Publications by authors named "Tamie Nakajima"

138 Publications

Associations among perfluorooctanesulfonic/perfluorooctanoic acid levels, nuclear receptor gene polymorphisms, and lipid levels in pregnant women in the Hokkaido study.

Sci Rep 2021 May 11;11(1):9994. Epub 2021 May 11.

Center for Environmental and Health Sciences, Hokkaido University, North-12, West-7, Kita-ku, Sapporo, 060-0812, Japan.

The effect of interactions between perfluorooctanesulfonic (PFOS)/perfluorooctanoic acid (PFOA) levels and nuclear receptor genotypes on fatty acid (FA) levels, including those of triglycerides, is not clear understood. Therefore, in the present study, we aimed to analyse the association of PFOS/PFOA levels and single-nucleotide polymorphisms (SNPs) in nuclear receptors with FA levels in pregnant women. We analysed 504 mothers in a birth cohort between 2002 and 2005 in Japan. Serum PFOS/PFOA and FA levels were measured using liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Maternal genotypes in PPARA (rs1800234; rs135561), PPARG (rs3856806), PPARGC1A (rs2970847; rs8192678), PPARD (rs1053049; rs2267668), CAR (rs2307424; rs2501873), LXRA (rs2279238) and LXRB (rs1405655; rs2303044; rs4802703) were analysed. When gene-environment interaction was considered, PFOS exposure (log scale) decreased palmitic, palmitoleic, and oleic acid levels (log scale), with the observed β in the range of - 0.452 to - 0.244; PPARGC1A (rs8192678) and PPARD (rs1053049; rs2267668) genotypes decreased triglyceride, palmitic, palmitoleic, and oleic acid levels, with the observed β in the range of - 0.266 to - 0.176. Interactions between PFOS exposure and SNPs were significant for palmitic acid (P = 0.004 to 0.017). In conclusion, the interactions between maternal PFOS levels and PPARGC1A or PPARD may modify maternal FA levels.
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http://dx.doi.org/10.1038/s41598-021-89285-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113244PMC
May 2021

Effect of prenatal exposure to phthalates on epigenome-wide DNA methylations in cord blood and implications for fetal growth: The Hokkaido Study on Environment and Children's Health.

Sci Total Environ 2021 Aug 17;783:147035. Epub 2021 Apr 17.

Hokkaido University Center for Environmental and Health Sciences, Sapporo, Japan. Electronic address:

Prenatal exposure to phthalates negatively affects the offspring's health. In particular, epigenetic alterations, such as DNA methylation, may connect phthalate exposure with health outcomes. Here, we evaluated the association of di-2-ethylhexyl phthalate (DEHP) exposure in utero with cord blood epigenome-wide DNA methylation in 203 mother-child pairs enrolled in the Hokkaido Study on Environment and Children's Health, using the Illumina HumanMethylation450 BeadChip. Epigenome-wide association analysis demonstrated the predominant positive associations between the levels of the primary metabolite of DEHP, mono(2-ethylhexyl) phthalate (MEHP), in maternal blood and DNA methylation levels in cord blood. The genes annotated to the CpGs positively associated with MEHP levels were enriched for pathways related to metabolism, the endocrine system, and signal transduction. Among them, methylation levels of CpGs involved in metabolism were inversely associated with the offspring's ponderal index (PI). Further, clustering and mediation analyses suggested that multiple increased methylation changes may jointly mediate the association of DEHP exposure in utero with the offspring's PI at birth. Although further studies are required to assess the impact of these changes, this study suggests that differential DNA methylation may link phthalate exposure in utero to fetal growth and further imply that DNA methylation has predictive value for the offspring's obesity.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147035DOI Listing
August 2021

One-Pot Extraction and Quantification Method for Bile Acids in the Rat Liver by Capillary Liquid Chromatography Tandem Mass Spectrometry.

ACS Omega 2021 Mar 16;6(12):8588-8597. Epub 2021 Mar 16.

Department of Legal Medicine & Bioethics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.

We developed a highly sensitive method for quantifying 21 bile acids (BAs) in the rat liver by capillary liquid chromatography tandem mass spectrometry (cLC/MS/MS) with one-pot extraction. High recovery rates were obtained for the one-pot methods with either methanol (MeOH) extraction or MeOH/acetonitrile (ACN) (1:1, v/v) mixture extraction; the results obtained for the MeOH/ACN mixture solution were better than the results obtained for MeOH. Thus, we determined that the one-pot method with MeOH/ACN was the most suitable method for the efficient extraction of BAs in the liver. Targeted BAs were well separated by cLC with gradient elution using ammonium acetate (NHOAc)-MeOH mobile phases. Method validation proved that the intra-day and inter-day accuracies and precisions were primarily less than ±20 and 20% relative standard deviation, respectively. Also, the limit of detection (LOD) and the limit of quantitation (LOQ) were 0.9-10 and 2.3-27 ng/g liver, which proves the high sensitivity of the method. Finally, we quantitated 21 BA concentrations in the liver samples of normal and nonalcoholic steatohepatitis (NASH) rats, both of which were derived from stroke-prone spontaneously hypertensive five (SHRSP5) /Dmcr rat. The hepatic BA profiles were found to be substantially different between the normal and NASH groups; the two groups were clearly separated along the first component axis in the score plots of the principal component analysis. In particular, 10 BAs (β-muricholic acid (MCA), glyco (G-) cholic acid (CA), G-chenodeoxycholic acid (CDCA), tauro (T-) CA, T-CDCA, T-ursodeoxycholic acid (UDCA), T-lithocholic acid (LCA), T-hiodeoxycholic acid (HDCA), T-α-MCA, and T-β-MCA) were significantly different between the two groups using Welch's -test with the false discovery rate correction method, demonstrating BA disruption in the NASH model rat. In conclusion, this method was able to quantify 21 BAs in the rat liver and will evaluate the hepatic BA pathophysiology of rat disease models.
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http://dx.doi.org/10.1021/acsomega.1c00403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015121PMC
March 2021

The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension.

PLoS One 2020 14;15(12):e0243846. Epub 2020 Dec 14.

College of Life and Health Sciences, Chubu University, Kasugai, Aichi, Japan.

Hypertension is an important risk factor for nonalcoholic steatohepatitis. We have previously demonstrated that hypertensive rats fed a high fat and cholesterol (HFC) diet incurred a more severe hepatic inflammatory response and fibrosis. Here we investigated the role of hypertension in NASH by comparing HFC-induced hepatic fibrogenesis between spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto counterpart. Compared to the counterpart, the HFC diet led to stronger aggregation of CD68-positive macrophages in SHRs. HFC feeding also resulted in significantly higher upregulation of the fibrosis-related gene alpha-smooth muscle actin in SHR. The HFC diet induced higher overexpression of serum tissue inhibitor of metalloproteinase-1 (TIMP1) and greater suppression of matrix metalloproteinase-2 (MMP2):TIMP1, MMP8:TIMP1, and MMP9:TIMP1 ratios, as a proxy of the activities of these MMPs in SHR. Administration of the antihypertensive agent hydralazine to SHRs significantly ameliorated HFC-induced liver fibrosis; it suppressed the aggregation of CD68-positive macrophages and the upregulation of platelet-derived growth factor receptor beta, and collagen, type 1, alpha-1 chain. In conclusion, a hypertensive environment exacerbated the hepatic fibrogenetic effects of the HFC diet; while the effects were partially reversed by the antihypertensive agent hydralazine. Our data suggest that antihypertensive drugs hold promise for treating NASH exacerbated by hypertension.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243846PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735612PMC
February 2021

Trichloroethylene and trichloroethanol induce skin sensitization with focal hepatic necrosis in guinea pigs.

J Occup Health 2020 Jan;62(1):e12142

Institute of Toxicology, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, China.

Objectives: Occupational exposure to trichloroethylene (TCE) induces trichloroethylene hypersensitivity syndrome (TCEHS), which causes hypersensitivity dermatitis and hepatitis. However, whether TCE itself or its two metabolites, trichloroethanol (TCEOH) and trichloroacetic acid (TCA), are involved in TCEHS remains unclear. Therefore, in this study we explored the allergens causing TCEHS and characterized TCEHS-related liver injury in guinea pigs.

Method: The guinea pig maximization test was performed using TCE, TCEOH, and TCA as candidate allergens. Skin inflammation was scored, and liver function and histopathological changes were evaluated by biochemical tests and hematoxylin and eosin staining, respectively.

Results: The sensitization rates for TCE, TCEOH, and TCA were 90.0%, 50.0%, and 0.0%, respectively. In the TCE and TCEOH experimental groups, the skin showed varying degrees of erythema with eosinophil granulocyte infiltration in the dermis. Additionally, serum alanine aminotransferase and γ-glutamyl transpeptidase levels increased significantly, and histological analysis revealed focal hepatocellular necrosis with inflammatory cell infiltration in the liver.

Conclusions: TCE is the main cause of allergy and TCEOH is a secondary factor for allergy in guinea pigs. TCE and TCEOH can cause immune-mediated skin sensitization complicated by focal hepatic necrosis.
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http://dx.doi.org/10.1002/1348-9585.12142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428806PMC
January 2020

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

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

Participation rate determines completion rate for specific health guidance as implemented by public health insurers.

Nagoya J Med Sci 2019 Aug;81(3):375-395

Department of Lifelong Sports for Health, College of Life and Health Sciences, Chubu University, Kasugai, Japan.

Completion rate for specific health guidance (SHG) based on specific health checkup (SHC) status in Japan is very low. This study aimed to clarify factors affecting the rate using questionnaire survey, which was conducted by mail between December 2016 and January 2017 for insurers in the Tokai Region of Japan. The subjects were 69 insurers and the collection rate was 25.1%. The SHG participation rate was 26.3%, and the SHG completion rate was even lower (23.6%) than the participation rate. The rate was significantly lower in dependents than in insured persons. Multiple regression analysis with SHG completion rate as the dependent variable indicated that only "participation rate in SHG" was positively related to completion rate. With SHG participation rate as the dependent variable, however, having an insurer who "implemented SHG," "provided a thorough explanation to the subscribers of the objectives and significance of SHC and SHG when the programs were begun," and "provided health guidance to non-obese individuals" and SHC implementation rate were positively correlated with participation rate. Multiple regression analysis using completion rates for the two types of SHG, i.e., motivational and active support, as the dependent variables indicated that SHG participation rate was a positive factor for each type. Participation rate in each type was positively correlated to "ex-post assessment of the SHG," and/or insured persons. The primary factor affecting SHG completion rates was the SHG participation rate. It is also important, however, that insurers encourage participation of subscribers, especially dependents, in SHG.
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http://dx.doi.org/10.18999/nagjms.81.3.375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728204PMC
August 2019

High-fat and high-cholesterol diet decreases phosphorylated inositol-requiring kinase-1 and inhibits autophagy process in rat liver.

Sci Rep 2019 08 29;9(1):12514. Epub 2019 Aug 29.

College of Life and Health Sciences, Chubu University, Kasugai, 487-8501, Japan.

Precise molecular pathways involved in the progression of non-alcoholic steatohepatitis (NASH) remain to be elucidated. As Mallory-Denk bodies were occasionally observed in the enlarged hepatocytes in NASH model rat (SHRSP5/Dmcr) fed high-fat and high-cholesterol (HFC) diet, we aimed to clarify the roles of autophagy and endoplasmic reticulum (ER) stress in NASH progression. Male SHRSP5/Dmcr were randomly divided into 4 groups. Two groups were fed a control diet; the other two groups were fed a HFC diet for 2 and 8 weeks, respectively. The HFC diet increased the autophagy-related proteins levels and microtubule-associated protein 1 light chain 3-II/I ratio after 2 and 8 weeks, respectively. However, regarding ER stress-related proteins, the HFC diet decreased the levels of phosphorylated (p-) inositol-requiring kinase-1 (p-IRE-1) and p-protein kinase RNA-like ER kinase after 2 weeks. Additionally, the HFC diet increased anti-ubiquitin-positive cells and the level of the autophagy substrate p62, suggesting that the HFC diet induced dysfunction in ubiquitin-dependent protein degradation pathways. In conclusion, the HFC diet arrested the autophagy process in the liver; this was particularly associated with decreases in p-IRE-1 expression.
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http://dx.doi.org/10.1038/s41598-019-48973-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715744PMC
August 2019

Di(2-ethylhexyl) phthalate-induced toxicity and peroxisome proliferator-activated receptor alpha: a review.

Environ Health Prev Med 2019 Jul 6;24(1):47. Epub 2019 Jul 6.

College of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi, 487-8501, Japan.

The plasticizer di(2-ethylhexyl) phthalate (DEHP) has been widely used in the manufacture of polyvinyl chloride-containing products such as medical and consumer goods. Humans can easily be exposed to it because DEHP is ubiquitous in the environment. Recent research on the adverse effects of DEHP has focused on reproductive and developmental toxicity in rodents and/or humans. DEHP is a representative of the peroxisome proliferators. Therefore, peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways are the expected mode of action of several kinds of DEHP-induced toxicities. In this review, we summarize DEHP kinetics and its mechanisms of carcinogenicity and reproductive and developmental toxicity in relation to PPARα. Additionally, we give an overview of the impacts of science policy on exposure sources.
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http://dx.doi.org/10.1186/s12199-019-0802-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612219PMC
July 2019

Simple method to detect triclofos and its metabolites in plasma of children by combined use of liquid chromatography tandem-mass spectrometry and gas chromatography-mass spectrometry.

Sci Rep 2019 06 26;9(1):9294. Epub 2019 Jun 26.

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

Triclofos sodium (TCS) and chloral hydrate (CH) are widely used as sedatives for children, but no analytical method to simultaneously monitor concentrations of blood TCS, CH and their metabolites, trichloroacetic acid (TCA) and trichloroethanol (TCEOH), has been reported. The present study aimed to develop a simple analytical method for TCS and its metabolites (TCA, TCEOH and CH) in small-volume plasma from children. After acidification of specimens, TCS formic acid adduct or the metabolites derivatized using water/sulfuric acid/methanol (6:5:1, v/v) were measured by combined use of liquid chromatography tandem-mass spectrometry and gas chromatography mass-spectrometry. The limits of detection and quantification levels (µg/ml) were 0.10 and 0.29 for TCS, 0.24 and 0.72 for TCA, 0.10 and 0.31 for TCEOH, and 0.25 and 0.76 for CH, respectively. The mean recoveries were 82.8-107% for TCS, 85.4-101% for TCA, 91.6-107% for TCEOH, and 88.9-109% for CH. Within-run and between-run precision (percent of relative standard deviation, %RSD) using this method ranged from 1.1 to 15.7% and 3.6 to 13.5%, respectively, for TCS and all of its metabolites. The calibration curves were obtained with standard spiked plasma, and all of the coefficients of determination were more than 0.975. Subsequently, we applied the present method to plasma taken from five children after sedation induced by CH and TCS. In addition to TCS and CH, elevated TCA and TCEOH concentrations were detected. This new method can be applied for the pharmacokinetic analysis of TCS and its metabolites and the determination of the optimal TCS dosage in children.
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http://dx.doi.org/10.1038/s41598-019-45790-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594997PMC
June 2019

Ablation of aryl hydrocarbon receptor promotes angiotensin II-induced cardiac fibrosis through enhanced c-Jun/HIF-1α signaling.

Arch Toxicol 2019 06 23;93(6):1543-1553. Epub 2019 Apr 23.

Nagoya University Graduate School of Medicine, Nagoya, Japan.

Aryl hydrocarbon receptor (AHR) is a transcription factor that binds to DNA as a heterodimer with the AHR nuclear translocator (ARNT) after interaction with ligands, such as polycyclic and halogenated aromatic hydrocarbons and other xenobiotics. The endogenous ligands and functions of AHR have been the subject of many investigations. In the present study, the potential role of AHR signaling in the development of left ventricular hypertrophy and cardiac fibrosis by angiotensin II (Ang II) infusion was investigated in mice lacking the AHR gene (Ahr). We also assessed the hypothesis that fenofibrate, a peroxisome proliferator-activated receptor-α (PPARα) activator, reduces cardiac fibrosis through the c-Jun signaling. Male Ahr and age-matched wild-type mice (n = 8 per group) were infused with Ang II at 100 ng/kg/min daily for 2 weeks. Treatment with Ang II increased systolic blood pressure to comparable levels in Ahr and wild-type mice. However, Ahr mice developed severe cardiac fibrosis after Ang II infusion compared with wild-type mice. Ang II infusion also significantly increased the expression of endothelin in the left ventricles of Ahr mice, but not in wild-type mice, and significantly increased the c-Jun signaling in Ahr mice. Ang II infusion also significantly enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and the downstream target vascular endothelial growth factor (VEGF) in the left ventricles of Ahr mice. These results suggested pathogenic roles for the AHR signaling pathway in the development of cardiac fibrosis. Treatment with fenofibrate reduced cardiac fibrosis and abrogated the effects of Ang II on the expression of endothelin, HIF-1α, and VEGF. The inhibitory effect of fenofibrate on cardiac fibrosis was mediated by suppression of VEGF expression through modulation of c-Jun/HIF-1α signaling.
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http://dx.doi.org/10.1007/s00204-019-02446-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395242PMC
June 2019

In utero exposure to di(2-ethylhexyl)phthalate suppresses blood glucose and leptin levels in the offspring of wild-type mice.

Toxicology 2019 03 17;415:49-55. Epub 2019 Jan 17.

College of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi, 487-8501, Japan. Electronic address:

Exposure of pregnant mice to di(2-ethylhexyl)phthalate (DEHP) induces maternal lipid malnutrition and decreases the number of live fetuses/pups. In this study, we aimed to clarify the relationship between maternal lipid malnutrition and the nutritional status of the neonatal, lactational, and adult offspring, as well as the role of peroxisome proliferator-activated receptor α (PPARα) in these relationships. Sv/129 wild-type (mPPARA), Ppara-null, and PPARα-humanized (hPPARA) mice were fed diets containing 0, 0.01, 0.05, or 0.1% DEHP in utero and/or during the lactational stage. The male offspring were killed on postnatal day 2 or 21, or after 11 weeks. Exposure to either 0.05% or 0.1% DEHP during both the in utero and lactational periods decreased serum glucose concentrations in 2-day-old mPPARA offspring. These dosages also decreased both serum and plasma leptin levels in both 2- and 21-day-old mPPARA offspring. In contrast, exposure to DEHP only during the lactational period did not decrease leptin levels, suggesting the importance of in utero exposure to DEHP. Exposure to 0.05% DEHP during the in utero and lactational periods also increased food consumption after weaning in both mPPARA and hPPARA mice; this was not observed in Ppara-null offspring. In conclusion, in utero exposure to DEHP induces neonatal serum glucose malnutrition via PPARα. DEHP also decreases serum and plasma leptin concentrations in offspring during the neonatal and weaning periods, in association with PPARα, which presumably results in increased of food consumption after weaning.
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http://dx.doi.org/10.1016/j.tox.2019.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628919PMC
March 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

Exposure reconstruction of trichloroethylene among patients with occupational trichloroethylene hypersensitivity syndrome.

Ind Health 2018 Jul 3;56(4):300-307. Epub 2018 Mar 3.

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

Occupational trichloroethylene (TCE) exposure can induce life-threatening generalized dermatitis accompanied by hepatitis: TCE hypersensitivity syndrome (HS). Since the patients' exposure levels have not been fully clarified, this study estimated end-of-shift urinary concentrations of trichloroacetic acid (TCA) and their lower limit below which the disease occurrence was rare. TCA concentration was measured in 78 TCE HS patients whose urine was collected at admission between 2nd and 14th d after their last shift. Then a linear regression model was used to calculate the mean TCA concentration with 95% confidence interval (95% CI) and 95% prediction interval (95% PI) in the end-of-shift urine. The estimated mean concentration was 83 (95% CI, 49-140) mg/l with 95% PI 9.6-720 mg/l. TCA concentrations were also measured in the end-of-shift urine of 38 healthy workers involved in the same job as were the patients. The geometric mean and its 95% CI were 127 mg/l and 16-984 mg/l, respectively. The exposure levels in HS patients might have thus overlapped with those in workers without HS. Accordingly, it was suggested that HS occurred in the environment where the workers were exposed to the TCE concentration corresponding to the urinary TCA concentration as low as 10 mg/l.
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http://dx.doi.org/10.2486/indhealth.2017-0202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066440PMC
July 2018

Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet.

PLoS One 2018 13;13(2):e0192863. Epub 2018 Feb 13.

College of Life and Health Sciences, Chubu University, Kasugai, Japan.

During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics. However, the BA detoxification-related enzymes UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) 2A1, and the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), were strongly suppressed in HFC-fed males, and were only slightly changed in HFC-diet fed females. Expression levels of the farnesoid X receptor and its small heterodimer partner were similarly regulated in a gender-dependent fashion following HFC feeding. Hence, the pronounced female resistance to HFC-induced liver damage likely reflects sustained expression of the nuclear receptors CAR and PXR and the BA detoxification enzymes UGT and SULT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192863PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811017PMC
April 2018

Epididymal phospholipidosis is a possible mechanism for spermatotoxicity induced by the organophosphorus insecticide fenitrothion in rats.

Toxicol Lett 2018 Mar 30;285:27-33. Epub 2017 Dec 30.

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

Fenitrothion (FNT) is used worldwide in agricultural and public health settings. Spermatogenesis is a toxicological target of FNT under high-dose exposure. Although anti-androgenic action is postulated to be the mechanism associated with this toxicity, few studies have examined histopathology of androgen-dependent male accessory sex organs. The present study aimed to reveal the effects of FNT on the accessory organs of rats exhibiting spermatotoxicity in the absence of testicular histopathological changes. Furthermore, a possible novel molecular target was clarified. Male Wistar rats were orally administered 5 or 10 mg/kg FNT or its major metabolite 3-methyl-4-nitrophenol (MNP), or vehicle only, 4 days per week for 9 weeks. Then the epididymis, prostate, and seminal vesicles were collected. FNT and MNP did not show anti-androgenic effects but FNT induced cytoplasmic vacuolation in the epithelial cells of epididymal ducts and hyperplasia of mucosal folds/epithelial papillomatosis in seminal vesicles. FNT and MNP induced epididymal phospholipidosis, which was presumably caused by inhibition of epididymal secreted phospholipase A2 (sPLA2). Percentages of morphologically normal sperm and immature sperm were significantly predicted from both epididymal sPLA2 and phospholipid levels and from epididymal sPLA2, respectively. These results suggest that epididymal phospholipidosis plays an important role in FNT-induced spermatotoxicity. Anti-androgenic actions were not observed.
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http://dx.doi.org/10.1016/j.toxlet.2017.12.023DOI Listing
March 2018

Effects of prenatal di(2-ethylhexyl) phthalate exposure on childhood allergies and infectious diseases: The Hokkaido Study on Environment and Children's Health.

Sci Total Environ 2018 Mar 28;618:1408-1415. Epub 2017 Oct 28.

Center for Environmental and Health Sciences, Hokkaido University, North 12, West 7, Kita-ku, Sapporo 060-0812, Japan. Electronic address:

Phthalates are widely used in consumer products, and experimental studies suggest that exposure to phthalates increase the risk of allergies. However, epidemiologic evidence on the associations between prenatal phthalate exposure and allergies/infectious diseases and cord blood immunoglobulin E (IgE) levels is limited. This study aimed to evaluate the associations between maternal mono(2-ethylhexyl) phthalate (MEHP) levels and cord blood IgE levels at birth (n=127), as well as the risk of allergies/infectious diseases in participants up to 7years of age; the participants were 1.5 (n=248), 3.5 (n=222), 7 (n=184) years of age. Maternal blood MEHP level in the second trimester was measured using gas chromatography-mass spectrometry. Participant characteristics were obtained from the medical birth records and self-administered questionnaires during pregnancy and after delivery. Wheeze and eczema were defined according to the Japanese version of the International Study of Asthma and Allergies in Childhood and the American Thoracic Society-Division of Lung Diseases questionnaire, respectively. Infectious diseases were defined using questionnaires for each specified age. To evaluate the associations between maternal MEHP and allergies or infectious diseases, we used logistic regression analysis and generalized estimating equations analysis. Maternal MEHP levels were negatively associated with cord blood IgE levels and increased risks of allergies and infectious diseases up to 7years of age. This is the first study to investigate the effects of prenatal MEHP exposure on IgE levels at birth and allergies/infectious diseases up to 7years of age. Further epidemiological studies should focus on other phthalate metabolites and their health effects on larger populations.
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http://dx.doi.org/10.1016/j.scitotenv.2017.09.270DOI Listing
March 2018

Combination of Hypertension Along with a High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-κB, MAPK, and Nrf2 Pathways.

Nutrients 2017 Sep 14;9(9). Epub 2017 Sep 14.

College of Life and Health Sciences, Chubu University, 487-8501 Kasugai, Japan.

Populations with essential hypertension have a high risk of nonalcoholic steatohepatitis (NASH). In this study, we investigated the mechanism that underlies the progression of hypertension-associated NASH by comparing differences in the development of high fat and cholesterol (HFC) diet-induced NASH among three strains of rats, i.e., two hypertensive strains comprising spontaneously hypertensive rats and the stroke-prone spontaneously hypertensive 5/Dmcr, and the original Wistar Kyoto rats as the normotensive control. We investigated histopathological changes and molecular signals related to inflammation in the liver after feeding with the HFC diet for 8 weeks. The diet induced severe lobular inflammation and fibrosis in the livers of the hypertensive rats, whereas it only caused mild steatohepatitis in the normotensive rats. An increased activation of proinflammatory signaling (transforming growth factor-β1/mitogen-activated protein kinases pathway) was observed in the hypertensive strains fed with the HFC diet. In addition, the HFC diet suppressed the nuclear factor erythroid 2-related factor 2 pathway in the hypertensive rats and led to lower increases in the hepatic expression of heme oxygenase-1, which has anti-oxidative and anti-inflammatory activities. In conclusion, these signaling pathways might play crucial roles in the development of hypertension-associated NASH.
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http://dx.doi.org/10.3390/nu9091018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622778PMC
September 2017

Prenatal di(2-ethylhexyl) phthalate exposure and disruption of adrenal androgens and glucocorticoids levels in cord blood: The Hokkaido Study.

Sci Total Environ 2017 Mar 30;581-582:297-304. Epub 2016 Dec 30.

Center for Environmental and Health Sciences, Hokkaido University, Kita 12, Nishi 7, Sapporo, Hokkaido, Japan. Electronic address:

Di(2-ethylhexyl) phthalate (DEHP) is known for its endocrine disrupting properties. We previously demonstrated that prenatal DEHP exposure is associated with decreased progesterone levels and testosterone/estradiol ratio in the cord blood. However, evidence of the effects of prenatal DEHP exposure on adrenal androgen and glucocorticoids in infants is scarce. Thus, the objectives of this study were to investigate the association between prenatal DEHP exposure and adrenal androgen and glucocorticoids, and to discuss its effects on steroid hormone profiles in infants. This is part of a birth cohort study: The Hokkaido Study on Environment and Children's Health, Sapporo Cohort. Among the 514 participants, 202 mother-infant pairs with available data on maternal mono(2-ethylhexyl) phthalate (MEHP), adrenal androgen (dehydroepiandrostenedione [DHEA] and androstenedione) and glucocorticoid (cortisol and cortisone) cord blood levels were included in this study. After adjusting for potential confounders, a linear regression analysis showed that maternal MEHP levels were associated with reduced cortisol and cortisone levels and glucocorticoid/adrenal androgen ratio, whereas increased DHEA levels and DHEA/androstenedione ratio. In a quartile model, when comparing the adjusted least square means in the 4th quartile of MEHP with those in the 1st quartile, cortisol and cortisone levels and glucocorticoid/adrenal androgen ratio decreased, whereas DHEA/androstenedione and cortisol/cortisone ratios increased. Significant p-value trends for cortisol and cortisone levels, cortisol/cortisone ratio, and glucocorticoid/adrenal androgen ratio were observed. In combination with the previous results of reduced progesterone levels and testosterone/estradiol ratio, prenatal exposure to DEHP altered the steroid hormone profiles of infants. Further studies investigating the long-term effects of DEHP exposure on growth, neurodevelopment, and gonad and reproductive function are required.
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http://dx.doi.org/10.1016/j.scitotenv.2016.12.124DOI Listing
March 2017

Prenatal di-2-ethylhexyl phthalate exposure and cord blood adipokine levels and birth size: The Hokkaido study on environment and children's health.

Sci Total Environ 2017 Feb 15;579:606-611. Epub 2016 Nov 15.

Center for Environmental and Health Sciences, Hokkaido University, Kita 12, Nishi 7, Kita-ku, Sapporo 060-0812, Japan. Electronic address:

Di-2-ethylhexyl phthalate (DEHP) is one of the most widely used phthalates. Metabolites of DEHP are detectable in majority of the population. Findings on adverse health outcomes, particularly birth weight in association with prenatal exposure to DEHP remain equivocal. Besides, there is insufficient evidence to address influence on metabolic function from epidemiological studies. Thus, our objective was to investigate cord blood adipokine levels and birth size in association with prenatal DEHP exposure in prospective birth cohort study. Mono-2-methylhexyl phthalate (MEHP), primary metabolite of DEHP was determined as exposure by using maternal blood sample of 3rd trimester. Leptin and adiponectin levels in cord blood were measured as markers of metabolic function. Birth weight and length were obtained from birth record. Association between maternal MEHP levels and cord blood adiponectin and leptin levels, birth weight and ponderal index (PI) were examined for 167 mother-child pairs who had both MEHP and cord blood adipokine measurements. The median MEHP level was 8.81ng/ml and the detection rate was 100%. There was no sex difference in MEHP levels. Both leptin and adiponectin levels were higher in girls than in boys. MEHP level was positively associated with adiponectin level among boys and was negatively associated with leptin level among girls. MEHP level were negatively associated with PI only in girls and this could be due to decreased leptin level. This study suggested that prenatal DEHP exposure may be associated with cord blood adipokine and birth size. The influence potentially be sex-specific and could be more significant in girls.
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http://dx.doi.org/10.1016/j.scitotenv.2016.11.051DOI Listing
February 2017

Effects of prenatal phthalate exposure on thyroid hormone levels, mental and psychomotor development of infants: The Hokkaido Study on Environment and Children's Health.

Sci Total Environ 2016 Sep 31;565:1037-1043. Epub 2016 May 31.

Center for Environmental and Health Sciences, Hokkaido University, Kita 12, Nishi 7, Kita-ku, Sapporo 060-0812, Japan. Electronic address:

Di (2-ethylhexyl) phthalate (DEHP) is commonly used phthalates and concerns of adverse effects of prenatal DEHP exposure on neonatal thyroid hormone (TH) and neurodevelopment are increasing. However, there is no report regarding association between prenatal DEHP exposure and infant neurodevelopment including TH levels in Japanese population. Thus the aim of present study was to evaluate the associations between prenatal DEHP exposure and mental and psychomotor development of infants 6 and 18months along with investigating influence on neonatal free thyroxine (FT4) and thyroid stimulating hormone (TSH) levels in the prospective birth cohort study. Maternal blood samples collected between 23 and 41weeks of gestation was analyzed for mono (2-ethylhexyl) phthalate (MEHP), metabolite of DEHP levels. Neonatal FT4 and TSH were obtained from mass screening data. Infant neurodevelopment was assessed by Bayley Scale of Infant Development second edition at 6 and 18month of age. For the final analysis, 328 participants were included. The median levels of maternal MEHP was 10.6ng/ml, neonatal TSH and FT4 was 2.20 μU/ml and 2.03ng/ml, respectively. We did not find any associations between prenatal DEHP exposure and neonatal TH levels or infant mental and psychomotor development at 6 and 18month. In this study, prenatal DEHP exposure did not show adverse effects on infant TH levels or mental and psychomotor development in early life stage. However, our previous study revealed negative effects of prenatal DEHP exposure on sex hormone levels, continuous investigation on neurodevelopment in later life in association with prenatal DEHP exposure is necessary.
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http://dx.doi.org/10.1016/j.scitotenv.2016.05.098DOI Listing
September 2016

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

Intact Endogenous Metabolite Analysis of Mice Liver by Probe Electrospray Ionization/Triple Quadrupole Tandem Mass Spectrometry and Its Preliminary Application to in Vivo Real-Time Analysis.

Anal Chem 2016 Apr 9;88(7):3556-61. Epub 2016 Mar 9.

Department of Legal Medicine & Bioethics, Nagoya University Graduate School of Medicine , 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Probe electrospray ionization (PESI) is a recently developed ionization technique that enables the direct detection of endogenous compounds like metabolites without sample preparation. In this study, we have demonstrated the first combination use of PESI with triple quadrupole tandem mass spectrometry (MS/MS), which was then applied to intact endogenous metabolite analysis of mice liver, achieving detection of 26 metabolites including amino acids, organic acids, and sugars. To investigate its practicality, metabolic profiles of control and CCl4-induced acute hepatic injury mouse model were measured by the developed method. Results showed clear separation of the two groups in score plots of principal component analysis and identified taurine as the primary contributor to group separation. The results were further validated by the established gas chromatography/MS/MS method, demonstrating the present method's usefulness. In addition, we preliminarily applied the method to real-time analysis of an intact liver of a living mouse. We successfully achieved monitoring of the real-time changes of two tricarboxylic acid cycle intermediates, α-ketoglutaric acid and fumaric acid, in the liver immediately after pyruvic acid injection via a cannulated tube to the portal vein. The present method achieved an intact analysis of metabolites in liver without sample preparation, and it also demonstrates future possibility to establish in vivo real-time metabolome analysis of living animals by PESI/MS/MS.
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http://dx.doi.org/10.1021/acs.analchem.5b04046DOI Listing
April 2016

Efficacy of Dietary Lipid Control in Healing High-Fat and High-Cholesterol Diet-Induced Fibrotic Steatohepatitis in Rats.

PLoS One 2016 4;11(1):e0145939. Epub 2016 Jan 4.

College of Life and Health Sciences, Chubu University, Kasugai, Japan.

Nonalcoholic steatohepatitis is related to lifestyle, particularly to dietary habits. We developed diet-induced fibrotic steatohepatitis model stroke-prone spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rats showing steatosis, hepatic inflammation, and severe fibrosis induced by high-fat and -cholesterol (HFC) diet feeding. We aimed to clarify the efficacy of dietary intervention on the disease before and after the appearance of fibrosis. Male SHRSP5/Dmcr rats were divided into 9 groups; of these, 6 groups were fed control or HFC diet for several weeks and the remaining 3 groups represented the dietary intervention groups, which were fed the control diet after HFC diet feeding for 2 (before the appearance of fibrosis) or 8 (after the appearance of fibrosis) weeks. Dietary intervention before the appearance of fibrosis significantly improved the steatosis and reset the increased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum total cholesterol (TC) levels. However, dietary intervention after the appearance of fibrosis was unable to reset the levels of hepatic TC, serum ALT, and fibrogenesis-related markers and had only a minor influence on hepatic fibrosis, although it reset the increased expression of transforming growth factor (TGF)-β1 and α-smooth muscle actin (SMA). It was noted that dietary intervention improved the increased AST levels; however, aggregated CD68-positive cells were still observed around the fibrosis area, which may be related to the findings of inflammatory cytokine mRNAs. Taken together, dietary intervention for fibrotic steatohepatitis improved steatosis, although it could not completely improve fibrosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145939PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699821PMC
July 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

[Mechanism Analysis and Prevention of Pathogenesis of Nonalcoholic Steatohepatitis].

Nihon Eiseigaku Zasshi 2015 ;70(3):197-204

College of Life and Health Sciences, Chubu University.

Nonalcoholic fatty liver disease (NAFLD) is a common disease in humans having a broad spectrum of liver histology from simple fatty liver to mixed inflammatory cell infiltration and fibrosis (nonalcoholic steatohepatitis, NASH), which is a more severe and progressing form. NASH/NAFLD is significantly associated with lifestyle such as diet and exercise, obesity, insulin resistance, type 2 diabetes, dyslipidemia and hypertension. Age and gender are also associated with the development. On the other hand, NAFLD has been found in a high percentage of nonobese individuals in the Asia-Pacific area. Some characteristic animal models of NAFLD/NASH have been developed to clarify the pathogenesis of human NAFLD/NASH. We have recently developed a novel NASH rat model (stroke-prone spontaneously hypertensive rats, SHRSP5/Dmcr), which showed hepatic steatosis and inflammation at 2 weeks, ballooning, macrovesicular steatosis and fibrosis at 8 weeks, and bridging fibrosis at 14 weeks by feeding of high-fat and -cholesterol (HFC) diet alone. This animal model does not have obesity, insulin resistance or diabetes. Therefore, this may be an excellent animal model of human NASH/NAFLD without obesity and diabetes. Sex and strain differences observed in fibrogenesis by the HFC diet in SHRSP5/Dmcr may be associated with the sensitivity to detoxification enzymes in the liver, because the levels of UGP-glucuronosyltransferase and sulfotransferase and their regulating nuclear receptors only decreased in male SHRSP5/Dmcr rats, but not in female and SHRSP rats. This suggests the importance of phase II reactions of drug-metabolizing enzymes in NASH progression. Importantly, SHRSP5/Dmcr rats are spontaneously hypertensive; therefore, when we use the original strain Wistar Kyoto, which has normal blood pressure, the involvement of blood pressure in the development of human NASH/NAFLD may also be clarified.
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http://dx.doi.org/10.1265/jjh.70.197DOI Listing
June 2016

Effects of in utero exposure to polychlorinated biphenyls, methylmercury, and polyunsaturated fatty acids on birth size.

Sci Total Environ 2015 Nov 11;533:256-65. Epub 2015 Jul 11.

Center for Environmental and Health Sciences, Hokkaido University, North 12 West 7 Kita-ku, Sapporo 060-0812, Japan. Electronic address:

The adverse effects of in utero exposure to polychlorinated biphenyls (PCBs) or methylmercury (MeHg), and the beneficial effects of nutrients from maternal fish intake might have opposing influences on fetal growth. In this study, we assessed the effects of in utero exposure to PCBs and MeHg on birth size in the Japanese population, which is known to have a high frequency of fish consumption. The concentrations of PCBs and polyunsaturated fatty acids in maternal blood, and the total mercury in hair (as a biomarker of MeHg exposure) were measured during pregnancy and at delivery. Maternal intakes of fish (subtypes: fatty and lean) and shellfishes were calculated from a food frequency questionnaire administered at delivery. Newborn anthropometric measurement data were obtained from birth records. The associations between chemical exposures and birth size were analyzed by using multiple regression analysis with adjustment for confounding factors among 367 mother-newborn pairs. The birth weight was 3073±37 g (mean±SD). The incidence of babies small for gestational age (SGA) by weight was 4.9%. The median concentrations of total PCBs and hair mercury were 108 ng/g lipid and 1.41 μg/g, respectively. There was no overall association between mercury concentrations and birth weight, birth length, chest circumference, and head circumference. We observed that the risk of SGA by weight decreased with increasing mercury concentration in regression analyses with adjustment for polyunsaturated fatty acids. Our results suggest that the beneficial effect of essential nutrition may mask the adverse effects of MeHg on birth size. The concentrations of PCBs had no association with birth size.
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http://dx.doi.org/10.1016/j.scitotenv.2015.06.108DOI Listing
November 2015
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