Mutagenic Activity of a Mixture of Heterocyclic Amines at Doses below the Biological Threshold Level of Each

Ohta, Toshihiro

doi:10.3123/jemsge.28.181

Cited by 5 publications

(6 citation statements)

References 17 publications

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“…Since the nucleotide excision repair system recognizes distortion of the DNA helix, but not adduct molecule itself, it is important to investigate the combined eŠect of multiple mutagens even if their doses are virtually nonmutagenic level. The present results as well as my previous work with 6 heterocyclic amines (6) suggest that DNA adduct formation at virtually non-mutagenic doses was additive, with the total amount re‰ecting the mutagenicity. One of the possible explanations for additive eŠect might be the formation of closely spaced opposing lesions.…”

Section: Discussionsupporting

confidence: 85%

“…Top agar (0.6z agar and 0.5z NaCl) contained 0.05 mM Dbiotin and 0.05 mM L-histidine. Reverse mutation assay: The His ＋ reversion assay (6,18) was conducted with S. typhimurium strains TA1975P and TA100. The bacteria were precultured overnight in nutrient broth.…”

Section: Methodsmentioning

confidence: 99%

“…Assuming that a biologically meaningful threshold dose indeed exists for DNA-targeting mutagens, it is important to clarify whether multiple mutagens at virtually non-mutagenic dose of each would exhibit additive mutagenicity, because most environmental exposures involve complex mixtures of chemicals. In my previous study (6), I reported the additive mutagenic eŠects of 6 heterocyclic amines in S. typhimurium TA1978P, a nucleotide excision repair-proˆcient strain. When the 6 heterocyclic amines were mixed together at virtually non-mutagenic dose level of each for TA1978P, a sig-niˆcant increase in the number of revertants was observed in the strain, suggesting the total amount of DNA adducts re‰ecting the mutagenicity.…”

Section: Introductionmentioning

confidence: 99%

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Additive Mutagenic Effects of DNA Damages Induced by Multiple Mutagens at Virtually Non-mutagenic Dose Level of Each

Ohta

2007

Genes and Environment

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DNA damages provoked by the six mutagens (furylframide, MX, 4-nitroquinoline N-oxide, sodium azide, 1nitropyrene, and captan) used in the present study have been known to subject to the nucleotide excision repair system. Therefore, they induced base-substitution mutations much more e‹ciently in Salmonella typhimurium TA100 (hisG46, rfa, uvrB/pKM101), a strain deˆcient in nucleotide excision repair, than in TA1975P (hisG46, rfa/pKM101). Doses below undetectable level in the reverse mutation assay were selected as those that were apparently mutagenic to the repair-deˆcient strain TA100 but not to the repair-proˆcient strain TA1975P in this study. Then, the six mutagens were mixed at virtually nonmutagenic dose level of each and a possible combined mutagenic eŠect was investigated. A signiˆcant and reproducible increase in the number of revertants in TA1975P was observed with combined mutagens. The results suggest that DNA adduct formation at virtually non-mutagenic dose level was additive, with the total amount re‰ecting the mutagenicity.

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Section: Discussionsupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Additive Mutagenic Effects of DNA Damages Induced by Multiple Mutagens at Virtually Non-mutagenic Dose Level of Each

Ohta

2007

Genes and Environment

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“…Therefore, it is suspected that detectable carcinogenic risk may appear when people are exposed to multiple DNA-reactive genotoxic carcinogens, even below the TTC. It is reported that mutagenicity in Salmonella typhimurium strains was detectable when six DNA-reactive genotoxic carcinogens were combined at quite low doses ( 70 ). Each single carcinogen did no exhibit any detectable mutagenicity owing to the low dose.…”

Section: Future Challenge: Risk Estimation Of Combined Exposure Of Gementioning

confidence: 99%

Thresholds of Genotoxic and Non-Genotoxic Carcinogens

Nohmi

2018

ToxicolRes

117

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Exposure to chemical agents is an inevitable consequence of modern society; some of these agents are hazardous to human health. The effects of chemical carcinogens are of great concern in many countries, and international organizations, such as the World Health Organization, have established guidelines for the regulation of these chemicals. Carcinogens are currently categorized into two classes, genotoxic and non-genotoxic carcinogens, which are subject to different regulatory policies. Genotoxic carcinogens are chemicals that exert carcinogenicity via the induction of mutations. Owing to their DNA interaction properties, there is thought to be no safe exposure threshold or dose. Genotoxic carcinogens are regulated under the assumption that they pose a cancer risk for humans, even at very low doses. In contrast, non-genotoxic carcinogens, which induce cancer through mechanisms other than mutations, such as hormonal effects, cytotoxicity, cell proliferation, or epigenetic changes, are thought to have a safe exposure threshold or dose; thus, their use in society is permitted unless the exposure or intake level would exceed the threshold. Genotoxicity assays are an important method to distinguish the two classes of carcinogens. However, some carcinogens have negative results in in vitro bacterial mutation assays, but yield positive results in the in vivo transgenic rodent gene mutation assay. Non-DNA damage, such as spindle poison or topoisomerase inhibition, often leads to positive results in cytogenetic genotoxicity assays such as the chromosome aberration assay or the micronucleus assay. Therefore, mechanistic considerations of tumor induction, based on the results of the genotoxicity assays, are necessary to distinguish genotoxic and non-genotoxic carcinogens. In this review, the concept of threshold of toxicological concern is introduced and the potential risk from multiple exposures to low doses of genotoxic carcinogens is also discussed.

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“…If genotoxicity of chemicals have no thresholds for the action, the exposure to multiple genotoxic agents should have additional eŠects. In fact, Ohta demonstrated that addition of six mutagenic heterocyclic amines at very low doses, each of which doesn't induce detectable mutations, give positive mutagenic results in S. typhimurium when they are combined (51). The results suggest that chemicals induce mutations even below the practical threshold levels when they are combined.…”

Section: Future Directionsmentioning

confidence: 99%

in vivo Approaches to Identify Mutations and in vitro Research to Reveal Underlying Mechanisms of Genotoxic Thresholds

Nohmi

Yamada

Masumura

2012

Genes and Environment

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In regulatory toxicology, it is assumed that genotoxic carcinogens, which induce cancer through genotoxic mechanisms, have no threshold for their action. However, humans possess a number of defense mechanisms against DNA damaging agents, which may reduce the genotoxic and cancer risk at low doses to the spontaneous levels. The defense mechanisms may constitute practical thresholds for genotoxic carcinogens. In fact, accumulating evidence with rodent carcinogenicity and genotoxicity assays suggest that some genotoxic compounds clearly exhibit threshold-like dose responses in vivo. These results challenge the paradigm that cancer risk induced by genotoxic compounds at high doses can be linearly extrapolated into low doses where people are exposed in daily life (linear non-threshold model). Here, we discuss two issues regarding the practical thresholds for genotoxic carcinogens. Theˆrst issue is how to deˆne``genotoxicity'' of chemicals. There are a number of genotoxicity assays in vitro and in vivo. Therefore, it is unclear what genotoxicity assay(s) should be employed to deˆne whether the compound is genotoxic or not. The second issue is possible mechanisms underlying the practical thresholds. In particular, we emphasize the importance of DNA repair and translesion DNA synthesis as the underlying mechanisms of the practical thresholds. Finally, we discuss issues associated with low dose exposure to genotoxic carcinogens, i.e., risk assessment of exposure to multiple genotoxic chemicals.

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Mutagenic Activity of a Mixture of Heterocyclic Amines at Doses below the Biological Threshold Level of Each

Cited by 5 publications

References 17 publications

Additive Mutagenic Effects of DNA Damages Induced by Multiple Mutagens at Virtually Non-mutagenic Dose Level of Each

Additive Mutagenic Effects of DNA Damages Induced by Multiple Mutagens at Virtually Non-mutagenic Dose Level of Each

Thresholds of Genotoxic and Non-Genotoxic Carcinogens

in vivo Approaches to Identify Mutations and in vitro Research to Reveal Underlying Mechanisms of Genotoxic Thresholds

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