Development of a repeated-dose liver micronucleus assay using adult rats: An investigation of diethylnitrosamine and 2,4-diaminotoluene

Narumi, Kazunori; Ashizawa, Koji; Takashima, Rie; Takasawa, Hironao; Katayama, Seiichi; Tsuzuki, Yasuhiro; Tatemoto, Hideki; Morita, Takeshi; Hayashi, Makoto; Hamada, Shuichi

doi:10.1016/j.mrgentox.2012.05.012

Cited by 57 publications

(42 citation statements)

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“…In the repeated-dose MN study, the incidences of MNHEPs in the vehicle-treated control rats were 0.04 and 0.03% after the 14-and 28-day treatments, respectively; these results are comparable to results of a previous study [6]. A significant increase in the induction of MNHEPs was observed in a dose-dependent manner in the MDA-treated groups receiving 62.5 (14-days) or 40 mg/kg (28 days) or higher doses.…”

Section: Discussionsupporting

confidence: 85%

“…A significant increase in the induction of MNHEPs was observed in a dose-dependent manner in the MDA-treated groups receiving 62.5 (14-days) or 40 mg/kg (28 days) or higher doses. Hepatocytes with chromosomal aberrations have been shown to accumulate by repeated doses of chemical carcinogens [6]. However, the MN frequency in the 28-day treated rats was comparable with that in the 14-day treated rats for the maximum dose groups.…”

Section: Discussionmentioning

confidence: 90%

“…However, hepatocyte MN tests have previously been regarded as unsuitable for integration into general toxicity tests because they require a surgical procedure or collagenase perfusion before the evaluation. Narumi et al [6] established a novel liver MN test, with repeated treatments using young adult rats, that requires no pre-treatment. Furthermore, this liver MN test can be directly integrated into a repeated-dose toxicity study.…”

Section: Introductionmentioning

confidence: 99%

“…Hepatocytes characteristically have a long life span and a slow turnover rate [7]. This enables repeated treatment to enhance the sensitivity to N-diethylnitrosamine, a well-known hepatocarcinogen [6]. These findings strongly suggest that the doses employed in general toxicity tests, as opposed to the maximum tolerable dose used in current in vivo genotoxicity tests, can be adopted for the detection of genotoxic chemicals.…”

Section: Introductionmentioning

confidence: 99%

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Repeated-dose liver micronucleus test of 4,4′-methylenedianiline using young adult rats

Sanada

Koyama

Wako³

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Repeated-dose liver micronucleus test of 4,4′-methylenedianiline using young adult rats

Sanada

Koyama

Wako³

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

Self Cite

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“…Single-cell suspensions from whole livers of 6-d-old mice were obtained as described. 35 Cells were seeded at high density in DMEM/10% FBS and were confluent the following day when cells were treated with Baf. Cultures were maintained in 20 mg/ml or 50 mg/ml (typically for primary cells) gentamicin and were cultured at 37 C with 5% CO 2 , in a humidified atmosphere.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological inhibition of lysosomes activates the MTORC1 signaling pathway in chondrocytes in an autophagy-independent manner

et al. 2015

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These authors contributed equally to this publication.Keywords: autophagy, bafilomycin, bone, chondrocyte, lysosome, MTOR, MTORC1Abbreviations: 3-MA, 3-methyladenine; ACAN, aggrecan; ACP5/TRAP, acid phosphatase 5, tartrate-resistant; ACTB, actin, b; ALPL, alkaline phosphatase, liver/bone/kindey; ATG, autophagy related; ATG5cKO, ATG5 conditional knockout in chondrocytes; BC, avidin-biotin complex; Baf, bafilomycin A 1 ; bGP, b-glycerophosphate; BrdU, bromodeoxyuridine; C5.18 cells, RCJ 3.1C5.18 rat mesenchymal cell line; COL2A1, collagen, type II, a 1; COL10A1, collagen, type X, a 1; CQ, chloroquine; DAPI, 4 0 , 6-diamidino-2-phenylindole, dihydrochloride; Dox, doxycycline; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; FBS, fetal bovine serum; GAG, glycosaminoglycan; IGF1, insulin-like growth factor 1 (somatomedin C); LAMP2, lysosomalassociated membrane protein 2; MEFs, mouse embryonic fibroblasts; MAP1LC3A, microtubule-associated protein 1 light chain 3 a;MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC, MTOR complex; p-, phosphorylated-; PFA, paraformaldehyde; RPS6, ribosomal protein S6; RPS6KB1/p70(S6K)-a/PS6K/S6K1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; RPTOR, regulatory associated protein of MTOR, complex 1; SGK1, serum/glucocorticoid regulated kinase 1; TSC, tuberous sclerosis complex; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; v-ATPase, vacuolar-type H C -ATPase.Mechanistic target of rapamycin (serine/threonine kinase) complex 1 (MTORC1) is a protein-signaling complex at the fulcrum of anabolic and catabolic processes, which acts depending on wide-ranging environmental cues. It is generally accepted that lysosomes facilitate MTORC1 activation by generating an internal pool of amino acids. Amino acids activate MTORC1 by stimulating its translocation to the lysosomal membrane where it forms a super-complex involving the lysosomal-membrane-bound vacuolar-type H C -ATPase (v-ATPase) proton pump. This translocation and MTORC1 activation require functional lysosomes. Here we found that, in contrast to this well-accepted concept, in epiphyseal chondrocytes inhibition of lysosomal activity by v-ATPase inhibitors bafilomycin A 1 or concanamycin A potently activated MTORC1 signaling. The activity of MTORC1 was visualized by phosphorylated forms of RPS6 (ribosomal protein S6) and EIF4EBP1, 2 well-known downstream targets of MTORC1. Maximal RPS6 phosphorylation was observed at 48-h treatment and reached as high as a 12-fold increase (p < 0.018). This activation of MTORC1 was further confirmed in bone organ culture and promoted potent stimulation of longitudinal growth (p < 0.001). Importantly, the same effect was observed in ATG5 (autophagy-related 5)-deficient bones suggesting a macroautophagy-independent mechanism of MTORC1 inhibition by lysosomes. Thus, our data show that in epiphyseal chondrocytes lysosomes inhibit MTORC1 in a macroautophagy-independent manner and this inhibition likely depends on v-ATPase activity.

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Aromatic Amino and Nitro–Amino Compounds and Their Halogenated Derivatives

Darby

2023

Patty's Toxicology

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The fundamental aromatic hydrocarbon benzene, when substituted by one or more functional groups of the amine, nitro, or halogen classes, alone or in various combinations, provides an enormous number of compounds of immense practical value, ubiquitous presence in the industrial world, and often heightened toxicity relative to benzene itself, a notorious cause of blood cancer. This chapter begins by providing a general overview of aromatic compounds possessing amino and/or nitro substituents, with or without halogen substituents. The production and uses, exposure and biomonitoring, toxicity, and toxic mechanism of action are introduced. The remainder of the chapter focuses on specific compounds in a roughly systematic order based upon chemical structure, expanding on the same subheadings as covered in the general overview. The nomenclature of these compounds can be very confusing since many have traditional names that sometimes markedly differ from their systematized formal names. In this chapter, the same traditional names are used as were used in the previous edition of this publication, but if there is ambiguity of nomenclature, the Chemical Abstracts Service (CAS) numbers provided herein correspond to unique structures, each of which may have several names depending upon the naming convention. In general, when an aromatic compound has an amino or a nitro substituent, it is referred to as an “aniline” or a “nitrobenzene,” respectively, based upon the names of the parent compounds, even though other substituents may be present. When amino and nitro groups are present on the same benzene ring, “aniline” takes precedence, and both “aniline” and “nitrobenzene” take precedence over halogens. There are many exceptions to these general rules, however.

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Development of a repeated-dose liver micronucleus assay using adult rats: An investigation of diethylnitrosamine and 2,4-diaminotoluene

Cited by 57 publications

References 20 publications

Repeated-dose liver micronucleus test of 4,4′-methylenedianiline using young adult rats

Repeated-dose liver micronucleus test of 4,4′-methylenedianiline using young adult rats

Pharmacological inhibition of lysosomes activates the MTORC1 signaling pathway in chondrocytes in an autophagy-independent manner

Aromatic Amino and Nitro–Amino Compounds and Their Halogenated Derivatives

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