担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Heart Journal Open  

Aims: There has been a shortage of human studies to elucidate the association between serum arsenic levels and the prevalence of hypertension. This study multidirectionally investigated associations among arsenic exposure, dietary ingestion, and the risk of hypertension by combined human epidemiological and mouse experimental studies. Methods and results: This study focused on the total arsenic level in fasting serum, a biomarker of arsenic exposure. Associations among ingestion frequencies of 54 diet items of Japanese food separated into six categories, total arsenic level in fasting serum, and the prevalence of hypertension were investigated in 2709 general people in Japan. Logistic regression analysis demonstrated a dose-dependent association between serum arsenic level and hypertension and a positive association between the ingestion of fish meat and hypertension. Further analysis showed that the latter association was fully mediated by increased fasting serum arsenic levels in humans. Similarly, oral exposure to the putative human-equivalent dose of arsenic species mixture with the same ratios in a common fish meat in Japan increased systolic blood pressure and arsenic levels in fasting serum in mice. Conclusion: This interdisciplinary approach suggests that fish-meat ingestion is a potential risk factor for arsenic-mediated hypertension. Because the increased consumption of fish meat is a recent global trend, health risks of the increased ingestion of arsenic via fish meat should be further investigated.

添付ファイル： oead074.pdf

DOI： 10.1093/ehjopen/oead074

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Toxicology  

Drug-induced acute kidney injury (AKI) is a frequent cause of adverse drug reaction. Serum creatinine (CRE) and blood urea nitrogen (BUN) are widely used as standard biomarkers for kidney injury; however, the sensitivity and specificity are considered to be low. In recent years, circulating microRNA (miRNAs) have been attracting considerable attention as novel biomarkers for organ injury, but there are currently no established miRNA biomarkers for drug-induced AKI. The present study aimed to identify plasma miRNAs that may enable early and specific detection of drug-induced tubular and glomerular injury through next-generation sequencing analysis. Six-week old male Sprague-Dawley (SD) rats were intravenously administered cisplatin (CSP, 6 mg/kg) and gentamicin (GEN, 120 mg/kg) to induce tubular injury. To create glomerular injury models, puromycin (PUR, 120 mg/kg) and doxorubicin (DOX, 7.5 mg/kg) were intravenously administered, and these models were always accompanied by tubular damage. Small RNA-sequencing was performed to analyze time-dependent changes in the plasma miRNA profiles. The cluster analyses showed that there were distinct plasma miRNA profiles according to the types of injury, and the changes reflected the progress of renal damages. In the differential analysis, miR-3473 was specifically up-regulated in the glomerular injury models. miR-143-3p and miR-122-5p were commonly down-regulated in all models, and the changes were earlier than the traditional biomarkers, such as plasma CRE and BUN. These data indicated that changes in the specific miRNAs in plasma may enable the early and sensitive detection of tubular and glomerular injuries. The present study suggests the potential utility of plasma miRNAs in the early and type-specific detection of drug-induced AKI.

DOI： 10.1016/j.tox.2019.01.011

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Toxicological Sciences  

Recently, studies on circulating microRNAs (miRNAs) as potential biomarkers of drug-induced liver injury (DILI) have received increasing attention. It has been demonstrated that miR-122 and miR-192, which are liver enriched, could be potential biomarkers of DILI; however, these miRNAs cannot discern types of injuries. In the present study, we comprehensively analyzed time-dependent plasma miRNA profiles in rats with drug- or chemical-induced hepatocellular injury, cholestasis, and steatosis with high-throughput miRNA sequencing. To enable the comparison of miRNA expression levels between DILI models with different severity and peak time of injuries, the stages of injury were defined as early, middle, and late, according to cluster patterns of miRNA expression profiles. Through differential analysis, we characterized miRNAs that were specifically up- or down-regulated in each DILI model. Several miRNAs were dramatically changed earlier than traditional biomarkers such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). For example, in an acetaminophen (APAP)-induced hepatocellular injury model, plasma let-7b-5p was up-regulated as early as 3 h after dosing, whereas a significant change in ALT level was observed at 12 h. We then focused on the DILI type-specific miRNAs in plasma that were up-regulated at the early stage of injury. RT-qPCR analysis validated that let-7b-5p and miR-1-3p for hepatocellular injury, miR-143-3p and miR-218a-5p for cholestasis, and miR-320-3p for steatosis models showed significant increases in the early stage of the injuries. The present study suggests the utility of miRNAs as specific biomarkers for the early detection of DILI.

DOI： 10.1093/toxsci/kfy200

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ecotoxicology and Environmental Safety  

Background: Exposure to arsenic increases the risk of hypertension. Indeed, a high level of arsenic in human serum, a reliable biomarker of arsenic exposure, was shown to be linked to increased prevalence of hypertension among a study of Japanese residents. However, no beneficial food that decreases the risk of arsenic-mediated hypertension has been determined by considering intake scores of multiple foods. Methods: The comprehensive effects of combined beverage intake on the risk of hypertension, mediated by decreased levels of total arsenic in fasting serum, were investigated among the same group of 2706 residents. Results: Our generalized linear regression analysis for each beverage showed significant negative associations of serum arsenic levels with milk and vegetable juice intake scores among 11 beverages. Weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) analyses of combined beverage intake scores reveal that milk was the beverage most strongly associated with lower serum arsenic levels. Subsequent causal mediation analysis further showed that increased milk intake reduced the prevalence of arsenic-mediated hypertension by lowering serum arsenic levels. Additionally, our cell-free assay revealed the adsorption-modifying effect of milk on arsenic components in a popular fish meat. An in vivo assay confirmed that milk intake significantly decreased total serum arsenic levels in mice. Conclusions: Our multidisciplinary approach, combining epidemiological, chemical and animal studies, suggests that milk consumption has a beneficial effect in reducing the prevalence of arsenic-induced hypertension by decreasing arsenic absorption. Considering the global trend for increased consumption of fish meat with high levels of total arsenic, milk may be globally useful for reducing the risk of arsenic-mediated hypertension.

添付ファイル： He et al. 2025_milk.pdf

DOI： 10.1016/j.ecoenv.2025.118581

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Allergy and Clinical Immunology Global  

Background: There is no information about the clinical implications and kinetics of zinc (Zn) in the nasal cavity, a center of allergic inflammation, and serum in subjects with allergic rhinitis (AR). Objective: Effects of intranasal Zn on symptoms before and after allergen provocation were investigated in humans and mice with or without AR. Methods: The first clinical follow-up study for Zn levels in nasal epithelial lining fluid (ELF) and serum was conducted in 57 control subjects and 44 patients with Japanese cedar pollinosis (JCP), a representative seasonal AR, from preseason to season. The clinical implications and kinetics of Zn levels in ELF and serum were further investigated in model mice with JCP. Results: This clinical study showed that the Zn level in nasal ELF from patients with JCP was increased after pollen exposure and became significantly higher than that in nasal ELF from controls in the JCP season. Conversely, the serum Zn level in patients was decreased after pollen exposure and became significantly lower than that in the controls in the JCP season. To further investigate the clinical implication of Zn level, model mice that mimicked the kinetics of intranasal and serum Zn levels as well as the symptoms in patients with JCP were established. The mouse interventional study showed that the symptoms of mice with provocative JCP were significantly improved by treatment with the putative human-equivalent dose of Zn. The relative number of mucin-secreting goblet cells, a sign of provocative allergic rhinitis, in the mice was decreased by intranasal treatment with Zn. Conclusion: The study's behavioral and pathologic results indicate that an increased level of intranasal Zn can alleviate symptoms of AR.

DOI： 10.1016/j.jacig.2025.100408

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人日本衛生学会  

Background: Motion sickness is a common transportation issue worldwide. Vestibular dysfunction has been reported to be a key etiology of motion sickness. However, there are limited technologies for alleviating motion sickness. Methods: The most appropriate frequency (Hz) and level (dBZ) of pure tone for modulation of vestibular function were determined by an ex vivo study using murine utricle explants. The preventive effects of the selected pure tone on motion sickness were then confirmed by using a beam balance test in mice. The alleviating effects of pure tone on motion sickness induced by a swing, driving simulator or real car were objectively assessed by using posturography and electrocardiography (ECG) and were subjectively assessed by using the Motion Sickness Assessment Questionnaire (MSAQ) in humans. Results: The effect of short-term (¯5 min) exposure to a pure tone of 80–85 dBZ (= 60.9–65.9 dBA) at 100 Hz on motion sickness was investigated in mice and humans. A mouse study showed a long-lasting (²120 min) alleviative effect on shaking-mediated exacerbated beam test scores by 5-min exposure to a pure tone of 85 dBZ at 100 Hz, which was ex vivo determined as a sound activating vestibular function, before shaking. Human studies further showed that 1-min exposure to a pure tone of 80–85 dBZ (= 60.9–65.9 dBA) at 100 Hz before shaking improved the increased envelope areas in posturography caused by the shakings of a swing, a driving simulator and a vehicle. Driving simulator-mediated activation of sympathetic nerves assessed by the heart rate variable (HRV) and vehicle-mediated increased scores of the MSAQ were improved by pure tone exposure before the shaking. Conclusion: Since the exacerbated results of posturography and HRV reflect shaking-mediated imbalance and autonomic dysfunction, respectively, the results suggest that the imbalance and autonomic dysregulation in motion sickness could be improved by just 1-min exposure to a pure tone with daily exposable sound pressure levels. Trial registration: Registration number: UMIN000022413 (2016/05/23–2023/04/19) and UMIN000053735 (2024/02/29–present).

添付ファイル： MS Gu et al., 2025.pdf

DOI： 10.1265/ehpm.24-00247

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Chemosphere  

Background: Blockage to divide downstream canals into upstream canals, into which tannery wastewater including a high concentration of trivalent chromium [Cr(III)] is directly discharged, has been constructed in Hazaribagh, a tannery built-up area in Bangladesh. However, there has been no study to verify the environmental significance of blockage construction for water pollution of Cr in nature. Methods: Consecutive fixed area monitoring for a total of 164 water samples collected outside and inside Hazaribagh from 2014 to 2023 was carried out to clarify the effects of stagnant and flowable canal water in the presence or absence of blockage on Cr(III) and hexavalent Cr [Cr(VI)] concentrations. Results: Since pollution of Cr(III) and Cr(VI) in Buriganga River (outside Hazaribagh) was not serious, this study then focused on their pollution in canal water (inside Hazaribagh) in the nonblockage period, blockage construction period and blockage destruction period. As expected, the mean Cr(III) concentration in downstream canal water samples in the blockage construction period was more than 98% lower than that in the upstream canal water samples in the same period, while the concentrations were comparable in downstream and upstream canal water samples in the nonblockage period and blockage destruction period. Unexpectedly, the mean concentration of Cr(VI) in the upstream canal water samples in the blockage construction period was 38.6-fold and 3.3-fold higher than that in the downstream canal water samples and the Cr(VI) guideline value by the US-EPA, respectively. Conclusion: This study demonstrated for the first time not only a merit of decreased Cr(III) pollution but also a demerit of increased Cr(VI) pollution in stagnant water derived from blockage construction in natural environments. This bitter lesson obtained by the enclosure of Cr(III)-polluted water is globally applicable for water pollution of Cr(III), which is used in various industries including the leather industry.

DOI： 10.1016/j.chemosphere.2023.141047

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Chemosphere  

Serious health hazards including renal, skin and hearing disorders have been reported in Bangladeshi tannery workers (TWs) who were chronically exposed to a large amount of trivalent chromium [Cr(III)]. However, the effects of Cr(III) exposure on the prevalence of hypertension and the prevalence of glycosuria in TWs remain unknown. Since the Cr level in toenails is an established marker reflecting long-term exposure to Cr(III) in humans, the associations of Cr levels in toenails with the prevalence of hypertension and the prevalence of glycosuria in male tannery and non-tannery office workers (non-TWs) in Bangladesh were investigated in this study. The mean toenail Cr level in non-TWs (0.5 μg/g, n = 49) was comparable to that in the general population reported previously. Mean Cr levels in TWs with a low toenail Cr level (5.7 μg/g, n = 39) and those with a high toenail Cr level (298.8 μg/g, n = 61) were >10-fold and >500-fold higher, respectively, than that in non-TWs. Our univariate and multivariate analyses indicated that the prevalence of hypertension and the prevalence of glycosuria in TWs with a high toenail Cr level, but not in TWs with a low toenail Cr level, were significantly lower than those in non-TWs. This study showed for the first time that long-term and excessive exposure to Cr(III) that is more than >500-fold but not >10-fold higher than the usual exposure level could decrease the prevalence of hypertension and the prevalence of glycosuria in TWs. Thus, this study revealed unexpected effects of exposure to Cr(III) on health.

DOI： 10.1016/j.chemosphere.2023.139190

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Science of the Total Environment  

Harmful health effects of exposure to low-frequency noise (LFN) defined as noise with frequencies at ≤100 Hz on the circulatory system have been a concern. However, there has been no study on the effects of exposure to LFN on the circulatory system with consideration of its frequencies and decibels. In this study, the effects of short-term exposure to broad-band LFNs and their pure-tone components (pure-tone LFNs) on cutaneous blood flow in the extremities including the hands were investigated. In our fieldwork study, we first sampled some kinds of common broad-band LFNs. Our human study then showed that broad-band LFN with a narrower frequency range more strongly increased cutaneous blood flow than did broad-band LFN with a wider frequency range. Pure-tone LFNs of 70–100 Hz at ≤85 dB(Z), but not pure-tone LFNs exceeding 100 Hz, further increased levels of cutaneous blood flow. Our wavelet-transform spectrum analysis of cutaneous blood flow next revealed that the nitric oxide (NO)-dependent and -independent vascular activities of the vascular endothelium were specifically increased by exposure to pure-tone LFN. Our animal study again indicated that exposure to pure-tone LFN increased cutaneous blood flow in mice with impairments of bilateral inner ears as well as cutaneous blood flow in control mice, suggesting a limited effect of inner ear function on the LFN-mediated increase in cutaneous blood flow. The NO-dependent suppressive effect of pure-tone LFN on cutaneous blood flow was confirmed by inhibition of vascular endothelial activity through intravenous injection of an NO inhibitor in wild-type mice. Taken together, the results of this study demonstrated that the vascular endothelium is a target tissue of LFN and that NO is an effector of the LFN-mediated increase in cutaneous blood flow. Since improvement of peripheral circulation could generally promote human health, short-term exposure to LFN may be beneficial for health.

DOI： 10.1016/j.scitotenv.2022.158828

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Applied Toxicology  

MicroRNAs (miRNA) have received considerable attention as potential biomarkers for drug-induced liver injury. We recently reported that the plasma levels of miR-143-3p and miR-218a-5p increased in severe cholestasis in rats. This study aimed to investigate whether these miRNAs increase in a severity-dependent manner and to elucidate their pathophysiological roles in cholestasis. Male Sprague–Dawley rats were orally administered different doses of α-naphthylisothiocyanate or 4,4-methylenedianiline to induce acute cholestasis. They were also orally administered acetaminophen or thioacetamide to induce hepatocellular injury. We found that plasma miR-143-3p and miR-218a-5p levels increased in a dose-dependent manner in cholestatic rats but not in hepatocellular injury. Bioinformatic analysis provided putative target genes of hsa-miR-218-5p, rno-miR-218a-5p, and mmu-miR-218-5p, among which GNAI2, PPP1CB, and PPP2R5A were experimentally validated as their direct target genes in human cholangiocyte line MMNK-1. Proliferation of MMNK-1 cells was significantly suppressed after overexpression of miR-218-5p and transduction of siRNAs for GNAI2, PPP1CB, and PPP2R5A. In the cholestatic livers of rats, Ppp1cb and Ppp2r5a expression levels decreased, whereas Gnai2 expression levels increased compared with those in vehicle-treated rats, suggesting that Ppp1cb and Ppp2r5a may be under the control of miR-218a-5p in vivo. In conclusion, our data suggest that miR-218(a)-5p is involved in the suppression of cholangiocyte proliferation by inhibiting the expression of PPP1CB and PPP2R5A, thereby contributing to the pathogenesis of cholestasis; and miR-218a-5p leaks into the plasma probably from damaged cholangiocytes in a severity-dependent manner in rats. Therefore, miR-218a-5p overexpression could be one of the underlying mechanisms of acute cholestatic liver injury in rats.

DOI： 10.1002/jat.4144

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担当区分：筆頭著者   記述言語：英語   出版者・発行元：Journal of Allergy and Clinical Immunology  

DOI： 10.1016/j.jaci.2021.05.025

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Toxicology  

Testicular injury is often observed in drug development. Serum hormones are usually used as noninvasive biomarkers for testicular injury; however, their sensitivities are low. Therefore, it is difficult to monitor testicular injury in drug development. In recent years, molecules in body fluid exosomes have attracted attention as biomarkers for diseases. In this study, small RNAs in serum exosomes were analyzed to identify noninvasive biomarkers of testicular injury in rats, which are often used in preclinical drug development. The rat models of testicular injury were prepared by a single oral administration of 2000 mg/kg ethylene glycol monomethyl ether, in which spermatocyte degeneration and Sertoli cell vacuolation were observed, or 400 mg/kg carbendazim, in which Sertoli cell vacuolation and seminiferous tubule dilation were observed. Serum exosomal small RNA-seq analysis of these models was performed. The analysis identified 3 small RNAs that fluctuated in common between the models, and miR-423-5p and miR-128-3p were selected as candidate markers. For evaluating these candidate markers in other testicular injury models, the models were prepared by a single oral administration of 60 mg/kg 1,3-dinitrobenzene or 500 mg/kg nitrofurazone, and spermatocyte degeneration and Sertoli cell vacuolation were observed. In qPCR analysis, these exosomal miRNAs were upregulated in all models except for the 1,3-dinitrobenzene model, in which severe hemolysis was observed. By contrast, these miRNAs in whole serum extracts did not significantly change in any of the models. In conclusion, we identified miR-423-5p and miR-128-3p in serum exosomes as noninvasive biomarkers for testicular injury in rats.

DOI： 10.1016/j.tox.2020.152490

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Carcinogenesis  

Owing to its rarity, the carcinogenesis and molecular biological characteristics of squamous cell carcinoma arising from mature teratoma remain unclear. This study aims to elucidate the molecular background of malignant transformation from the aspects of microRNA (miRNA) profiling. We examined 7 patients with squamous cell carcinoma and 20 patients with mature teratoma and extracted their total RNA from formalin-fixed paraffin-embedded tissues. Then we prepared small RNA libraries and performed comprehensive miRNA sequencing. Heatmap and principal component analysis revealed markedly different miRNA profiling in cancer, normal ovarian and mature teratoma tissues. Then we narrowed down cancer-related miRNAs, comparing paired-cancer and normal ovaries. Comparisons of cancer and mature teratoma identified two markedly upregulated miRNAs (miR-151a-3p and miR-378a-3p) and two markedly downregulated miRNAs (miR-26a-5p and miR-99a-5p). In addition, these findings were validated in fresh cancer tissues of patient-derived xenograft (PDX) models. Moreover, several miRNAs, including miR-151a-3p and miR-378a-3p, were elevated in the murine plasma when tumor tissues were enlarged although miR-26a-5p and miR-99a-5p were not elucidated in the murine plasma. Finally, we performed target prediction and functional annotation analysis in silico and indicated that targets genes of these miRNAs markedly correlated with cancer-related pathways, including 'pathway in cancer' and 'cell cycle'. In conclusion, this is the first study on miRNA sequencing for squamous cell carcinoma arising from mature teratoma. The study identified four cancer-related miRNAs that were considered to be related to the feature of malignant transformation. Moreover, miRNAs circulating in the murine plasma of the PDX model could be novel diagnostic biomarkers.

DOI： 10.1093/carcin/bgz135

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記述言語：日本語   出版者・発行元：日本毒性学会  

<p><b>[Introduction]</b> Drug-induced acute kidney injury (AKI) is a frequent cause of adverse drug reaction. Serum creatinine (CRE) and blood urea nitrogen (BUN) are widely used as standard biomarkers for kidney injury; however, the sensitivity and specificity are considered to be low. In recent years, circulating microRNA (miRNAs) have been attracting considerable attention as novel biomarkers for organ injury, but there are currently no established miRNA biomarkers for drug-induced AKI. The present study aimed to identify plasma miRNAs that may enable early and specific detection of drug-induced tubular and glomerular injury through next-generation sequencing analysis. <b>[Methods]</b> Six-week old male Sprague-Dawley rats were administered cisplatin and gentamicin to induce tubular injury. To create glomerular injury models, puromycin and doxorubicin were administered, and these models were always accompanied by tubular damage. Small RNA-sequencing was performed to analyze time-dependent changes in the plasma miRNA profiles. <b>[Results and Discussion]</b> In the differential analysis, miR-3473 was specifically up-regulated in the glomerular injury models. miR-143-3p and miR-122-5p were commonly down-regulated in all models, and the changes were earlier than the traditional biomarkers, such as plasma CRE and BUN. These data indicated that changes in the specific miRNAs in plasma may enable the early and sensitive detection of tubular and glomerular injuries. The present study suggests the potential utility of plasma miRNAs in the early and type-specific detection of drug-induced AKI.</p>

DOI： 10.14869/toxpt.46.1.0_p-233

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記述言語：日本語   出版者・発行元：日本毒性学会  

<p>[背景・目的] 近年、薬や化合物に起因する肝障害の新規バイオマーカー候補として血中microRNA (miRNA) が注目されている。中でも肝細胞特異的に存在するmiR-122の肝障害予測バイオマーカーとしての有用性が期待されているが、病型判断には不十分である。本研究では肝細胞障害、胆汁うっ滞および脂肪肝について、早期に病型判断可能なmiRNAの探索と評価を目的とした。[方法] 肝障害モデル作成には6週齢の雄性SDラットを用いた。肝細胞障害モデル作成にはアセトアミノフェン (1500 mg/kg) とチオアセトアミド (100 mg/kg)、胆汁うっ滞モデルにはα-ナフチルイソチオシアネート (150 mg/kg) と4,4’-メチレンジアニリン (250 mg/kg)、脂肪肝モデルには四塩化炭素 (300 mg/kg) とデキサメタゾン (15 mg/kg) をそれぞれラットに経口投与した。経時的に血液を採取し、血漿からRNAを抽出後、次世代シーケンサーを用いて血漿中miRNAを網羅的に解析した。ピーク時点や障害の程度が異なる病型間でのmiRNA発現を比較するために、時系列的miRNAプロファイルのクラスターパターンから肝障害の初期、中期、後期を定義し、各時点において増加または減少したmiRNAを、ベン図を用いて病型別、または網羅的に解析した。[結果・考察] 病型別肝障害モデルにおいて、ALTやASTなどの生化学値や、組織学的に変化の認められない障害初期の段階から変動するmiRNAを複数同定することができた。その中から全病型に共通して上昇するmiR-122および、病型特異的miRNAに着目し、RT-PCRによる検証実験を行なった。その結果、肝細胞障害からはmiR-1-3pとlet-7b-5p、胆汁うっ滞からはmiR-218a-5p、脂肪肝からはmiR-320-3pが病型初期に上昇し、全病型におけるmiR-122の経時的増加も確認された。本研究結果から肝障害の病型別、早期予測におけるmiRNAの有用性が示された。</p>

DOI： 10.14869/toxpt.45.1.0_p-6

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記述言語：日本語   出版者・発行元：日本毒性学会  

【背景・目的】

環境中に存在する化学物質の曝露による内分泌系や生殖機能への影響が懸念されている。食品や医療機器の滅菌に使用されるエチレンオキシドをはじめとして、動物試験において生殖機能及び性ホルモンに与える影響が懸念されているにも関わらず、ヒトの日常曝露における影響評価が十分ではない化学物質が多く存在する。本研究では汎用される化学物質のヒト血中レベルと性ホルモンとの関連性を調査することを目的とした。

【方法】米国国民健康栄養調査（NHANES, 2013-2016）の参加者のうち成人男性816人を解析対象とした。機械学習アルゴリズムの一つであるランダムフォレスト回帰モデルを用いて、汎用化学物質40種類の血中レベルと血中テストステロン（TST）及びエストラジオール（EST）との関係性を変数重要度を指標に解析し、順位付けした。変数重要度が最も大きかったエチレンオキシド（EtO）について、TSTならびにESTレベルとの用量依存性を多変量回帰分析により調査した。

【結果・考察】

ランダムフォレスト回帰分析において、TST及びESTレベル変動に対する影響は、評価した化学物質の中でEtOが最も大きかった。さらにEtOのTST及びESTレベルにおける重要度は、性ホルモンへの影響が既知の因子である年齢や喫煙習慣よりも大きかった。平滑化スプライン回帰ならびに重回帰分析による多変量解析の結果から、血中EtOレベルが高濃度のグループにおいて、EtOがTSTレベル増加に有意に寄与することが明らかとなった。なお回帰分析においてはEtOとESTとの間に統計学的有意な関係性は認められなかった。以上より、EtOは日常曝露されうるレベルにおいて男性のTSTを増加させる作用があることが示唆された。今後、女性を対象とした調査ならびにEtO以外の物質の詳細な評価を実施する。

DOI： 10.14869/toxpt.49.1.0_o-28

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J-GLOBAL

記述言語：日本語   出版者・発行元：日本毒性学会  

[Purpose] MicroRNAs (miRNA) have received much attention as potential biomarkers of drug-induced liver injury. We recently reported that plasma miR-143-3p and miR-218a-5p were increased in the early stage of severe cholestasis in rats. In this study, we investigated whether these miRNAs increase in a severity-dependent manner and pathophysiological roles of them.

[Method] Male SD rats were orally administered different doses of 4,4-methylenedianiline or α-naphthylisothiocyanate to induce cholestasis. Rats were also orally administered acetaminophen or thioacetamide to induce hepatocellular injury. The miRNA expression levels were measured by RT-qPCR. Effects of miR-218a-5p on proliferation were investigated in an immortalized human cholangiocyte line MMNK-1. Target genes of miR-218a-5p were predicted by in silico analysis, and expression levels of target mRNAs after overexpression of miR-218-5p were determined.

[Result and discussion] Plasma miR-218a-5p and miR-143-3p levels were dose-dependently increased in cholestatic rats. Proliferation of MMNK-1 cells was significantly suppressed after overexpression of miR-218a-5p. The mRNA levels of GNAI2, PPP1CB and PPP2R5A, which were potential targets, were decreased by overexpression of miR-218a-5p in MMNK-1 cells. In conclusions, our data suggest that 1) miR-218a-5p decreases cholangiocyte proliferation by inhibiting the expression of GNAI2, PPP1CB and PPP2R5A thereby associated with pathogenesis of cholestasis; and 2) miR-218a-5p was leaked into plasma probably from damaged cholangiocytes in a severity-dependent manner.

DOI： 10.14869/toxpt.47.1.0_p-219

CiNii Research

J-GLOBAL

J-GLOBAL

J-GLOBAL

記述言語：日本語   出版者・発行元：日本毒性学会  

近年、薬剤や化合物の暴露に起因する肝障害のバイオマーカー候補として血中microRNA (miRNA) が注目されており、様々な非臨床安全性試験における利用が進展しつつある。血中miRNAに関連した我々の最近の研究紹介と、今後の課題について考える。（１）我々はニューキノロン系抗菌薬とスタチンの併用による横紋筋融解症マウスモデルを確立した。さらに、本年会でGSHを低下させるのみで、急性腎障害マウスモデル確立した報告をした。肝由来miR-122-5pのみならず、心筋由来miR-208-3p、骨格筋由来miR-206-3p、および心筋と骨格筋両由来miR-133-3pの血中での発現変動profileが、臓器別病態と重篤度等の予測に有効である。（２）我々は肝細胞障害型、胆汁うっ滞型肝障害および脂肪肝の３つの代表的なDILIについて、病型判断及び早期発見可能なmiRNAの同定を目的とし、各ラット病態モデルを用いて、血漿中miRNAを次世代シーケンサーにより網羅的に解析した結果を、本年会で発表した。発症早期に各病型特異的なmiRNAを同定・評価した。（３）肝類洞内皮細胞は、抗癌剤の副作用の標的となることが知られている。我々は、肝類洞内皮細胞に特異的に高発現するmiR-511-3pを特定し報告した。miR-122-5pはヘパトサイトにのみ由来するため、肝臓の病型のさらなる情報が血液から得られる。抗癌剤治療を中断する副作用である類洞閉塞症候群の予知予防への適用が期待される。（４）同じ系統のげっ歯類に、同一条件で薬剤性肝障害を惹起させても、その重篤度には著しい個体差が認められる場合が多い。この現象がヒトにおけるidiosyncraticな薬剤性臓器毒性と同じ機序であるかは依然として不明であるが、より稀で重篤な副作用の予知予防のさらなる研究が待たれている。

DOI： 10.14869/toxpt.45.1.0_s9-5

CiNii Research

J-GLOBAL

J-GLOBAL