Publications by authors named "Yukie Yanagiba"

43 Publications

Increased risk of occupational trichloroethylene hypersensitivity syndrome at exposure levels higher than 15 mg/L of urinary trichloroacetic acid, regardless of whether the patients had the HLA-B*13:01 allele.

Environ Res 2020 12 3;191:109972. Epub 2020 Aug 3.

Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, 467-8601, Nagoya, Japan. Electronic address:

Occupational trichloroethylene (TCE) exposure can cause hypersensitivity syndrome (TCE-HS). The human leukocyte antigen (HLA)-B*13:01 is reportedly an important allele involved in TCE-HS onset. However, the threshold exposure level causing TCE-HS in relation to HLA-B*13:01 remains unknown. We conducted a case-control study comprising 37 TCE-HS patients and 97 age- and sex-matched TCE-tolerant controls from the Han Chinese population. Urine and blood of patients were collected on the first day of hospitalization, and those of controls were collected at the end of their shifts. Urinary trichloroacetic acid (TCA) was measured as an exposure marker, and end-of-shift levels in the patients were estimated using the biological half-life of 83.7 h. HLA-B genotype was identified using DNA from blood. Crude odds ratios (ORs) for TCE-HS in the groups with urinary TCA concentration >15 mg/L to ≤50 mg/L and of >50 mg/L were 21.9 [95% confidence interval (CI) 4.2-114.1] and 27.6 (6.1-125.8), respectively, when the group with urinary TCA ≤15 mg/L was used as a reference. The frequency of HLA-B*13:01, the most common allele in the patients, was 62.2% (23/37), which was significantly higher than 17.5% (17/97) in the TCE-tolerant controls, with a crude OR of 8.4 (3.1-22.6). The mutually-adjusted ORs for urinary TCA >15 to ≤50 mg/L, >50 mg/L, and for HLA-B*13:01 were 33.4 (4.1-270.8), 34.0 (5.3-217.1), and 11.0 (2.4-50.7), respectively. In conclusion, reduction of TCE exposure to ≤15 mg/L is required for TCE-HS prevention because urinary TCA concentration >15 mg/L showed increased risk of TCE-HS, regardless of whether the patients had the HLA-B*13:01 allele.
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http://dx.doi.org/10.1016/j.envres.2020.109972DOI Listing
December 2020

Correction to: Genotoxicity assessment of titanium dioxide nanoparticle accumulation of 90 days in the liver of delta transgenic mice.

Genes Environ 2020 3;42:10. Epub 2020 Mar 3.

1Division of Industrial Toxicology and Health Effects Research, National Institute of Occupational Safety and Health, 6-21-1 Nagao, Tama-ku, Kawasaki, Kanagawa 214-8585 Japan.

[This corrects the article DOI: 10.1186/s41021-020-0146-3.].
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http://dx.doi.org/10.1186/s41021-020-00151-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053085PMC
March 2020

Genotoxicity assessment of titanium dioxide nanoparticle accumulation of 90 days in the liver of delta transgenic mice.

Genes Environ 2020 10;42. Epub 2020 Feb 10.

1Division of Industrial Toxicology and Health Effects Research, National Institute of Occupational Safety and Health, 6-21-1 Nagao, Tama-ku, Kawasaki, Kanagawa 214-8585 Japan.

Backgound: A variety of in vivo and in vitro studies to assess the genotoxicity of titanium dioxide nanoparticles (TiO NPs) have been reported, but the results are inconsistent. Recently, we reported that TiO NPs exhibit no genotoxic effects in the liver and erythrocytes during a relatively brief period following intravenous injection into mice. However, there is no information about long-term genotoxicity due to TiO NP accumulation in tissues. In this study, we investigated the long-term mutagenic effects of TiO NPs and the localization of residual TiO NPs in mouse liver after multiple intravenous injections.

Results: Male delta C57BL/6 J mice were administered with various doses of TiO NPs weekly for 4 consecutive weeks. The long-term mutagenic effects on the liver were analyzed using and Spi mutation assays 90 days after the final injection. We also quantified the amount of titanium in the liver using inductively coupled plasma mass spectrometry and observed the localization of TiO NPs in the liver using transmission electron microscopy. Although TiO NPs were found in the liver cells, the and Spi mutation frequencies in the liver were not significantly increased by the TiO NP administration.

Conclusions: These results clearly show that TiO NPs have no mutagenic effects on the liver, even though the particles remain in the liver long-term.
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http://dx.doi.org/10.1186/s41021-020-0146-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011542PMC
February 2020

Aldehyde dehydrogenase 2 deficiency significantly exacerbates tert-butyl alcohol-induced toxicity in mice.

J Appl Toxicol 2020 07 14;40(7):979-990. Epub 2020 Feb 14.

Japan National Institute of Occupational Safety and Health, Kawasaki, Japan.

Owing to the use of ethyl tert-butyl ether (ETBE) as a fuel additive, the possible adverse effects of ETBE exposure have become a public concern. Our previous study showed that ETBE-induced toxicity in aldehyde dehydrogenase 2 (Aldh2) gene knockout (KO) mice was caused by its primary metabolite acetaldehyde, which was toxic. However, it is unclear whether tert-butyl alcohol (TBA), another main metabolite of ETBE, plays a role in ETBE-induced toxicity. To investigate this relationship, we analyzed the changes of TBA concentrations in tissues after ETBE exposure, and then evaluated the toxicity after direct TBA treatment in both KO and wild-type (WT) mice. An exposure to 500 ppm ETBE via inhalation resulted in the formation of its three metabolites, TBA, 2-methyl-1,2-propanediol and ethanol, whose concentrations in the liver, brain, fat and testis of male KO mice were significantly higher than the corresponding concentrations observed in male WT mice. Direct treatment to TBA (20 mg/mL of drinking water) caused significant changes in relative organ weights and histopathology, and increased levels of genetic damages in both types of mice. These toxic effects were also seen in KO mice exposed to a lower concentration of TBA (5 mg/mL), which was associated with increased oxidative stress in serum (reduced glutathione and reduced glutathione/oxidized glutathione ratio decreased). Our findings indicate that ALDH2 is involved in the metabolism of ETBE and TBA, and ALDH2 deficiency could greatly increase the sensitivity to TBA-induced toxicity.
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http://dx.doi.org/10.1002/jat.3957DOI Listing
July 2020

Promotion effects of acetoaceto-o-toluidide on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder carcinogenesis in rats.

Arch Toxicol 2019 12 31;93(12):3617-3631. Epub 2019 Oct 31.

Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Abeno-ku, 1-4-3 Asahi-machi, Osaka, Japan.

Recent epidemiological studies have indicated that occupational exposure to the aromatic amine acetoaceto-o-toluidide (AAOT) was associated with a marked increase in urinary bladder cancers in Japan. However, little is known about the carcinogenicity of AAOT. To evaluate the urinary bladder carcinogenicity of AAOT, male and female F344 rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks followed by dietary administration of 0, 0.167, 0.5, or 1.5% AAOT for 31 weeks. The incidences and multiplicities of bladder tumors were significantly increased in the 0.5 and 1.5% groups of male and female rats in a dose-response manner. AAOT and seven downstream metabolites were detected in the urine of the male and female rats administered AAOT with levels increasing in a dose-dependent manner. The most abundant urinary metabolite of AAOT was the human bladder carcinogen o-toluidine (OTD), which was at least one order of magnitude higher than AAOT and the other AAOT metabolites. In a second experiment, male F344 rats were administered 0, 0.167, or 1.5% AAOT for 4 weeks. Gene expression analyses revealed that the expression of JUN and its downstream target genes was increased in the urothelium of male rats treated with 1.5% AAOT. These results demonstrate that AAOT promotes BBN-induced urinary bladder carcinogenesis in rats and suggest that overexpressed of JUN and its downstream target genes may be involved the bladder carcinogenicity of AAOT. In conclusion, AAOT, like other carcinogenic aromatic amines, is likely to be a carcinogen to the urinary bladder, and OTD metabolized from AAOT is the ultimate carcinogen.
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http://dx.doi.org/10.1007/s00204-019-02605-4DOI Listing
December 2019

Inhalation exposure to low levels of ethyl tertiary butyl ether: Its genetic effects were significantly modified by ALDH2 activity.

Environ Mol Mutagen 2019 03 25;60(2):145-153. Epub 2018 Nov 25.

National Institute of Occupational Safety and Health, Kawasaki, Japan.

Previous experiments showed that high concentrations of ethyl tertiary butyl ether (ETBE) exposure (500-5,000 ppm) significantly resulted in DNA damages in aldehyde dehydrogenase 2 (Aldh2) knockout (KO) mice. This study was aimed to verify the genotoxic effects in three genetic types, Aldh2 KO, heterogeneous (HT), and wild type (WT), of mice exposed to lower concentrations of ETBE (50-500 ppm) by inhalation. Histopathology assessments in the livers, measurements of genotoxic biomarkers in blood and livers, and urinary 8-hydroxydeoxyguanosion (8-OH-dG) for the oxidative DNA damage of whole body were performed. Significant histopathological changes and DNA strand breaks both in hepatocytes and leukocytes were found in HT and KO male mice exposed to ≥200 ppm ETBE, but not in 50 ppm ETBE. 8-OH-dG levels either in liver or urine were higher in the HT and KO male mice exposed to ≥200 ppm ETBE. The pathological and genetic effects of ETBE were almost at the same extents for HT and KO mice. Thus, 50 ppm could be the no observed adverse effect level for ETBE in HT and KO male mice, which was far lower than the 500 ppm in WT mice. These results suggested that decrease and deficiency of ALDH2 activity would significantly increase the sensitivity to ETBE-induced genotoxicity as well as hepatotoxic effects after exposure even to low concentrations of ETBE. Environ. Mol. Mutagen. 60: 145-153, 2019. © 2018 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/em.22256DOI Listing
March 2019

Acute inhalation co-exposure to 1,2-dichloropropane and dichloromethane cause liver damage by inhibiting mitochondrial respiration and defense ability in mice.

J Appl Toxicol 2019 02 21;39(2):260-270. Epub 2018 Sep 21.

Japan National Institute of Occupational Safety and Health, Kawasaki, Japan.

1,2-Dichloropropane (1,2-DCP) is used as an industrial solvent, insecticide fumigant and household dry cleaning product. Carcinogenicity caused by long-term exposure to 1,2-DCP is well established. However, the possible liver damage and related toxic mechanisms associated with acute inhalation exposure to 1,2-DCP are rarely reported. In this study, we investigated the effects of individual and combined exposure to 1,2-DCP and dichloromethane (DCM) on mice liver. The results showed that 1,2-DCP significantly caused liver necrosis, possibly due to 1,2-DCP-induced inhibition of the mitochondrial respiratory chain complex I-IV activities, resulting in mitochondrial dysfunction and extreme ATP consumption. Moreover, 1,2-DCP also decreased mitochondrial defense ability by inhibiting the mitochondrial glutathione S-transferase 1 (MGST1) activity, further aggravating liver damage. Additionally, we found that DCM co-exposure potentially enhanced 1,2-DCP toxicity. Our findings suggest that inhibition of mitochondrial function and MGST1 activity play critical roles in modulating 1,2-DCP-induced liver damage. Furthermore, our results contribute to study the new mechanism of mitochondria-dominated signaling pathways underlying liver injury induced by 1,2-DCP and DCM.
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http://dx.doi.org/10.1002/jat.3715DOI Listing
February 2019

2,4-Dimethylaniline generates phosphorylated histone H2AX in human urothelial and hepatic cells through reactive oxygen species produced by cytochrome P450 2E1.

Arch Toxicol 2018 10 21;92(10):3093-3101. Epub 2018 Aug 21.

Industrial Toxicology and Health Effects Research Group, National Institute of Occupational Safety and Health, 6-21-1 Nagao, Tama-ku, Kawasaki, Kanagawa, 214-8585, Japan.

The Japanese Ministry of Health, Labour, and Welfare recently reported an outbreak of bladder cancer among workers who handled aromatic amines in Japan. 2,4-dimethylaniline (2,4-DMA) is one of the chemicals that workers are considered to have the most opportunities to be exposed. Genotoxic events are known to be crucial steps in the initiation of cancer. However, studies on the genotoxicity of 2,4-DMA are limited, particularly studies investigating the mechanism behind the genotoxicity by 2,4-DMA are completely lacking. We examined genotoxic properties of 2,4-DMA using phosphorylated histone H2AX (γ-H2AX), a sensitive and reliable marker of DNA damage, in cultured human urothelial and hepatic cells. Our results clearly showed that 2,4-DMA at a concentration range of 1-10 mM generates γ-H2AX in both cell lines, indicating that 2,4-DMA is genotoxic. During mechanistic investigation, we found that 2,4-DMA boosts intracellular reactive oxygen species, an effect clearly attenuated by disulfiram, a strong inhibitor of cytochrome P450 2E1 (CYP2E1). In addition, CYP2E1 inhibitors and the antioxidant, N-acetylcysteine, also attenuated γ-H2AX generation following exposure to 2,4-DMA. Collectively, these results suggest that γ-H2AX is formed following exposure to 2,4-DMA via reactive oxygen species produced by CYP2E1-mediated metabolism. Continuous exposure to genotoxic aromatic amines such as 2,4-DMA over a long period of time may have contributed to the development of bladder cancer. Our results provide important insights into the carcinogenicity risk of 2,4-DMA in occupational bladder cancer outbreaks at chemical plants in Japan.
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http://dx.doi.org/10.1007/s00204-018-2289-6DOI Listing
October 2018

Trichloroethylene exposure results in the phosphorylation of histone H2AX in a human hepatic cell line through cytochrome P450 2E1-mediated oxidative stress.

J Appl Toxicol 2018 09 3;38(9):1224-1232. Epub 2018 May 3.

Industrial Toxicology and Health Effects Research Group, National Institute of Occupational Safety and Health, Japan.

Trichloroethylene (TCE), a chlorinated hydrocarbon, was recently reclassified as a human carcinogen by the International Agency for Research on Cancer. Genotoxic events are known to be crucial steps in the initiation of cancer. The genotoxic properties of TCE have been examined in many studies using a standard battery of genotoxicity tests both in vitro and in vivo. However, consistent results have not been obtained, and studies investigating the mechanism behind the genotoxicity of this compound are lacking. In the present study, we examined the genotoxicity of TCE by assessing phosphorylated histone H2AX (γ-H2AX), a new sensitive and reliable marker of DNA damage, in WRL-68 cells, cultured human hepatocytes and mouse livers. Our results showed that TCE exposure results in the generation of γ-H2AX, both in vitro and in vivo. By investigating the in vitro mechanism, we found that TCE increases the levels of intracellular reactive oxygen species (ROS) and that this increase in ROS levels is attenuated in the presence of disulfiram, a specific cytochrome P450 2E1 (CYP2E1) inhibitor. Furthermore, γ-H2AX induced by TCE was also attenuated by CYP2E1 inhibitors and the antioxidant N-acetylcysteine. These results suggested that ROS, produced via cytochrome P450 2E1-mediated metabolic processing, is a major causal factor for γ-H2AX generation upon exposure to TCE.
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http://dx.doi.org/10.1002/jat.3632DOI Listing
September 2018

1,2-Dichloropropane generates phosphorylated histone H2AX via cytochrome P450 2E1-mediated metabolism.

Toxicol Lett 2017 Apr 12;272:60-67. Epub 2017 Mar 12.

Industrial Toxicology and Health Effects Research Group, National Institute of Occupational Safety and Health, Japan.

1,2-Dichloropropane (1,2-DCP), a synthetic chlorinated solvent, was recently classified as carcinogenic. Genotoxic events are known as a crucial step in the initiation of cancer. However, studies on the genotoxicity of 1,2-DCP are very limited, particularly studies investigating the mechanism behind DNA damage by 1,2-DCP. In this study, we examined the genotoxicity of 1,2-DCP using phosphorylated histone H2AX (γ-H2AX), a sensitive DNA damage marker. 1,2-DCP showed dose- (1-10mM: 4h) and time-dependent (1-24h: 5mM) γ-H2AX generation in cultured human hepatocytes (WRL-68) and cholangiocytes (MMNK-1). Additionally, γ-H2AX generation was observed in the livers of mice inhalationally exposed to 1,2-DCP at concentrations of 100, 200, and 400 ppm. During an in vitro mechanistic investigation, we found that γ-H2AX generation by 1,2-DCP was clearly attenuated in the presence of disulfiram and 4-methylpyrazole, a specific cytochrome P450 2E1 (CYP2E1) inhibitor. Furthermore, we showed that 1,2-DCP increased the levels of intracellular reactive oxygen species (ROS), with the increase significantly inhibited by CYP2E1 inhibitors. These results suggested that ROS produced via the cytochrome P450 2E1 metabolic process of 1,2-DCP was a major causal factor for γ-H2AX generation by treatment with 1,2-DCP.
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http://dx.doi.org/10.1016/j.toxlet.2017.03.009DOI Listing
April 2017

Importance of detoxifying enzymes in differentiating fibrotic development between SHRSP5/Dmcr and SHRSP rats.

Environ Health Prev Med 2016 Sep 21;21(5):368-381. Epub 2016 May 21.

Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objectives: High-fat and -cholesterol diet (HFC) induced fibrotic steatohepatitis in stroke-prone spontaneously hypertensive rat (SHRSP) 5/Dmcr, the fifth substrain from SHRSP, by dysregulating bile acid (BA) kinetics. This study aimed to clarify the histopathological and BA kinetic differences in HFC-induced fibrosis between SHRSP5/Dmcr and SHRSP.

Methods: Ten-week-old male SHRSP5/Dmcr and SHRSP were randomly allocated to groups and fed with either control diet or HFC for 2 and 8 weeks. The liver histopathology, biochemical features, and molecular signaling involved in BA kinetics were measured.

Results: HFC caused more severe hepatocyte ballooning, macrovesicular steatosis and fibrosis in SHRSP5/Dmcr than in SHRSP. It was noted that fibrosis was disproportionately formed in retroperitoneal side of both strains. As for BA kinetics, HFC greatly increased the level of Cyp7a1 and Cyp7b1 to the same degree in both strains at 8 weeks, while multidrug resistance-associated protein 3 was greater in SHRSP5/Dmcr than SHRSP. The diet decreased the level of bile salt export pump by the same degree in both strains, while constitutive androstane receptor, pregnane X receptor, and UDP-glucuronosyltransferase activity more prominent in SHRSP5/Dmcr than SHRSP at 8 weeks. In the fibrosis-related genes, only expression of collagen, type I, alpha 1 mRNA was greater in SHRSP5/Dmcr than SHRSP.

Conclusions: The greater progression of fibrosis in SHRSP5/Dmcr induced by HFC may be due to greater suppression of UDP-glucuronosyltransferase activity detoxifying toxicants, such as hydrophobic BAs.
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http://dx.doi.org/10.1007/s12199-016-0539-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5305991PMC
September 2016

Genotoxicity assessment of intravenously injected titanium dioxide nanoparticles in gpt delta transgenic mice.

Mutat Res Genet Toxicol Environ Mutagen 2016 May 29;802:30-7. Epub 2016 Mar 29.

Division of Health Effects Research, National Institute of Occupational Safety and Health, 6-21-1 Nagao, Tama-ku, Kawasaki, Kanagawa 214-8585, Japan. Electronic address:

Titanium dioxide (TiO2) nanoparticles are increasingly manufactured in large amounts for use in industrial applications such as cosmetics, pigments, foods, and as photo-catalysts. Many in vitro studies have examined the genotoxicity of TiO2 nanomaterials; some of these studies suggest that TiO2 nanoparticles (NPs) are genotoxic. Several in vivo studies have also been reported recently, but the results are inconsistent. In this study, we investigated, using several genotoxicity endpoints, the effects of dispersed TiO2 suspensions following multiple intravenous injections in mice. Male gpt Delta C57BL/6J mice were administered TiO2 NPs at doses of 2, 10 or 50mg/kg body weight per week for 4 consecutive weeks. Genotoxic effects were then analyzed by the Pig-a gene mutation assay and the micronucleus assay on peripheral blood, and by the alkaline comet, gpt mutation, and Spi(-) mutation assays on the liver. We also assessed the localization of TiO2 NPs in the liver, by transmission electron microscopy. Administration of TiO2 NPs did not significantly increase any of the following endpoints: frequency of Pig-a mutants (erythrocytes); frequency of micronuclei (reticulocytes); level of DNA damage (liver); frequencies of gpt and Spi(-) mutants (liver). Most TiO2 NPs in the liver were found in the sinuses and inside Kupffer cells, although some were occasionally observed in liver parenchymal cells. These results indicate that TiO2 NPs do not have genotoxic effects on mouse liver or bone marrow.
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http://dx.doi.org/10.1016/j.mrgentox.2016.03.007DOI Listing
May 2016

Control banding assessment of exposure of offset printing workers to organic solvents.

J Occup Health 2016 Jun 22;58(3):314-9. Epub 2016 Apr 22.

Department of Preventive Medicine and Public Health, Shinshu University School of Medicine.

Objectives: We aimed to assess the exposure of offset printing workers to hazardous substances in the rinsing processes of small-sized companies using a control banding method.

Methods: We obtained half-year amounts of hazardous substances purchased through a questionnaire survey and the hazardous information from the safety data sheets (SDSs) and related literature.

Results: The amount of petroleum kerosine and carbon hydride markedly increased in 2013 compared with that in 2010. In contrast, the amount of dichloromethane (DCM) decreased in 2013, and 1,2-dichloropropane (DCP) was not used in either 2010 or 2013. Mineral oil and xylene were allocated to Hazard Group D and judged to require Control Approach 3. In addition to DCM with Global Harmonization System's carcinogenic category 1, mildly treated mineral oil and solvent naphtha, allocated into Hazard Group E, are carcinogenic to humans and were judged to require Control Approach 4. There are two limitations of the control banding assessment: first, only limited and scarce hazard information could be obtained from SDSs, and second, safe-sided judgment for control technology for industrial hygiene.

Conclusion: Small-sized enterprises are encouraged to implement control banding assessment for hazardous substances and to access expert advice available from Regional Industrial Health Centers. Easy access to appropriate expert advice is important to compensate for the limited and scarce hazard information and safe-sided judgment for control technology for Control Approaches 3 and 4.
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http://dx.doi.org/10.1539/joh.15-0324-BRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356956PMC
June 2016

Chemical management and occupational cholangiocarcinoma among workers in printing industry.

Sangyo Eiseigaku Zasshi 2016 06 16;58(2):78-83. Epub 2016 Mar 16.

National Institute of Occupational Safety and Health.

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http://dx.doi.org/10.1539/sangyoeisei.wadai15005DOI Listing
June 2016

Nanoparticle-rich diesel exhaust-induced liver damage via inhibited transactivation of peroxisome proliferator-activated receptor alpha.

Environ Toxicol 2016 Dec 29;31(12):1985-1995. Epub 2015 Sep 29.

Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Japan.

Diesel exhaust emission contains a high amount of nano-sized particles and is considered to be systemically distributed in the body. However, few studies about the effects of nanoparticle rich-diesel exhaust (NR-DE) on liver have been reported. The present investigation focuses on the effects of NR-DE on livers in rats, especially concerning inflammation and lipid metabolism. Male F344 rats were exposed to fresh air or low (24 ± 7 µg/m ), medium (39 ± 4 µg/m ) and high (138 ± 20 µg/m ) concentrations of NR-DE for 1, 2, or 3 months (5 hours/day, 5 days/week). Exposure to both medium and high concentrations of NR-DE for one month increased plasma asparate aminotransferase and alanine aminotransferase activities, while only high concentrations increased plasma interleukin-6 and hepatic nuclear factor kappa B (NFκB), suggesting that activation of hepatic inflammatory signaling took place. Although these exposures elevated peroxisome proliferator-activated receptor (PPAR) α levels or its binding activity to the response element, neither activated PPARα-target genes such as β-oxidative enzymes nor inhibited NFκB elevation. Thus, NR-DE may contain some materials that inhibit PPARα activation in relation to lipid metabolism and inflammation. Taken together, NR-DE exposure at one month may cause inflammation; however, this finding may not be observed after a longer exposure period. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1985-1995, 2016.
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http://dx.doi.org/10.1002/tox.22199DOI Listing
December 2016

Cytochrome P450 2E1 is responsible for the initiation of 1,2-dichloropropane-induced liver damage.

Toxicol Ind Health 2016 Sep 13;32(9):1589-97. Epub 2015 Feb 13.

Division of Health Effects Research, National Institute of Occupational Safety and Health, Kawasaki, Japan

1,2-Dichloropropane (1,2-DCP), a solvent, which is the main component of the cleaner used in the offset printing companies in Japan, is suspected to be the causative agent of bile duct cancer, which has been recently reported at high incidence in those offset printing workplaces. While there are some reports about the acute toxicity of 1,2-DCP, no information about its metabolism related to toxicity in animals is available. As part of our efforts toward clarifying the role of 1,2-DCP in the development of cancer, we studied the metabolic pathways and the hepatotoxic effect of 1,2-DCP in mice with or without cytochrome P450 2E1 (CYP2E1) activity. In an in vitro reaction system containing liver homogenate, 1,2-DCP was only metabolized by liver tissue of wild-type mice but not by that of cyp2e1-null mice. Furthermore, the kinetics of the solvent in mice revealed a great difference between the two genotypes; 1,2-DCP administration resulted in dose-dependent hepatic damage, as shown biochemically and pathologically, but this effect was only observed in wild-type mice. The nuclear factor κB p52 pathway was involved in the liver response to 1,2-DCP. Our results clearly indicate that the oxidative metabolism of 1,2-DCP in mice is exclusively catalyzed by CYP2E1, and this step is indispensable for the manifestation of the hepatotoxic effect of the solvent.
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http://dx.doi.org/10.1177/0748233714568801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300984PMC
September 2016

Assessment of the genotoxicity of 1,2-dichloropropane and dichloromethane after individual and co-exposure by inhalation in mice.

J Occup Health 2014 17;56(3):205-14. Epub 2014 Apr 17.

Division of Health Effects Research, National Institute of Occupational Safety and Health.

Objective: Occurrence of cholangiocarcinoma was recently reported at a high incidence rate among the employees working for an offset printing company in Osaka, Japan. 1,2-Dichloropropane (1,2-DCP) and dichloromethane (DCM) are suspected to be the causes of the cancer, as they had been used as ink cleaners in large amounts. However, it is not clear whether these chlorinated organic solvents played a role in the occurrence of cholangiocarcinoma or why the incidence rate is so high among the workers in this industry. To provide possible evidence for this severe occupational problem, we investigated the genotoxic effects of 1,2-DCP and DCM.

Methods: Male B6C3F1 and gpt Delta C57BL/6J mice were exposed by inhalation to the individual solvents or both solvents at multiple concentrations including the levels that were possibly present in the workplaces. The genotoxicity was analyzed by Pig-a gene mutation and micronuclei assays in peripheral blood and gpt mutation and comet assays in the livers of mice after repeated inhalation of 1,2-DCP or/and DCM.

Results: The Pig-a mutant frequencies and micronuclei incidences were not significantly increased by exposure of either 1,2-DCP or/and DCM at any concentration, suggesting there was no genotoxic potential in bone marrow for both solvents. In the liver, DNA damage, as measured by the comet assay, was dose dependently increased by 1,2-DCP but not by DCM. The gpt mutant frequency was 2.6-fold that of the controls in the co-exposure group.

Conclusions: These results indicate that 1,2-DCP showed stronger genotoxicity in the liver and that the genotoxic effects were greatly enhanced by simultaneous exposure to DCM.
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http://dx.doi.org/10.1539/joh.13-0236-oaDOI Listing
August 2015

Assessment of the reproductive toxicity of inhalation exposure to ethyl tertiary butyl ether in male mice with normal, low active and inactive ALDH2.

Arch Toxicol 2014 Apr 22;88(4):1007-21. Epub 2014 Jan 22.

Japan National Institute of Occupational Safety and Health, Kawasaki, Japan.

No data are available regarding aldehyde dehydrogenase 2 (ALDH2) polymorphisms related to the reproductive toxicity possibly caused by ethyl tertiary butyl ether (ETBE). In this study, two inhalation experiments were performed in Aldh2 knockout (KO), heterogeneous (HT) and wild type (WT) C57BL/6 male mice exposed to ETBE, and the data about general toxicity, testicular histopathology, sperm head numbers, sperm motility and sperm DNA damage were collected. The results showed that the 13-week exposure to 0, 500, 1,750 and 5,000 ppm ETBE significantly decreased sperm motility and increased levels of sperm DNA strand breaks and 8-hydroxy-deoxyguanosine in both WT and KO mice, the effects were found in 1,750 and 5,000 ppm groups of WT mice, and all of the three exposed groups of KO mice compared to the corresponding control; furthermore, ETBE also caused decrease in the relative weights of testes and epididymides, the slight atrophy of seminiferous tubules of testis and reduction in sperm numbers of KO mice exposed to ≥500 ppm. In the experiment of exposure to lower concentrations of ETBE (0, 50, 200 and 500 ppm) for 9 weeks, the remarkable effects of ETBE on sperm head numbers, sperm motility and sperm DNA damage were further observed in KO and HT mice exposed to 200 ppm ETBE, but not in WT mice. Our findings suggested that only exposure to high concentrations of ETBE might result in reproductive toxicity in mice with normal active ALDH2, while low active and inactive ALDH2 enzyme significantly enhanced the ETBE-induced reproductive toxicity in mice, even exposed to low concentrations of ETBE, mainly due to the accumulation of acetaldehyde as a primary metabolite of ETBE.
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http://dx.doi.org/10.1007/s00204-014-1192-zDOI Listing
April 2014

Mechanisms of cadmium-induced chronotoxicity in mice.

J Toxicol Sci 2013 ;38(6):947-57

Division of Health Effects Research, Japan National Institute of Occupational Safety and Health.

Biological defense factors show diurnal variations in their expression levels or activities. These variations can induce the different sensitivity to external toxicants of a day. We reported earlier that mice showed clear diurnal variation of cadmium (Cd)-induced toxicity, i.e., chronotoxicity. In this report, we investigated additional new evidences for the cadmium (Cd)-induced chronotoxicity, and considered the mechanisms contributed to this chronotoxicity. Male C57BL/6J mice were injected with CdCl₂ (6.4 mg/kg, one shot) intraperitoneally at 6 different time points of a day (zeitgeber time (ZT); ZT2, ZT6, ZT10, ZT14, ZT18 or ZT22) followed by monitoring the mortality until 14 days after the injection. We observed extreme difference in survival numbers: surprisingly, all mice died at ZT2 injection while all mice survived at ZT18 injection. Moreover, in non-lethal dose of Cd (4.5 mg/kg), the values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) used as indexes of hepatotoxicity markedly increased at ZT6 injection while mostly unchanged at ZT18 injection. To consider the mechanisms of this extreme diurnal variation, we examined biochemical studies and concluded that the diurnal variation was not caused by the differences in hepatic Cd level, basal hepatic metallothionein (MT) level, and induction level or induction speed of hepatic MT. We suggested that one of the candidate determination factors was glutathione. We believe that the "chronotoxicology" for metal toxicity may be classic, yet new viewpoint in modern toxicology field.
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http://dx.doi.org/10.2131/jts.38.947DOI Listing
September 2014

Occupational trichloroethylene hypersensitivity syndrome: human herpesvirus 6 reactivation and rash phenotypes.

J Dermatol Sci 2013 Dec 16;72(3):218-24. Epub 2013 Jul 16.

Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. Electronic address:

Background: Trichloroethylene (TCE) is an industrial solvent which can cause severe generalized dermatitis, i.e., occupational TCE hypersensitivity syndrome. Reactivation of latent human herpesvirus 6 (HHV6) can occur in such patients, which has made TCE known as a causative chemical of drug-induced hypersensitivity syndrome (DIHS).

Objective: This study aimed to clarify HHV6 status, cytokine profiles and their association with rash phenotypes in patients with TCE hypersensitivity syndrome.

Methods: HHV6 DNA copy numbers, anti-HHV6 antibody titers, and cytokines were measured in blood prospectively sampled 5-7 times from 28 hospitalized patients with the disease.

Results: The patients (19 had exfoliative dermatitis (ED) and 9 had non-ED type rash) generally met the diagnostic criteria for DIHS. Viral reactivation defined as increases in either HHV6 DNA (≥100 genomic copies/10(6) peripheral blood mononuclear cells) or antibody titers was identified in 24 (89%) patients. HHV6 DNA, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-5, IL-6 and IL-10 concentrations were remarkably higher in the patients than in the healthy workers (p<0.01). Positive correlations between HHV6 DNA, TNF-α, IFN-γ, IL-6 and IL-10 were significant (p<0.05) except for that between HHV6 DNA and IFN-γ. An increase in HHV6 DNA was positively associated with an increase in TNF-α on admission (p<0.01). HHV6 DNA, the antibody titers, TNF-α and IL-10 concentrations were significantly higher in ED than in the non-ED type (p<0.05).

Conclusion: Reactivated HHV6 and the increased cytokines could be biomarkers of TCE hypersensitivity syndrome. The higher-level reactivation and stronger humoral responses were associated with ED-type rash.
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http://dx.doi.org/10.1016/j.jdermsci.2013.07.003DOI Listing
December 2013

Dysregulated bile acid synthesis, metabolism and excretion in a high fat-cholesterol diet-induced fibrotic steatohepatitis in rats.

Dig Dis Sci 2013 Aug 4;58(8):2212-22. Epub 2013 Jul 4.

Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.

Background And Aims: Cholesterol over-intake is involved in the onset of nonalcoholic steatohepatitis (NASH), and hepatocellular bile acid (BA) accumulation correlates with liver injuries. However, how dietary cholesterol influences cholesterol and BA kinetics in NASH liver remains ambiguous and needs to be clarified.

Methods: Molecular markers involved in cholesterol and BA kinetics were investigated at protein and mRNA levels in an already-established stroke-prone spontaneously hypertensive 5/Dmcr rat model with fibrotic steatohepatitis, by feeding a high fat-cholesterol (HFC) diet.

Results: Unlike the control diet, the HFC diet deposited cholesterol greatly in rat livers, where 3-hydroxy-3-methylglutaryl CoA reductase, low-density lipoprotein (LDL) receptor and LDL receptor-related protein-1 were expectedly downregulated, especially at 8 and 14 weeks, suggesting that cholesterol synthesis and uptake in response to cholesterol accumulation may not be disorganized. The HFC diet did not upregulate liver X receptor-α, conversely, it enhanced classic BA synthesis by upregulating cholesterol 7α-hydroxylase but downregulating sterol 12α-hydroxylase, and influenced alternative synthesis by downregulating sterol 27-hydroxylase but upregulating oxysterol 7α-hydroxylase, mainly at 8 and 14 weeks, indicating that there were different productions of primary BA species. Unexpectedly, no feedback inhibition of BA synthesis by farnesoid X receptor occurred. Additionally, the HFC diet impaired BA detoxification by UDP-glucuronosyltransferase and sulfotransferase 2A1, and decreased excretion by bile salt export pump at 8 and 14 weeks, although it induced compensatory export by multidrug resistance-associated protein-3. The disturbed BA detoxification may correlate with suppressed pregnane X receptor and constitutive androstane receptor.

Conclusions: The HFC diet may accumulate BA in rat livers, which influences fibrotic steatohepatitis progression.
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http://dx.doi.org/10.1007/s10620-013-2747-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731517PMC
August 2013

Influence of injection timing on severity of cadmium-induced testicular toxicity in mice.

J Toxicol Sci 2013 Feb;38(1):145-50

Division of Hazard Evaluation and Epidemiology, National Institute of Occupational Safety and Health Japan, Kawasaki, Japan.

Cadmium (Cd) is one of the endocrine disrupter and is a well-known testicular toxicant. Recently, we reported that Cd-induced mortality was markedly different by injection timing. In this report, we investigated whether severity of testicular toxicity was affected by injection timing of Cd. C57BL/6J mice (male, 7 w) were received single intraperitoneal injection of CdCl(2) (4.5 mg/kg) at zeitgeber time 6 (ZT6) or ZT18; these injection timings showed highest (ZT6) or lowest (ZT18) mortality in our previous study (Miura, 2012). After one week of the injection, several parameters for testicular toxicity such as epididymal sperm motility and numbers of sperm head both in cauda epididymidis and testis were measured. At ZT6 injection group, all parameters examined were significantly reduced compared to the control group. However, very interestingly, no significant changes were observed at ZT18 injection group. We obtained similar results by another experiment in which mice were received single subcutaneous injection of CdCl(2) (4 or 6 mg/kg) followed by measuring the parameters ten days after the injection. This diurnal variation was not contradictory to the result of the lethal toxicity which we showed earlier. Therefore, our results indicate that the testicular toxicity of Cd is also influenced by the injection timing.
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http://dx.doi.org/10.2131/jts.38.145DOI Listing
February 2013

Evidence for diazinon-mediated inhibition of cis-permethrin metabolism and its effects on reproductive toxicity in adult male mice.

Reprod Toxicol 2012 Dec 3;34(4):489-97. Epub 2012 Aug 3.

Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.

The potential toxicity resulting from combinatorial effects of organophosphorus and pyrethroid insecticides are not completely known. We evaluated male reproductive toxicity in mice co-exposed to diazinon and cis-permethrin. Nine-week-old male Sv/129 mice were exposed to diazinon (10 μmol/kg/day) or cis-permethrin (90 μmol/kg/day) alone or in combination (100 μmol/kg/day), or vehicle (corn oil), for 6 weeks. Diazinon and the diazinon-permethrin mixture inhibited plasma and liver carboxylesterase activities. In the mixture group, urinary excretion of cis-permethrin metabolite 3-phenoxybenzoic acid decreased along with increased plasma and testicular concentrations of cis-permethrin, while excretion of diazinon metabolites, diethylphosphate and diethylthiophosphate, did not change, versus mice exposed to each chemical alone, which suggested that inhibition of carboxylesterase decreased the metabolic capacity to cis-permethrin. Though the co-exposure decreased testosterone biosynthesis, increased degenerate germ cells in seminiferous tubule and sperm morphological abnormalities versus controls more clearly than exposure to cis-permethrin alone, the expected potentiation of toxicity was not evident.
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http://dx.doi.org/10.1016/j.reprotox.2012.07.007DOI Listing
December 2012

Plasticizers May Activate Human Hepatic Peroxisome Proliferator-Activated Receptor α Less Than That of a Mouse but May Activate Constitutive Androstane Receptor in Liver.

PPAR Res 2012 20;2012:201284. Epub 2012 Jun 20.

Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.

Dibutylphthalate (DBP), di(2-ethylhexyl)phthalate (DEHP), and di(2-ethylhexyl)adipate (DEHA) are used as plasticizers. Their metabolites activate peroxisome proliferator-activated receptor (PPAR) α, which may be related to their toxicities. However, species differences in the receptor functions between rodents and human make it difficult to precisely extrapolate their toxicity from animal studies to human. In this paper, we compared the species differences in the activation of mouse and human hepatic PPARα by these plasticizers using wild-type (mPPARα) and humanized PPARα (hPPARα) mice. At 12 weeks old, each genotyped male mouse was classified into three groups, and fed daily for 2 weeks per os with corn oil (vehicle control), 2.5 or 5.0 mmol/kg DBP (696, 1392 mg/kg), DEHP (977, 1953 mg/kg), and DEHA (926, 1853 mg/kg), respectively. Generally, hepatic PPARα of mPPARα mice was more strongly activated than that of hPPARα mice when several target genes involving β-oxidation of fatty acids were evaluated. Interestingly, all plasticizers also activated hepatic constitutive androstane receptor (CAR) more in hPPARα mice than in mPPARα mice. Taken together, these plasticizers activated mouse and human hepatic PPARα as well as CAR. The activation of PPARα was stronger in mPPARα mice than in hPPARα mice, while the opposite was true of CAR.
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http://dx.doi.org/10.1155/2012/201284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3388330PMC
August 2012

Effect of nanoparticle-rich diesel exhaust on testicular and hippocampus steroidogenesis in male rats.

Inhal Toxicol 2012 Jul 20;24(8):459-67. Epub 2012 Jun 20.

Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Japan.

Background: Nanoparticle-rich diesel exhaust (NR-DE) has potentially adverse effects on testicular steroidogenesis. However, it is unclear whether NR-DE influences steroidogenic systems in the brain.

Objective: To investigate the effect of NR-DE on hippocampal steroidogenesis of adult male rats in comparison with its effect on the testis.

Methods: F344 male rats (8-week-old) were randomly divided into four groups (n = 8 or 9 per group) and exposed to clean air with 4.6 ± 3.2 μg/m(3) in mass concentration, NR-DE with 38 ± 3 μg/m(3) (a level nearly equivalent to the environmental standard in Japan (low NR-DE)), NR-DE with 149 ± 8 μg/m(3) (high NR-DE), or filtered diesel exhaust with 3.1 ± 1.9 μg/m(3) (F-DE), for 5 hours/day, 5 days/week, for 1, 2 or 3 months. F-DE was prepared by removing only particulate matters from high NR-DE with an HEPA filter.

Results: Exposures to the high NR-DE for 1 month, and low NR-DE for 2 months, significantly increased or tended to increase plasma and testicular testosterone levels compared to clean air exposure, which might have resulted from the increased expression of mRNA of steroidogenic acute regulatory protein and its protein in the testes of rats. In the hippocampus, high NR-DE exposure for 1 month significantly increased the androstendione level compared to the clean air exposure, while no significant difference was observed in the steroidogenesis between fresh air exposure and any exposure to NR-DE or F-DE.

Conclusion: NR-DE may influence steroidogenic enzymes in the testis, but not those in the hippocampus.
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http://dx.doi.org/10.3109/08958378.2012.688225DOI Listing
July 2012

The modulation of hepatic adenosine triphosphate and inflammation by eicosapentaenoic acid during severe fibrotic progression in the SHRSP5/Dmcr rat model.

Life Sci 2012 Jun 30;90(23-24):934-43. Epub 2012 Apr 30.

Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Aims: Eicosapentaenoic acid (EPA) can ameliorate certain liver lesions involved in non-alcoholic steatohepatitis (NASH). A previous study has found that stroke-prone spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rats fed a high fat-cholesterol (HFC) diet developed fibrotic steatohepatitis with histological similarities to NASH. This study evaluated the potential effects and mechanisms of action of EPA supplementation using this rodent model.

Main Methods: Male rats were randomly assigned to groups that were fed with either the stroke-prone (SP) diet or HFC diet with or without EPA for 2, 8 and 14 weeks, respectively. The liver histopathology, biochemical features, mRNA and protein levels, and nuclear factor-κB (NF-κB) DNA binding activity were determined.

Key Findings: The SP diet-fed rats presented normal livers. Conversely, the HFC diet-fed rats developed microvesicular/macrovesicular steatosis, inflammation, ballooning degeneration and severe fibrosis. At 2 weeks, the administration of EPA inhibited hepatic inflammatory recruitment by blocking the phosphorylation of inhibitor of κB-α (IκBα), which antagonizes the NF-κB activation pathway. The dietary supplementation of EPA for 8 weeks ameliorated hepatic triglyceride accumulation and macrovesicular steatosis by inhibiting the HFC diet-induced decrease in the protein levels of enzymes involved in fatty acid β-oxidation including carnitine palmitoyltransferase 1, very long chain acyl-CoA dehydrogenase and peroxisomal bifunctional protein. Although the administration of EPA elicited no histologically detectable effects on severe fibrosis at 14 weeks, it restored an HFC diet-induced decline in hepatic adenosine triphosphate (ATP) levels and suppressed ballooning degeneration, suggesting that EPA may inhibit HFC diet-induced ATP loss and cell death.

Significance: Initial amelioration of the inflammation and steatosis in the rats after EPA supplementation indicates a possibility to treat steatohepatitis. Additionally, this study provides new insights into the roles of EPA in hepatic ATP depletion and subsequent hepatocellular injury during severe fibrosis.
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http://dx.doi.org/10.1016/j.lfs.2012.04.029DOI Listing
June 2012

Simultaneous changes in high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis and those underlying molecular mechanisms in novel SHRSP5/Dmcr rat.

Environ Health Prev Med 2012 Nov 11;17(6):444-56. Epub 2012 Mar 11.

Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.

Objectives: The aim of this study was to identify the molecular mechanisms underlying high-fat and high-cholesterol (HFC) diet-induced steatohepatitis and associated liver fibrosis progression in a novel stroke-prone, spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rat model.

Methods: SHRSP5/Dmcr rats were given the control or HFC-diet for 2, 8, and 16 weeks. Plasma and hepatic gene expression of key molecules involved in fatty acid oxidation, inflammation, oxidative stress, and fibrosis were subsequently analyzed.

Results: Rats fed the HFC-diet showed increased plasma tumor necrosis factor-α (TNF-α) and hepatic p50/p65 signals, but reduced hepatic Cu(2+)/Zn(2+)-superoxide dismutase across the treatment period and reduced plasma total adiponectin at 8 weeks. In HFC-diet-fed rats, transforming growth factor-β1 (TGF-β1) was elevated prior to the appearance of obvious liver fibrosis pathology at 2 weeks, followed by elevations in platelet-derived growth factor-B (PDGF-B) and α-smooth muscle actin (α-SMA), corresponding to evident liver fibrosis, at 8 weeks and by α(1) type I collagen production at 16 weeks. The HFC-diet increased hepatic total cholesterol accumulation, although hepatic triglyceride declined by 0.3-fold from 2 to 16 weeks due to reduced hepatic triglyceride synthesis, as suggested by the diacylglycerol acyltransferase 1 and 2 measurements.

Conclusions: TNF-α and p50/p65 molecular signals appeared to be major factors for HFC-diet-induced hepatic inflammation and oxidative stress facilitating liver disease progression. While the up-regulation of TGF-β1 prior to the appearance of any evident liver fibrosis could be an early signal for progressive liver fibrosis, elevated PDGF-B and α-SMA levels signified evident liver fibrosis at 8 weeks, and subsequent increased α(1) type I collagen production and reduced triglyceride synthesis indicated extensive liver fibrosis at 16 weeks in this novel SHRSP5/Dmcr model.
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http://dx.doi.org/10.1007/s12199-012-0273-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493629PMC
November 2012

Diurnal variation of cadmium-induced mortality in mice.

J Toxicol Sci 2012 Feb;37(1):191-6

Division of Health Effects Research, Japan National Institute of Occupational Safety and Health, 6-21-1, Nagao, Tama-ku, Kawasaki 214-8585, Japan.

Circadian timing largely modifies efficacy of many medicinal drugs. This viewpoint has been applied in the clinical medicine, known as chronotherapy. We think this viewpoint should also be introduced into toxicology as "chronotoxicology", however, information about the diurnal variation in toxicant sensitivity is still very scarce. We present here a clear and reproducible diurnal variation of cadmium (Cd)-induced mortality in mice. Male ICR mice kept under standard condition (12 hr light/dark cycle, lights on at 08:00) were injected with CdCl(2) (7.2 mg/kg, one shot) intraperitoneally at different time points in the day (zeitgeber time (ZT) 0, 4, 8, 12, 16 or 20). Survival number was determined at 14 days after injection. Interestingly, mice were sensitive to Cd acute toxicity at ZT8, while tolerant at mid-dark to early-light phase (ZT16, ZT20 and ZT0). Hepatic GSH level showed small daily fluctuation, lowest at ZT8 and highest at ZT20, and this fluctuation was similar to the diurnal variation of Cd sensitivity. In contrast, hepatic metallothionein (MT) level was not significant in these time points, although their level also showed small daily fluctuation. Our results indicated that Cd-induced mortality had clear diurnal variation, and suggested that the hepatic GSH level was one of the important factors for determination of this Cd-induced diurnal mortality.
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http://dx.doi.org/10.2131/jts.37.191DOI Listing
February 2012

Differences in metabolite burden of di(2-ethylhexyl)phthalate in pregnant and postpartum dams and their offspring in relation to drug-metabolizing enzymes in mice.

Arch Toxicol 2012 Apr 13;86(4):563-9. Epub 2011 Dec 13.

Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Tsurumai-Cho, Showa-Ku, Nagoya 466-8550, Japan.

Di(2-ethylhexyl)phthalate (DEHP) induced adverse effects on mice offspring, and the metabolite mono(2-ethylhexyl)phthalate (MEHP) may be essential to determine the toxicity. In this experiment, we measured liver MEHP levels and the factors determining the metabolism, two enzyme activities [lipase and uridine 5'-diphosphate-glucuronosyltransferase (UGT)] or expression of cytochrome P450 4A14 (CYP4A14) in dams (on gestational day 18 and postnatal day 2) and their offspring. MEHP concentrations in the liver from pregnant dams were 1.5 times higher than those of postpartum dams at exposure to 0.05% DEHP. Accordingly, MEHP concentrations were 1.7 times higher in fetuses than in pups at the dose. Interestingly, lipase activity was 1.8-fold higher in pregnant dams than postpartum ones, but no such difference was noted in the activity between fetuses and pups. UGT activity was also 1.5-fold higher in pregnant dams than postpartum ones, whereas the activity in the fetuses was 1/2 that of pups. No difference was noted in CYP4A14 levels between pregnant and postpartum mice, whereas the levels in the fetuses were <1/10 those of pups. DEHP exposure did not influence lipase activity, whereas it slightly enhanced UGT activity and exclusively increased CYP4A14 levels in pregnant and/or postpartum dams. Taken together, the higher MEHP levels in pregnant dams than postpartum ones may be primarily due to higher lipase activities in pregnant dams, which may closely reflect those in fetuses and pups.
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http://dx.doi.org/10.1007/s00204-011-0790-2DOI Listing
April 2012

[Exposure to nanoparticle-rich diesel exhaust may cause liver damage].

Nihon Eiseigaku Zasshi 2011 Sep;66(4):638-42

Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Japan.

Diesel exhaust (DE) is one of the air pollutants in the world, and exposure to DE is an environmental health concern. Most studies amongst the limited number of studies on hepatotoxicity have focused on genotoxicity or mutagenicity. However, DE exposure may cause liver damage because one prospective study suggests that DE exposure is associated with increased mortality due to arteriosclerosis and cirrhosis of the liver. Peroxisome proliferator-activated receptor (PPAR) α plays a role in the regulation of lipid homeostasis and inflammation and thereby may be involved in the progression of atherosclerosis. We investigated whether nanoparticle-rich diesel exhaust (NR-DE) affects the liver and how PPARα is involved in the NR-DE induced effects. We report these results briefly in this minireview. Our results suggest NR-DE-induced hepatic inflammation and dyslipidemia. PPARα may be involved in the development of these disorders.
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http://dx.doi.org/10.1265/jjh.66.638DOI Listing
September 2011
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