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ABSTRACT: Maternal exposure to di(2-ethylhexyl) phthalate (DEHP) decreased the plasma triglyceride in prepartum mice. To identify the fatty acid (FA) species involved and to understand the underlying mechanisms, pregnant Sv/129 wild-type (mPPARα), peroxisome proliferator-activated receptor α-null (Pparα-null) and humanized PPARα (hPPARα) mice were treated with diets containing 0%, 0.01%, 0.05% or 0.1% DEHP. Dams were dissected on gestational day 18 together with fetuses, and on postnatal day 2 together with newborns. n-3/n-6 polyunsuturated, saturated, and monounsaturated FAs in maternal plasma and in liver of wild-type offspring, and representative enzymes for FA desaturation and elongation in maternal liver, were measured. The plasma levels of linoleic acid, α-linolenic acid, palmitic acid and oleic acid were higher in the pregnant control mPPARa mice than in Ppara-null and hPPARa mice. DEHP exposure significantly decreased the levels of these four FAs only in pregnant mPPARα mice. Plasma levels of many FAs were higher in pregnant mice than in postpartum ones in a genotype-independent manner, while it was lower in the livers of fetuses than pups. DEHP exposure slightly increased hepatic arachidonic acid, α-linolenic acid, palmitoleic acid and oleic aicd in fetuses, but not in pups. However, DEHP exposure did not clearly influence FA desaturase 1 and 2 nor elongase 2 and 5 expressions in the liver of all maternal mice. Taken together, the levels of plasma four FAs with shorter carbon chains were higher in pregnant mPPARα mice than in other genotypes, and DEHP exposure decreased these specific FA concentrations only in mPPARα mice, similarly to triglyceride levels.
Toxicology 04/2013; · 3.68 Impact Factor
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ABSTRACT: 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 (10μmol/kg/day) or cis-permethrin (90μmol/kg/day) alone or in combination (100μmol/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.
Reproductive Toxicology 08/2012; 34(4):489-497. · 3.23 Impact Factor
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Xiaofang Jia, Hisao Naito,
Husna Yetti,
Hazuki Tamada,
Kazuya Kitamori,
Yumi Hayashi,
Nozomi Yamagishi,
Dong Wang,
Yukie Yanagiba,
Yuki Ito,
Juncai Wang,
Naoki Tanaka,
Katsumi Ikeda,
Yukio Yamori,
Tamie Nakajima
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ABSTRACT: 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.
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.
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.
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.
Life sciences 04/2012; 90(23-24):934-43. · 2.56 Impact Factor
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Takashi Moriya,
Kazuya Kitamori, Hisao Naito,
Yukie Yanagiba,
Yuki Ito,
Nozomi Yamagishi,
Hazuki Tamada,
Xiaofang Jia,
Satoru Tsuchikura,
Katsumi Ikeda,
Yukio Yamori,
Tamie Nakajima
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ABSTRACT: 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.
Environmental Health and Preventive Medicine 03/2012;
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02/2012; , ISBN: 978-953-307-895-3
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ABSTRACT: 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.
PPAR Research 01/2012; 2012:201284. · 2.73 Impact Factor
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ABSTRACT: 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.
Archive für Toxikologie 12/2011; 86(4):563-9. · 4.67 Impact Factor
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Kazuya Kitamori, Hisao Naito,
Hazuki Tamada,
Miya Kobayashi,
Daisuke Miyazawa,
Yuko Yasui,
Kunihiro Sonoda,
Satoru Tsuchikura,
Naomi Yasui,
Katsumi Ikeda,
Takashi Moriya,
Yukio Yamori,
Tamie Nakajima
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ABSTRACT: Patients with nonalcoholic fatty liver disease are increasing worldwide, and preventive measures are an urgent need and primary concern today.
This study aimed to develop and clarify the usefulness of the SHRSP5/Dmcr rat, derived from a stroke-prone spontaneously hypertensive rat, as a novel animal model for time-course analysis of steatohepatitis and the severe fibrosis progression often observed in the disease.
Ten-week-old male SHRSP5/Dmcr rats were divided into six groups: half were fed a high-fat and high-cholesterol-containing diet (HFC diet), and the others the control, stroke-prone (SP) diet for 2, 8, and 14 weeks.
The HFC diet significantly increased serum transaminase and gamma glutamyl transpeptidase activities, tumor necrosis factor alpha levels, and serum and hepatic total cholesterol levels over time. In contrast, this diet decreased serum albumin, glucose, and adiponectin levels throughout or the later stage of the feeding period, but did not influence serum insulin levels. Histopathologically, the HFC diet increased microvesicular steatosis, and focal or spotty necrosis with lymphocyte infiltrations were observed in the liver at 2 weeks, macrovesicular steatosis, ballooned hepatocytes with Mallory-Denk body formation in some, and multilobular necrosis and fibrosis at 8 weeks. Interestingly, this fibrosis formed a honeycomb network at 14 weeks. These changes are very similar to those observed in patients with non-alcoholic steatohepatitis.
SHRSP5/Dmcr rats appear to be a useful model for analyzing the time-dependent changes of HFC diet-induced steatohepatitis and fibrosis progression.
Environmental Health and Preventive Medicine 08/2011; 17(3):173-82.
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Emi Morita,
Nobuyuki Hamajima,
Asahi Hishida,
Kyoko Aoyama,
Rieko Okada,
Sayo Kawai,
Koutaro Tomita,
Sayaka Kuriki,
Takashi Tamura,
Mariko Naito, [......],
Yoko Hori,
Junko Hoshinos,
Ritsuko Hamamotos,
Sanae Tsukamoto,
Joji Onishi,
Shoichi Hagikura, Hisao Naito,
Satoshi Hibi,
Yoshinori Ito,
Kenji Wakai
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ABSTRACT: The Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study) is a long-term cohort study to investigate the interactions among genotypes, lifestyles, and lifestyle-related diseases, especially cancer. This article reports the outline of the baseline survey of the Daiko Study, one site of the J-MICC Study. That survey was conducted between June 9, 2008 and May 31, 2010 at the Daiko Medical Center of Nagoya University in Nagoya, Japan. Subjects were registered residents of Nagoya City aged 35 to 69 years who had not participated in other J-MICC sites. Recruitment was mainly announced through leaflets distributed in mailboxes citywide, personal communications, and regional information, such as posters in public or commercial facilities. Participants provided blood plasma, serum, buffy coat, urine, and data on health check-ups. They also completed a self-reported questionnaire on lifestyle, disease history, family history, and for women, reproductive history. As of the end of September 2010, 4 out of 5172 registered participants had withdrawn from the study, leaving data from 5168 participants (1467 males and 3701 females) available for analysis. Mean age +/- standard deviation (SD) was 52.5 +/- 10.3 years. Current smokers accounted for 24.1% (n=354) of males and 6.9% (n=256) of females. Current drinkers included 74.9% (n=1099) of males and 45.9% (n=1699) of females. Lifestyle data and specimens were successfully collected to examine any associations among disease biomarkers, lifestyles, and genotypes.
Nagoya journal of medical science 08/2011; 73(3-4):187-95.
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Yufei Li,
Doni Hikmat Ramdhan, Hisao Naito,
Nozomi Yamagishi,
Yuki Ito,
Yumi Hayashi,
Yukie Yanagiba,
Ai Okamura,
Hazuki Tamada,
Frank J Gonzalez,
Tamie Nakajima
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ABSTRACT: Perfluorooctanoate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, has the potential to lower testosterone levels as a result of testicular toxicity. To elucidate the mechanism and impact of PPARα on this reproductive toxicity, ammonium perfluorooctanoate (APFO) at doses of 0, 1.0 (low) mg/kg/day, or 5.0 (high) mg/kg/day was orally given daily to 129/sv wild-type (mPPARα), Pparα-null and PPARα-humanized (hPPARα) mice for 6 weeks. Both low- and high-dose APFO significantly reduced plasma testosterone concentrations in mPPARα and hPPARα mice, respectively. These decreases may, in part, be associated with decreased expression of mitochondrial cytochrome P450 side-chain cleavage enzyme, steroidogenic acute regulatory protein or peripheral benzodiazepine receptor as well as microsomal cytochrome P450(17α) involved in the steroidogenesis. Additionally, both doses increased abnormalities in sperm morphology and vacuolated cells in the seminiferous tubules of both mouse lines. In contrast, APFO caused only a marginal effect either on the testosterone synthesis system or sperm and testis morphology in Pparα-null mice. These results suggest that APFO may disrupt testosterone biosynthesis by lowering the delivery of cholesterol into the mitochondria and decreasing the conversion of cholesterol to pregnenolone and androstandione in the testis of mPPARα and hPPARα mice, which may, in part, be related to APFO-induced mitochondrial damage.
Toxicology Letters 06/2011; 205(3):265-72. · 3.23 Impact Factor
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Tomohiko Nakagawa,
Doni Hikmat Ramdhan,
Naoki Tanaka, Hisao Naito,
Hazuki Tamada,
Yuki Ito,
Yufei Li,
Yumi Hayashi,
Nozomi Yamagishi,
Yukie Yanagiba,
Toshifumi Aoyama,
Frank J Gonzalez,
Tamie Nakajima
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ABSTRACT: Perfluorooctanoic acid is a ligand for peroxisome proliferator-activated receptor (PPARα). Ammonium perfluorooctanoate (APFO) at 0.1 and 0.3 mg/kg doses activated mouse PPARα, but not human PPARα. This study aimed to clarify whether milligram-order APFO can activate human PPARα, and the receptor is involved in APFO-induced chronic hepatic damage. Male Sv/129 wild-type (mPPARα), Pparα-null, and humanized PPARα (hPPARα) mice (8 weeks old) were divided into three groups. The first was treated with water and the other two with 1.0 and 5.0 mg/kg APFO for 6 weeks, orally, respectively. Both doses activated mouse and human PPARα to a similar or lower degree in the latter. APFO dose dependently increased hepatic triglyceride levels in Pparα-null and hPPARα mice, but conversely decreased those in mPPARα ones. APFO-induced hepatic damage differed markedly among the three genotyped groups: single-cell necrosis was observed in all genotyped mice; inflammatory cells and macrovesicular steatosis only in Pparα-null mice; and microvesicular steatosis and hydropic degenerations in hPPARα and Pparα-null mice. The molecular mechanism underlying these differences may be attributable to those of gene expressions involved in lipid homeostasis (PPARα, β- and ω-oxidation enzymes, and diacylglycerol acyltransferases) and uncoupling protein 2. Thus, milligram-order APFO activated both mouse and human PPARα in a different manner, which may reflect histopathologically different types of hepatic damage.
Archive für Toxikologie 04/2011; 86(1):63-74. · 4.67 Impact Factor
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Yumi Hayashi,
Yuki Ito,
Nozomi Yamagishi,
Yukie Yanagiba,
Hazuki Tamada,
Dong Wang,
Doni Hikmat Ramdhan, Hisao Naito,
Yukiko Harada,
Michihiro Kamijima,
Frank J Gonzales,
Tamie Nakajima
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ABSTRACT: Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with adverse effects on offspring, and the metabolites are agonists of peroxisome proliferator-activated receptor (PPAR) α, which exhibits species differences in expression and function. This study aimed to clarify the mechanism of DEHP-induced adverse effects on offspring in relation to maternal mouse and human PPARα. Male and female Sv/129 wild-type (mPPARα), Pparα-null and humanized PPARα (hPPARα) mice were treated with diets containing 0%, 0.01%, 0.05% (medium) or 0.1% (high) DEHP. After 4 weeks, males and females were mated. Dams were killed on gestational day 18 and postnatal day (PND) 2. High-dose DEHP decreased the number of total and live fetuses, and increased resorptions in mPPARα mice. In hPPARα mice, resorptions were increased above the medium dose, and the number of births was decreased at the high dose. The number of live pups on PND2 was decreased over the medium dose in mPPARα and at the high dose in hPPARα mice. No such findings were observed in Pparα-null mice. High-dose DEHP decreased plasma triglyceride in pregnant mPPARα mice, but not in Pparα-null and hPPARα ones. Above the medium dose in mPPARα mice significantly reduced hepatic microsomal triglyceride transfer protein (MTP) expression. Medium- and/or high-dose DEHP increased the levels of maternal PPARα target genes in mPPARα and hPPARα mice. Taken together, PPARα expression is required for the toxicity of DEHP in fetuses and pups and altered plasma triglyceride levels, through regulation of MTP may be important in mPPARα mice and not in hPPARα mice.
Toxicology 02/2011; 289(1):1-10. · 3.68 Impact Factor
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Doni Hikmat Ramdhan,
Michihiro Kamijima,
Dong Wang,
Yuki Ito, Hisao Naito,
Yukie Yanagiba,
Yumi Hayashi,
Naoki Tanaka,
Toshifumi Aoyama,
Frank J Gonzalez,
Tamie Nakajima
[show abstract]
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ABSTRACT: Trichloroacetic acid, an oxidative metabolite of trichloroethylene (TRI), is a ligand of the peroxisome proliferator-activated receptor alpha (PPAR) alpha, which is involved in lipid homeostasis and anti-inflammation.
We examined the role of mouse and human PPARalpha in TRI-induced hepatic steatosis and toxicity.
Male wild-type (mPPARalpha), Pparalpha-null, and humanized PPARalpha (hPPARalpha) mice on an Sv/129 background were exposed via inhalation to 0, 1,000, and 2,000 ppm TRI for 8 hr/day for 7 days. We assessed TRI-induced steatosis or hepatic damage through biochemical and histopathological measurements.
Plasma alanine aminotransferase and aspartate aminotransferase activities increased in all mouse lines after exposure to 1,000 and 2,000 ppm TRI. Exposure induced hepatocyte necrosis and inflammatory cells in all mouse lines, but hepatic lipid accumulation was observed only in Pparalpha-null and hPPARalpha mice. No differences were observed in TRI-mediated induction of hepatic PPARalpha target genes except for a few genes that differed between mPPARalpha and hPPARalpha mice. However, TRI significantly increased expression of triglyceride (TG)-synthesizing enzymes, diacyl-glicerol acyltransferases, and PPARgamma in Pparalpha-null and hPPARalpha mice, which may account for the increased TG in their livers. TRI exposure elevated nuclear factor-kappa B (NFkappaB) p52 mRNA and protein in all mice regardless of PPARalpha genotype.
NFkappaB-p52 is a candidate molecular marker for inflammation caused by TRI, and PPARalpha may be involved in TRI-induced hepatosteatosis. However, human PPARalpha may afford only weak protection against TRI-mediated effects compared with mouse PPARalpha.
Environmental Health Perspectives 11/2010; 118(11):1557-63. · 7.04 Impact Factor
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Daichi Nakamura,
Yukie Yanagiba,
Zhiwen Duan,
Yuki Ito,
Ai Okamura,
Nobuyuki Asaeda,
Yoshiaki Tagawa,
Chunmei Li,
Kazuyoshi Taya,
Shu-Yun Zhang, Hisao Naito,
Doni Hikmat Ramdhan,
Michihiro Kamijima,
Tamie Nakajima
[show abstract]
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ABSTRACT: Bisphenol A (BPA) causes reproductive toxicities, but the mechanisms are still unclear. In the present study, we sought to clarify these mechanisms in comparison with those of 17beta-estradiol (E2). Prepubertal Wistar/ST male rats (4 weeks old) were subcutaneously administered BPA (0, 20, 100 and 200 mg/kg/day) or E2 (10 and 100 microg/kg/day) for 6 weeks. Both BPA and E2 treatments decreased plasma and testicular testosterone levels, and plasma luteinizing hormone (LH), but not E2 and follicle-stimulating hormone levels, though E2 treatment increased its plasma level. In relation to the decreased testosterone levels, BPA and E2 decreased expressions of steroidogenic enzymes and cholesterol carrier protein in Leydig cells. Thus, decreased testosterone levels in plasma might have resulted from decreased expressions of these enzymes and protein as well as from decreased plasma LH levels. Interestingly, the changes in steroidogenic enzymes and carrier protein were observed at lower levels of exposure to BPA or E2 than those inhibiting plasma LH levels. Microscopically, 200 mg/kg BPA and 100 microg/kg E2 significantly decreased Leydig cell numbers in the testis. In addition, BPA and E2 also decreased expression of estrogen receptor alpha-mRNA, which might be related to the decreased numbers of Leydig cells. Thus, BPA directly affects not only the Leydig cells but also the pituitary gland, but the former may be impaired at lower exposure concentrations than the latter.
Toxicology Letters 02/2010; 194(1-2):16-25. · 3.23 Impact Factor
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ABSTRACT: The purpose of this review to collate current leading scientific advances of molecular mechanisms in alcoholic liver diseases and to propose a working "hypothesis of seven balances" in relation to peroxisome proliferator activated receptor alpha (PPARalpha), which has important roles in fatty acid oxidation, oxidative stress, inflammatory responses, and possibly liver fibrosis.
We conducted an extensive literature review of over a hundred publications and collated the findings with evidence generated in our laboratory.
Our research points to a working hypothesis of seven balances for alcoholic liver diseases consisting of: 1) ethanol oxidation balance in hepatocytes; 2) PPAR alpha activities in liver; 3) fatty acid metabolism balance in hepatic mitochondria; 4) gastrointestinal response to ethanol, acetaldehyde and lipopolysaccharide (LPS); 5) Kupffer cells response to LPS, oxidative stress and inflammatory cytokines; 6) adiponectin levels in plasma interchangeably regulated by tumor necrosis factor-alpha (TNF-alpha); and 7) stellate cells response to all of the above promoting hepatic fibrosis. Cellular mechanisms behind alcoholic liver diseases reveal close temporal associations of PPARalpha, adiponectin, TNF-alpha, cellular inflammation, proliferation, and potentially fibrosis as illustrated in "the hypothesis of seven balances."
The regulation and adjustment of PPARalpha activation underlying the balance of molecular cascades might resolve the progression of alcoholic liver diseases by reducing oxidative stress and inflammatory effects induced by nuclear factor-kappaB as well as the associated adiponectin pathway. Further elucidation of these pathways would reveal exciting new prospects for treating alcoholic liver diseases and other related liver disorders.
Journal of Occupational Health 09/2009; 51(5):391-403. · 1.55 Impact Factor
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Toshiki Nakamura,
Yuki Ito,
Yukie Yanagiba,
Doni Hikmat Ramdhan,
Yasuhide Kono, Hisao Naito,
Yumi Hayashi,
Yufei Li,
Toshifumi Aoyama,
Frank J Gonzalez,
Tamie Nakajima
[show abstract]
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ABSTRACT: Perfluorooctanoic acid (PFOA) is a ligand for peroxisome proliferator-activated receptor (PPAR) alpha, which exhibits marked species differences in expression and function, especially between rodents and humans. We investigated the functional difference in PFOA response between mice and humans, using a humanized PPARalpha transgenic mouse line. Three genotyped mice, 129/Sv wild-type (mPPARalpha), Pparalpha-null mice and humanized PPARalpha (hPPARalpha) mice (8-week-old males) were divided into three groups: the first was treated with water daily for 2 weeks by gavage (control group), and the remaining two groups were treated with 0.1 and 0.3mg/kg ammonium perflurooctanate (APFO), respectively, for 2 weeks by gavage. The APFO dosages used did not influence the plasma triglyceride or total cholesterol levels in any mouse line, but the high dose increased both hepatic lipid levels only in mPPARalpha mice. APFO increased mRNA and/or protein levels of PPARalpha target genes cytochrome P450 Cyp4a10, peroxisomal thiolase and bifunctional protein only in the liver of mPPARalpha mice, but not in Pparalpha-null or hPPARalpha mice. This chemical also increased expression of mitochondrial very long chain acyl-CoA dehydrogenase only in the liver of mPPARalpha mice. Taken together, human PPARalpha may be less responsive to PFOA than that of mice when a relatively low dose is applied. This information may be very valuable in considering whether PFOA influences the lipid metabolism in humans.
Toxicology 09/2009; 265(1-2):27-33. · 3.68 Impact Factor
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Dong Wang,
Michihiro Kamijima,
Ryota Imai,
Takayoshi Suzuki,
Yohei Kameda,
Kazumi Asai,
Ai Okamura, Hisao Naito,
Jun Ueyama,
Isao Saito,
Tamie Nakajima,
Masahiro Goto,
Eiji Shibata,
Takaaki Kondo,
Kenji Takagi,
Kenzo Takagi,
Shinya Wakusawa
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ABSTRACT: Synthetic pyrethroids such as cypermethrin, deltamethrin and permethrin, which are usually used in pest control operations, are metabolized to 3-phenoxybenzoic acid (3-PBA) and excreted in urine. Though 3-PBA can be used to assess exposure to pyrethroids, there are few reports describing urinary 3-PBA levels in Japan. This study aimed to investigate the seasonal variation of the exposure levels of pyrethroids and the concentration of urinary 3-PBA among pest control operators (PCOs) in Japan. The study subjects were 78 and 66 PCOs who underwent a health examination in December 2004 and in August 2005, respectively. 3-PBA was determined using gas chromatography-mass spectrometry. The geometric mean concentration of urinary 3-PBA in winter (3.9 microg/g creatinine) was significantly lower than in summer (12.2 microg/g creatinine) (p<0.05). Geometric mean concentrations of urinary 3-PBA in the spraying workers and the not-spraying workers within 2 d before the survey were 5.4 microg/g creatinine and 0.9 microg/g creatinine for winter with a significant difference between the groups (p<0.05), and 12.3 microg/g creatinine and 8.7 microg/g creatinine for summer (p>0.05), respectively. A significant association of 3-PBA levels and pyrethroid spraying was thus observed only in winter. In conclusion, the results of the present study show that the exposure level of pyrethroids among PCOs in Japan assessed by monitoring urinary 3-PBA was higher than that reported in the UK but comparable to that in Germany. Further research should be accumulated to establish an occupational reference value in Japan.
Journal of Occupational Health 12/2007; 49(6):509-14. · 1.55 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor alpha (PPARA alpha) plays a pivotal role in lipid metabolism. Our previous study reported that PPARA-V227A was a major polymorphism in Japanese, which was associated with markedly lower serum total cholesterol (TC) levels, which were significantly affected by alcohol drinking compared to subjects with the wild-type (PPARA-WT) allele. However, serum lipids are also associated with aging and exercise frequency. The objective of the present study was to evaluate the relationship between PPARA-V227A and these factors. Genetic analysis of the polymorphism was performed in 1058 Japanese men and 281 women, and the relationship with aging, drinking and exercise on serum lipids was analyzed in 989 men and 245 women after exclusion criteria had been applied. In men, drinking increased high-density lipoprotein cholesterol (HDL-C) levels in both PPARA-WT and A227 carriers, but to a significantly higher degree in the latter. In women, TC and low-density lipoprotein cholesterol (LDL-C) levels in the A227 carriers drinking at least once a week were significantly higher than in PPARA-WT carriers. TC and LDL-C levels in males with PPARA-WT increased with aging regardless of drinking habit, while LDL-C levels in the A227 drinking carriers were significantly lower in 45-yr-old or older subjects than in 35- to 45-yr-olds. In addition, no effect of exercising was observed in the A227 carriers, while increase in the HDL-C of the PPARA-WT carriers was exercise frequency dependent. These results suggest that the influence of drinking, aging or exercise on TC, LDL-C and HDL-C levels in the A227 carriers may be different from those in the PPARA-WT subjects.
Journal of Occupational Health 10/2007; 49(5):353-62. · 1.55 Impact Factor
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Chul-Ho Lee,
Michihiro Kamijima,
Heon Kim,
Eiji Shibata,
Jun Ueyama,
Takayoshi Suzuki,
Kenji Takagi,
Isao Saito,
Masahiro Gotoh,
Hatsuki Hibi, Hisao Naito,
Tamie Nakajima
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ABSTRACT: In order to investigate a role of paraoxonase 1 (PON1) polymorphism in organophosphorus (OP)-induced 8-hydroxydeoxyguanosine (8-OHdG) levels, urinary metabolites of OP, PON1 genotypes, and 8-OHdG levels in leukocyte and urine were measured in OP indoor insecticide sprayers and controls in summer and winter.
The study population contained 18 male sprayers and age-matched 18 male controls. Sprayers were primarily exposed to OP insecticides (mainly fenitrothion, dichlorvos, chlorpyrifos, and diazinon), and partially to pyrethroids (mainly permethrin) and carbamates (mainly propoxur). Urinary metabolites of OP were measured by gas chromatography-mass spectrometry. 8-OHdG levels in leukocyte and urine were measured by ELISA kit. PON1 genotype was identified using allele-specific fluorogenic TaqMan probes.
The mean concentrations of urinary dimethyl phosphate (DMP) and total dialkyl phosphates (DAP) in summer and those of 8-OHdG in summer and winter were significantly higher in OP sprayers than controls. This resulted in a significant positive correlation between 8-OHdG levels and urinary DMP or DAP, suggesting a correlation between OP metabolites and production of oxidative stress. Of PON1 genotypes, incidences of Q/Q, Q/R, and R/R types were 17, 39, and 44% in OP sprayers and controls, respectively. Although PON1 polymorphism did not contribute to the leukocyte and urinary 8-OHdG levels, the urinary OP metabolite concentrations in summer showed a significant decrease as the number Q allele decreased.
These results indicate that an increase in OP metabolites is associated with a high level of oxidative stress in OP sprayers, although the contribution of the PON1 polymorphism to the metabolism of OP is still unclear.
Archiv für Gewerbepathologie und Gewerbehygiene 02/2007; 80(3):217-27. · 1.89 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor (PPAR) alpha plays a major role in alcoholic liver disease in rodents. The two-fold objective of our study was to determine the presence of PPARalpha polymorphisms and their frequencies in Japanese populations and then to evaluate the effects of any alleles on metabolic parameters and alcohol drinking.
Analysis of coding SNP in PPARalpha was performed in 706 Japanese men; from these subjects 655 men were further studied after exclusion criteria were applied.
PPARalpha-V227A, which has not been reported in Europe and North America as a major polymorphism, was discovered with the frequency of 0.05. PPARalpha-L162V was found in European and North American populations, but not in Japanese, thus confirming the ethnic differences in PPARalpha allele frequencies. The A227 allele was associated with increased serum concentrations of gamma glutamyltranspeptidase. In non-drinkers, the total cholesterol (TC) levels were significantly lower in those having the PPARalpha-V227A polymorphism. In drinkers, however, it was comparable among V227A polymorphisms, and conversely higher in those having both A227 and aldehyde dehydrogenase 2 (ALDH2) variants when further divided according to the ALDH2 polymorphism. Significant interactions between PPARalpha-V227A polymorphism and drinking were also found for TC, triglyceride levels and AST/ALT ratios. These results suggest that the activity of the A227 allele without drinking may be higher than in wild-type allele, but its activity may become lower during drinking habits.
PPARalpha-V227A is a major polymorphism in the Japanese population, and its activity may be greater compared to wild-type, but decreased by alcohol drinking.
Pharmacogenetics and Genomics 09/2006; 16(8):569-77. · 3.48 Impact Factor
