 12 wk. DSP was also markedly reduced at 5 and 12 wk. Histological examination showed multinucleated giant cells in the seminiferous tubules of the exposed group as well as partial vacuolation of the seminiferous tubules. Follicle-stimulating hormone receptor (FSHR) mRNA expression and steroidogenesis acute regulatory (StAR) protein were significantly increased at 5 wk and 12 wk, respectively. This study suggests that prenatal exposure to DE has detrimental effects on mouse spermatogenesis in offspring. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAH) and reactive oxygen species (ROS) derived from diesel exhaust particles (DEP) are implicated in the pathophysiology of respiratory diseases. Cytochrome P450 (Cyp) 1A1 can be induced by several kinds of PAH and produce ROS. We determined whether acute inhalation exposure to DEP induced the expression of Cyp 1A1 in murine lung. Intratracheal instillation of DEP dose-dependently increased the lung expression of Cyp 1A1 at the levels of both mRNA and protein, whereas DEP decreased expression in the lung of aryl hydrocarbon receptors in a dose-dependent manner. In contrast, charcoal particles as the control did not affect the expression of these molecules. These results suggest that the lung expression of Cyp 1A1 can be a biomarker of acute inhalation exposure to DEP and may be implicated in an accelerated production of ROS and the subsequent aggravation of lung injury. [ABSTRACT FROM AUTHOR]

Several recent reports have suggested that sperm count and quality in normal men are declining. Various environmental chemical compounds may affect the male reproductive system. We propose here that diesel exhaust is an environmental pollutant with the potential to influence male reproductive function. Ultrastructural changes were observed in Leydig cells of mice exposed to diesel exhaust (0.3 mg diesel exhaust particles (DEP)/m3 through the airway, 12 h daily, up to 6 months) and reduction in LH receptor mRNA expression in Leydig cells was observed at a concentration of 1 mg DEP/m3. Daily sperm production per gram of testis dose-dependently decreased with exposure to DE for 6 months; 29%, 36%, and 53% reductions were observed at 0.3, 1.0, and 3.0 mg DEP/m3, respectively. A no-observed-adverse-effect level (NOAEL) was observed with approximately 30 μg DEP/m3, which is lower than the WHO-recommended limit. [ABSTRACT FROM AUTHOR]

Exposure to diesel exhaust (DE) exacerbates non-alcoholic fatty liver disease, and may systemically affect lipid metabolism. Omega-3 polyunsaturated fatty acids (n-3 PUFA) have anti-inflammatory activity and suppresses hepatic triacylglycerol accumulation, but many daily diets are deficient in this nutrient. Therefore, the effect of DE exposure in mice fed n-3 PUFA–deficient diet was investigated. Mice were fed control chow or n-3 PUFA–deficient diet for 4 weeks, then exposed to clean air or DE by inhalation for further 4 weeks. Liver histology, plasma parameters, and expression of fatty acid synthesis-related genes were evaluated. N-3 PUFA–deficient diet increased hepatic lipid droplets accumulation and expression of genes promoting fatty acid synthesis: Acaca , Acacb , and Scd1 . DE further increased the plasma leptin and the expression of fatty acid synthesis-related genes: Acacb , Fasn , and Scd1 . N-3 PUFA–deficient diet and DE exposure potentially enhanced hepatic fatty acid synthesis and subsequently accumulation of lipid droplets. The combination of low-dose DE exposure and intake of n-3 PUFA–deficient diet may be an additional risk factor for the incidence of non-alcoholic fatty liver disease. The present study suggests an important mechanism for preventing toxicity of DE on the liver through the incorporation of n-3 PUFAs in the diet. [ABSTRACT FROM AUTHOR]

Diesel exhaust consists of diesel exhaust particles (DEPs) and gaseous compounds. Previous studies reported that in utero exposure to diesel exhaust affects the central nervous system. However, there was no clear evidence that these effects were caused by diesel exhaust particles themselves, gaseous compounds, or both. Here, we explored the effects of in utero exposure to DEPs on learning and memory in male ICR mice. DEP solutions were administered subcutaneously to pregnant ICR mice at a dose of 0 or 200 μg/kg body weight on gestation days 6, 9, 12, 15, and 18. We examined learning and memory in 9-to-10-week-old male offspring using the Morris water maze test and passive avoidance test. Immediately after the behavioral tests, hippocampi were isolated. Hippocampal N -methyl- d -aspartate receptor (NR) expression was also measured by quantitative RT-PCR analysis. Mice exposed to DEPs in utero showed deficits in the Morris water maze test, but their performance was not significantly different from that of control mice in the passive avoidance test. In addition, DEP-exposed mice exhibited decreased hippocampal NR2A expression. The present results indicate that maternal DEP exposure disrupts learning and memory in male offspring, which is associated with reduced hippocampal NR2A expression. [ABSTRACT FROM AUTHOR]

Exposure to ambient particulate matter (PM) has been associated with the onset of cardiovascular and respiratory diseases. Diesel exhaust particles (DEP) are major components of ambient PM. We first reported DEP in the central nervous system of offspring utilizing maternal inhalation to diesel exhaust (DE). In addition, we found that the effects of maternal exposure to DE reduced spontaneous motor activity. However, it is still unknown whether maternal exposure to DE affects higher order behavioral function. Therefore, the aim of the present study was to examine the effects of fetal exposure to DE on motor coordination, impulsive behavior and monoaminergic systems in various brain regions. The results of the rotating rod test showed that DE-exposed mice displayed decreased time on the rota rod compared to control mice. However, no changes were detected between the two groups in the hanging test. Furthermore, the cliff avoidance test revealed that DE-exposed mice spent more time in the corner and fell off an inverted glass beaker compared to control mice. High performance liquid chromatography analysis revealed that noradrenaline turnover in the cerebellum was decreased by prenatal exposure to DE, and was significantly increased in the hypothalamus. Dopamine and serotonin levels in various brain regions were also changed by prenatal exposure to DE. Our study found that prenatal exposure to DE alters motor coordination, impulsive behavior and related monoamine levels. Therefore, the present study underscores the role of behavioral changes related to monoamine in response to maternal inhalation of DE. [ABSTRACT FROM AUTHOR]

Previous studies have shown that prenatal and postnatal exposure to diesel exhaust (DE), which is known to be one of the main constituents of air pollution, enhances the persistence of endometriosis in a rat model. The aim of this study is to investigate the pathological changes induced by DE exposure in a rat model of endometriosis. Pregnant Sprague-Dawley rats were exposed to DE or clean air beginning on gestational day 2 and neonatal rats were persistently exposed to DE or clean air. Endometriosis was induced by autotransplantation of endometrium onto the peritoneum of eight-week-old female offspring. Endometriotic lesions were examined at 7 and 14 days post-transplantation. As a result, infiltration of activated mast cells remained in deeper area of peritoneal tissue around the endometriosis model compared to the control group at 14 days post-autotransplantation. In the DE exposure group, 14 days post-transplant, the remaining lesions contained fibroblasts and activated mast cells, which were surrounded by collagen fibers. The data showed that prenatal and postnatal DE exposure enhances the activation of mast cells and prolongs the persistence of collagen fibers in the induced rat model of endometriosis. [ABSTRACT FROM AUTHOR]

Diesel exhaust particles (DEP), a well-known air pollutant, exacerbate type I hypersensitivity conditions, such as asthma and pollen allergy. In this study, we examined the effect of diesel exhaust (DE) exposure on delayed-type hypersensitivity (DTH), a type IV hypersensitivity, induced with methyl-bovine serum albumin (mBSA) in C57BL/6 mice. Mice were exposed to DE containing DEP at a dose of 1.78 mg/m3 in an inhalation chamber for 14 days. On Day 7, DTH mice and DE-exposed DTH mice were injected s.c. with 200 μl of 1.25 mg/ml mBSA emulsified with CFA in the dorsal region as initial sensitization. On Day 14, mice were injected s.c. into one footpad with 20 μl of 10 mg/ml mBSA dissolved in PBS as challenge. On Day15, footpad thickness and spleen weight were measured. Significant footpad swelling (%) was observed in DTH mice compared with normal control mice, and this swelling was significantly augmented by DE exposure. The levels of pro-inflammatory cytokines, including IFN-γ, TNF-α, and IL-6, in DTH mice were significantly higher than in normal mice, and were also further enhanced by DE exposure. DE exposure increased production of IL-17, which enhances local tissue inflammation through up-regulation of pro-inflammatory cytokines, while production of IL-10, which inhibits local tissue inflammation through suppression of immune cell proliferation, was unchanged. No change was observed in the percentage of CD4+CD25+Foxp3+ T regulatory (Treg) cells in splenic lymphocytes following DE exposure. IL-6 production was increased by DE, and this would facilitate the differentiation of naïve T cells to IL-17-producing Th17 cells, while concomitantly suppressing the competing differentiation pathway to IL-10-producing Treg cells. Our results indicate that DE inhalation may, in part, exacerbate the pathological symptoms of DTH and induction of pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-6 and IL-17. [ABSTRACT FROM AUTHOR]

Abstract: Diesel exhaust (DE) is composed of particles and gaseous compounds. It has been reported that DE causes pulmonary and cardiovascular disease. We have previously reported that fetal exposure to DE had deleterious effects to the reproductive system of mice offspring. However, there is still little known about the effects of prenatal exposure to DE to the central nervous system (CNS). In the present study, we found that prenatal exposure to DE induced reduction of locomotion, furthermore, dopamine (DA) turnover was significantly decreased in the striatum and nucleus accumbens. These results suggest that prenatal exposure to DE has an effect on the CNS. Hypolocomotion could be due to a decrease in DA turnover associated with DA nervous system abnormality. The present study provides the possibility that maternally inhaled DE might influence the development of central dopaminergic system and result in behavior disorder. [Copyright &y& Elsevier]

Abstract: We have indicated the possibility that nanoparticles such as diesel exhaust particles (DEP) and titanium dioxide (TiO2) may impair the male mouse reproductive system. In this study, to evaluate the direct effect of nanoparticles on testis-constituent cells, we examined the effect of DEP, TiO2 and carbon black (CB) on mouse Leydig TM3 cells, the testosterone-producing cells of the testis. The uptake of three nanoparticles into Leydig cells was detected using transmission electron microscopy (TEM) or field emission type scanning electron microscopy/energy-dispersive X-ray spectroscopy (FE-SEM/EDS). We examined the cytotoxicity and the effect on gene expression by treatment with nanoparticles. TiO2 was more cytotoxic to Leydig cells than other nanoparticles. The proliferation of Leydig cells was suppressed transiently by treatment with TiO2 or DEP. The expression of heme oxygenase-1 (HO-1), a sensitive marker for oxidative stress, was induced remarkably by treatment with DEP. Furthermore, CB and DEP slightly increased the gene expression of the steroidogenic acute regulatory (StAR) protein, the factor that controls mitochondrial cholesterol transfer. In this study, we found that DEPs, TiO2 and CB nanoparticles were taken up by Leydig cells, and affected the viability, proliferation and gene expression. The patterns were unique for each nanoparticle. [Copyright &y& Elsevier]

Murine Leydig TM3 cells, derived from mouse testis, were exposed to diesel exhaust particles (DEP) and DEP components for 24h. mRNA expression of estrogen receptor (ER) α and CYP1A1 were then measured by real-time PCR. Exposure to DEP (10μg/ml) reduced ERα mRNA expression by approximately 50% and increased P450 1A1 mRNA expression by approximately fivefold. Cycloheximide (CHX), an inhibitor of protein synthesis, abolished the DEP-induced effects on ERα mRNA expression. Thus, protein synthesis mediated the DEP-induced reduction of ERα mRNA expression. [Copyright &y& Elsevier]