Promotion of liver and kidney carcinogenesis by ethyl &lt;i&gt;tertiary&lt;/i&gt;-butyl ether (ETBE) in male Wistar rats

Hagiwara, Akeo; Doi, Yuko; Imai, Norio; Suguro, Mayuko; Kawabe, Mayumi; Furukawa, Fumio; Tamano, Seiko; Nagano, Kasuke; Fukushima, Shoji

doi:10.1293/tox.2015-0023

Cited by 6 publications

(7 citation statements)

References 20 publications

(45 reference statements)

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“…The mean absolute and relative liver weights in rats given ETBE were significantly higher as compared with those of controls at all examined time points ( Table 1 ). The observed increase in liver weights was similar to that of previously reported studies when ETBE was administered by inhalation or by gavage 1 , 5 , 6 , 7 , 9 . In addition, significant increases in the mean relative kidney weights at all experimental time points and absolute kidney weights at days 17 and 28 in rats given ETBE as compared with control rats were found ( Table 1 ).…”

Section: Resultssupporting

confidence: 90%

“…ETBE has been shown to be not genotoxic 1 , 2 ; however, recently it has been reported that ETBE administered to male F344 rats by inhalation at a dose of 5,000 ppm for 2 years induced the development of liver preneoplastic lesions (eosinophilic and basophilic foci) and hepatocellular adenomas 4 , 5 . In other studies, the promoting effect of ETBE on rat hepatocarcinogenesis, when administered by gavage at a dose of 1,000 mg/kg body weight/day, was detected in a multiorgan carcinogenesis bioassay and in an initiation/promotion carcinogenicity assay using N-ethyl-N-(2-hydroxyethyl)nitrosamine (EHEN) as an initiator 6 , 7 .…”

Section: Introductionmentioning

confidence: 98%

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Induction of cell proliferation in the rat liver by the short-term administration of ethyl tertiary-butyl ether

Kakehashi

Hagiwara²,

Imai³

et al. 2015

J Toxicol Pathol

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In the present study, in continuation of our previous experiment in order to investigate the mode of action (MOA) of ethyl tertiary-butyl ether (ETBE) hepatotumorigenicity in rats, we aimed to examine alterations in cell proliferation, that are induced by short-term administration of ETBE. F344 rats were administered ETBE at doses of 0, and 1,000 mg/kg body weight twice a day by gavage for 3, 10, 17 and 28 days. It was found that the previously observed significant increase of P450 total content and hydroxyl radical levels after 7 days of ETBE administration, and 8-OHdG formation at day 14, accompanied by accumulation of CYP2B1/2B2, CYP3A1/3A2, CYP2C6, CYP2E1 and CYP1A1 and downregulation of DNA oxoguanine glycosylase 1, was preceded by induction of cell proliferation at day 3. Furthermore, we observed an increase in regenerative cell proliferation as a result of ETBE treatment at day 28, followed by induction of cell cycle arrest and apoptosis by day 14. These results indicated that short-term administration of ETBE led to a significant early increase in cell proliferation activity associated with induction of oxidative stress, and to a regenerative cell proliferation as an adaptive response, which could contribute to the hepatotumorigenicity of ETBE in rats.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 98%

Induction of cell proliferation in the rat liver by the short-term administration of ethyl tertiary-butyl ether

Kakehashi

Hagiwara²,

Imai³

et al. 2015

J Toxicol Pathol

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“…In the human ETBE PBK model, tissue volumes were calculated on the basis of weight and height of respective subjects and blood flow rates to tissues under workload, and the kinetics of ETBE and TBA metabolism were represented by hepatic clearance obtained by fitting to the experimental data measured in respective subjects (Nihlén and Johanson, 1999). For toxicology, subchronic toxicity studies (Medinsky et al, 1999;Hagiwara et al, 2015;U.S. EPA, 2021) and carcinogenicity studies (Saito et al, 2013;Suzuki et al, 2012) through the inhalation and oral routes, in addition to reproductive (Fujii et al, 2010;U.S.…”

Section: Introductionmentioning

confidence: 99%

A physiologically based kinetic modeling of ethyl tert-butyl ether in humans–An illustrative application of quantitative structure-property relationship and Monte Carlo simulation

Watanabe-Matsumoto¹,

Yoshida²,

Meiseki³

et al. 2022

J. Toxicol. Sci.

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Although physiologically based kinetic (PBK) modeling is informative for the risk assessment of industrial chemicals, chemical-specific input values for partition coefficients and metabolic parameters, including V max and K m are mostly unavailable; however, in silico methods, such as quantitative structure-property relationship (QSPR) could fill the absence. To assess the PBK model validity using necessary toxicokinetic (TK) parameters predicted by QSPR, the PBK model of ethyl tert-butyl ether (ETBE) as a model substance was constructed, in which the values of the partition coefficients, V max , and K m of ETBE were predicted using those of the related chemicals previously reported in the literature, and toxicokinetics of inhaled ETBE were stochastically estimated using the Monte Carlo simulation. The calculated ETBE concentrations in venous blood were comparable to the measured values in humans, implying that the reproducibility of ETBE toxicokinetics in humans was established in this PBK model. The Monte Carlo simulation was used to conduct uncertainty and sensitivity analyses of the dose metrics in terms of maximum blood concentration (C max ) and area under the blood concentration-time curve (AUC) and the estimated C max and AUC were highly and moderately reliable, respectively. Conclusively, the PBK model validity combined with in silico methods of QSPR was demonstrated in an ETBE model substance. QSPR-PBK modeling coupled with the Monte Carlo simulation is effective for estimating chemical toxicokinetics for which input values are unavailable and for evaluating the estimation validity.

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“…In addition, we have observed that various histopathological changes and genetic damage may occur in WT mice exposed to high concentrations of ETBE (5000 ppm) (Weng et al, ; Weng et al, ). Moreover, multiple studies have indicated that exposure to high doses of ETBE (inhalation: ≥1750 ppm; oral gavage: ≥1000 mg/kg) causes an increase in malignant tumors such as renal tubule cells and hepatocellular adenomas in Fischer‐344 rats (Hagiwara et al, ; Hagiwara et al, ; Saito et al, ). The causative mechanisms related with high‐dose ETBE‐induced carcinogenicity in animals with normal ALDH2 activity are inconclusive at present.…”

Section: Introductionmentioning

confidence: 99%

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

Lin

Suda

et al. 2020

J of Applied Toxicology

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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. K E Y W O R D Saldehyde dehydrogenase 2, ethyl tert-butyl ether, knockout, metabolism, tert-butyl alcohol, toxicology

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Promotion of liver and kidney carcinogenesis by ethyl <i>tertiary</i>-butyl ether (ETBE) in male Wistar rats

Cited by 6 publications

References 20 publications

Induction of cell proliferation in the rat liver by the short-term administration of ethyl <i>tertiary</i>-butyl ether

Induction of cell proliferation in the rat liver by the short-term administration of ethyl <i>tertiary</i>-butyl ether

A physiologically based kinetic modeling of ethyl <i>tert</i>-butyl ether in humans–An illustrative application of quantitative structure-property relationship and Monte Carlo simulation

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

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