In vivo genotoxicity of dichloroacetic acid: Evaluation with the mouse peripheral blood micronucleus assay and the single cell gel assay

Fuscoe, James C.; Afshari, Arash; George, Michael H.; DeAngelo, Anthony B.; Tice, Raymond R.; Salman, Tarek; Allen, James W.

doi:10.1002/(sici)1098-2280(1996)27:1<1::aid-em1>3.0.co;2-l

Cited by 51 publications

(3 citation statements)

References 41 publications

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“…This result is consistent with reports that methylated trivalent arsenicals induce DNA strand breaks [Mass et al, 2001]. The absence of K ϩ MN in PCEs or NCEs of control animals is not unusual for either bone marrow or peripheral blood analyses [Gudi et al, 1992;Fuscoe et al, 1996]. Folate deficiency alone did not induce K ϩ MN in our studies, consistent with reports of a lack of correlation in clinical studies between folate deficiency and numerical chromosome abnormalities [Das et al, 1986]; however, several reports have demonstrated increases in K ϩ MN in blood lymphocytes in low-folate individuals [Odagiri and Uchida, 1998;Titenko-Holland et al, 1998].…”

Section: Discussionsupporting

confidence: 91%

Dietary folate deficiency enhances induction of micronuclei by arsenic in mice†

McDorman

Collins

Allen

2002

Environ and Mol Mutagen

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Folate deficiency increases background levels of DNA damage and can enhance the genotoxicity of chemical agents. Arsenic, a known human carcinogen present in drinking water supplies around the world, induces chromosomal and DNA damage. The effect of dietary folate deficiency on arsenic genotoxicity was evaluated using a mouse peripheral blood micronucleus (MN) assay. In duplicate experiments, male C57Bl/6J mice were fed folate-deficient or folate-sufficient diets for 7 weeks. During week 7, mice on each diet were given four consecutive daily doses of sodium arsenite (0, 2.5, 5, or 10 mg/kg) via oral gavage. Over the course of the study the folate-deficient diet produced an approximate 60% depletion of red blood cell folate. Folate deficiency by itself was associated with small but significant increases in MN in normochromatic erythrocytes (NCEs) and polychromatic erythrocytes (PCEs). Arsenic exposure was associated with significant increases in MN-PCEs in both folate-deficient and folate-sufficient mice. MN-PCE frequencies at the 10 mg/kg dose of arsenic were increased 4.5-fold over vehicle control in folate-deficient mice and 2.1-fold over control in folate-sufficient mice. At the 5 and 10 mg/kg doses of arsenic, MN-PCE levels were significantly higher (1.3-fold and 2.4-fold, respectively) in folate-deficient mice compared to folate-sufficient mice. Very few MN from either control or treated animals in either experiment exhibited kinetochore immunostaining, suggesting that the MN were derived from chromosome breakage rather than from whole chromosome loss. These results indicate that folate deficiency enhances arsenic-induced clastogenesis at doses of 5 mg/kg and higher.

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Section: Discussionsupporting

confidence: 91%

Dietary folate deficiency enhances induction of micronuclei by arsenic in mice†

McDorman

Collins

Allen

2002

Environ and Mol Mutagen

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“…Although the comet assay may be considered more sensitive for the assessment of induced DNA damage, the micronucleus test has the advantage of detecting the manifestation of damage as chromosomal aberrations. Some previous studies comparatively investigated these two endpoints [Belpaeme et al, 1996;Fuscoe et al, 1996;Goethem et al, 1997], but none of them was an in vivo study with humans occupationally exposed to X-radiation. The high values of standard deviation in the comet assay in the present study elucidate the high interindividual variation of this technique [DeMéo et al, 1991;Tice, 1995].…”

Section: Discussionmentioning

confidence: 99%

Assessment of DNA damage in lymphocytes of workers exposed to X‐radiation using the micronucleus test and the comet assay

Maluf

Passos

Bacelar

et al. 2001

Environ and Mol Mutagen

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The mutagenic and carcinogenic effects of genotoxic agents on exposed people have constituted an increasing concern. Therefore, the objective of this work was to assess DNA damage in lymphocytes of workers exposed to X-radiation using the cytokinesis-blocked micronucleus test and the comet assay (single-cell gel electrophoresis), and to compare these two techniques in the monitoring of exposed populations. The cytokinesis-blocked micronucleus test and the comet assay were employed in the monitoring of 22 workers occupationally exposed to X-radiation in a hospital in southern Brazil. The frequency of dicentric bridges was also measured. The results of both assays and the frequency of dicentric bridges revealed a significant increase in genetic effects on the cells of exposed individuals. Age was significantly correlated with micronucleus frequency and damage index in the comet assay. The concomitant analysis of dicentric bridges when determining micronucleus frequency does not require much extra work, and may serve as a reference to the type of mutagenic effect (clastogenic or aneugenic). The combination of the alkaline comet assay with the cytokinesis-blocked micronucleus test appears to be very informative for the monitoring of populations chronically exposed to genotoxic agents.

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“…Sodium dichloroacetate is a genotoxic agent [139,140,141,142]. The Moore and Harrington-Brock review concluded that the available genotoxicity data indicate DCA to be a weakly mutagenic agent causing DNA point mutations and chromosomal aberrations [143].…”

Section: Preclinical Research Of Dca Pharmacologymentioning

confidence: 99%

The Importance of Gender-Related Anticancer Research on Mitochondrial Regulator Sodium Dichloroacetate in Preclinical Studies In Vivo

Stakišaitis

Juknevičienė

Damanskienė

et al. 2019

Cancers

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Sodium dichloroacetate (DCA) is an investigational medicinal product which has a potential anticancer preparation as a metabolic regulator in cancer cells’ mitochondria. Inhibition of pyruvate dehydrogenase kinases by DCA keeps the pyruvate dehydrogenase complex in the active form, resulting in decreased lactic acid in the tumor microenvironment. This literature review displays the preclinical research data on DCA’s effects on the cell pyruvate dehydrogenase deficiency, pyruvate mitochondrial oxidative phosphorylation, reactive oxygen species generation, and the Na+–K+–2Cl− cotransporter expression regulation in relation to gender. It presents DCA pharmacokinetics and the hepatocarcinogenic effect, and the safety data covers the DCA monotherapy efficacy for various human cancer xenografts in vivo in male and female animals. Preclinical cancer researchers report the synergistic effects of DCA combined with different drugs on cancer by reversing resistance to chemotherapy and promoting cell apoptosis. Researchers note that female and male animals differ in the mechanisms of cancerogenesis but often ignore studying DCA’s effects in relation to gender. Preclinical gender-related differences in DCA pharmacology, pharmacological mechanisms, and the elucidation of treatment efficacy in gonad hormone dependency could be relevant for individualized therapy approaches so that gender-related differences in treatment response and safety can be proposed.

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In vivo genotoxicity of dichloroacetic acid: Evaluation with the mouse peripheral blood micronucleus assay and the single cell gel assay

Cited by 51 publications

References 41 publications

Dietary folate deficiency enhances induction of micronuclei by arsenic in mice†

Dietary folate deficiency enhances induction of micronuclei by arsenic in mice†

Assessment of DNA damage in lymphocytes of workers exposed to X‐radiation using the micronucleus test and the comet assay

The Importance of Gender-Related Anticancer Research on Mitochondrial Regulator Sodium Dichloroacetate in Preclinical Studies In Vivo

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