Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

File： oead074.pdf

DOI： 10.1093/ehjopen/oead074

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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.

File： He et al. 2025_milk.pdf

DOI： 10.1016/j.ecoenv.2025.118581

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Hygiene  

<p><b>Background:</b> 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.</p><p><b>Methods:</b> The most appropriate frequency (Hz) and level (dBZ) of pure tone for modulation of vestibular function were determined by an <i>ex vivo</i> 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.</p><p><b>Results:</b> 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 (≥120 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 <i>ex vivo</i> 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.</p><p><b>Conclusion:</b> 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.</p><p><b>Trial registration:</b> Registration number: UMIN000022413 (2016/05/23–2023/04/19) and UMIN000053735 (2024/02/29–present)</p>

File： MS Gu et al., 2025.pdf

DOI： 10.1265/ehpm.24-00247

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.chemosphere.2023.141047

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.chemosphere.2023.139190

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.scitotenv.2022.158828

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/jat.4144

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Authorship：Lead author   Language：English  

DOI： 10.1016/j.jaci.2021.05.025

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.tox.2020.152490

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/carcin/bgz135

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Language：Japanese   Publisher：The Japanese Society of Toxicology  

<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

CiNii Research

Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>[in Japanese] </p>

DOI： 10.14869/toxpt.45.1.0_p-6

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Language：Japanese   Publisher：The Japanese Society of Toxicology  

【Background & Aim】

There is an increasing concern about the effects of environmental chemical substances on the endocrine system and reproductive function. Some chemical substances such as ethylene oxide have been suspected to affect reproductive function and sex hormones in animal studies. However, there are limited evidences in the effect of commonly used chemicals on human sex hormone levels. The purpose of this study is to analyze the association between blood levels of frequently used chemical substances and sex hormone levels in human.

【Methods】

Of the participants in NHANES (2013-2016), 816 adult males were included in the analysis. Using random forest regression model, we analyzed the relationship between blood levels of 40 common chemical substances and blood testosterone (TST) and estradiol (EST) by variable importance. Ethylene oxide (EtO), which had the highest variable importance, was investigated for dose dependence on TST and EST levels by multivariate regression analysis.

【Results&Discussion】

In random forest regression, EtO had the greatest importance on TST and EST levels among the 40 evaluated chemicals. In addition, the importance of EtO on the levels of TST and EST was greater than age and smoking habits, whose effects on sex hormones are known. The results of multivariate analysis by smoothing spline regression and linear regression analysis revealed that higher level of EtO significantly contributed to the increase in TST level. There was no statistically significant relationship between EtO and EST levels. These results suggest that EtO is associated with increasing level of TST in men.

DOI： 10.14869/toxpt.49.1.0_o-28

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Language：Japanese   Publisher：The Japanese Society of Toxicology  

[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

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Language：Japanese   Publisher：The Japanese Society of Toxicology  

[in Japanese]

DOI： 10.14869/toxpt.45.1.0_s9-5

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