Benzene‐induced micronuclei formation in mouse fetal liver blood, peripheral blood, and maternal bone marrow cells

Ning, Hansun; Kado, Norman Y.; Kuzmicky, Paul A.; Hsieh, Dennis P. H.

doi:10.1002/em.2850180102

Cited by 25 publications

(8 citation statements)

References 21 publications

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“…This eect of the compound as well as its perinatal genotoxicity (Cole et al 1982;Ning et al 1991) and hematotoxicity Snyder 1986, 1988;Corti and Snyder 1996) could be due, at least in part, to our observed perinatal bioactivation of the compound.…”

Section: Discussionmentioning

confidence: 63%

“…Our ®ndings of substantial perinatal benzene metabolism and bioactivation provide metabolic insights into the reported sensitivity of the immature to the toxic effects of the compound (Cole et al 1982;Ning et al 1991). The relative contributions of the enzymes involved in benzene bioactivation, e.g.…”

Section: Discussionmentioning

confidence: 85%

“…Of the few studies reported, some have judged benzene (Mehlman et al 1980) and its metabolites (DeCaprio 1999) to be of minimal hazard to the immature at doses that are nontoxic to the mother. Other studies, on the other hand, have demonstrated a higher genotoxicity by the compound, as estimated by micronucleus formation, in late fetuses of benzene-treated pregnant mice than in the dams themselves (Cole et al 1982(Cole et al , 1983Ning et al 1991;Xing et al 1992). Furthermore, ospring of benzene-treated pregnant mice were reported to exhibit abnormal hematopoiesis that persists into adulthood Snyder 1986, 1988;Corti and Snyder 1996).…”

Section: Introductionmentioning

confidence: 99%

“…Cellular macromolecules to which the resulting reactive benzene metabolites bind include DNA (Creek et al 1997) and protein (Irons and Neptun 1980;Chen and Eastmond 1995 ). Given the reported characteristically low levels of hepatic xenobiotic-bioactivation enzymes in the immature than in adults (Hong et al 1987;Umeno et al 1988) and the essentiality of metabolic bioactivation to benzene toxicity (Andrews et al 1977), the reported enhanced perinatal toxicity of benzene (Cole et al 1982(Cole et al , 1983Snyder 1986, 1988;Ning et al 1991;Xing et al 1992;Corti and Snyder 1996) raises the question of the relative contributions of the dam and the immature to the formation of the metabolites of benzene responsible for the perinatal toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Comparative metabolism of [ 14 C]benzene to excretable products and bioactivation to DNA-binding derivatives in maternal and neonatal mice

Iba

Ghosal

Snyder

2001

Archives of Toxicology

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Lactating adult female mice treated with a single dose of 880 mg/kg i.p. [14C]benzene, and their 2-day-old sucklings similarly treated or nursed by their treated dams were compared in terms of their ability to metabolize benzene to urinary products or reactive intermediates as assessed by covalently-bound benzene derivatives in whole blood or liver DNA. Six metabolite fractions were identified in the urine of sucklings by high performance liquid chromatographic (HPLC) analysis at 5 h following intraperitoneal (direct) treatment with benzene. Three of the metabolite fractions co-chromatographed with authentic phenol, phenyl glucuronide, and muconic acid, and contributed 11, 6.9 and 0.6%, respectively, to the total urinary benzene metabolites. Two of the fractions were unidentified. The sixth and most polar fraction consisted of multiple metabolites, 21% of which were conjugates, and accounted for 72% of the total urinary metabolites. A similar metabolite profile was observed in 24-h urine samples from treated dams with the exception that one of the unidentified fractions in the sucklings was absent and levels of the metabolites were quantitatively higher than those observed in sucklings 5 h following their treatment with benzene. Furthermore, 78% of the most polar fraction from the dams consisted of conjugates compared with 21% of that from the sucklings. The metabolite pattern in urine of sucklings nursed by treated dams was qualitatively similar to, but quantitatively different from the pattern in treated dams. Five hours following intraperitoneal treatment with benzene, covalent binding of the compound to DNA (expressed as pmol benzene equivalents/mg DNA) in sucklings was slightly higher in whole blood (1.15+/-0.07) than in liver (0.77+/-0.07), whereas in the dam, it was slightly lower in whole blood (0.88+/-0.48) than in liver (1.63+/-0.61). Twenty four hours following benzene exposure in sucklings of benzene-treated dams, DNA binding by the compound in whole blood (3.85+/-1.05) and liver (0.11+/-0.03) was higher and lower, respectively than the binding observed in benzene-injected sucklings 5 h following the injection. Our results show that excretable as well as reactive metabolites of benzene are formed substantially by the neonatal mouse, and that the extent of bioactivation of the compound is comparable in the adult and the suckling mouse. The results show also that sucklings of benzene-exposed mothers are exposed to substantial levels of the compound and are potentially susceptible to its toxic effects.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparative metabolism of [ 14 C]benzene to excretable products and bioactivation to DNA-binding derivatives in maternal and neonatal mice

Iba

Ghosal

Snyder

2001

Archives of Toxicology

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“…Although animal models have not illustrated transplacental carcinogenesis with benzene, these models have shown that benzene is an in utero clastogen. In particular, in utero exposure to benzene has been shown to cause increases in micronuclei formation in mouse fetal liver and bone marrow tissues, suggesting that fetal DNA from developing hematopoietic tissue is a potential target of maternal benzene exposure (Ning et al, 1991; Ciranni et al, 1988). Other studies in mice have shown that in utero exposure to benzene causes a depression in the number of erythroid precursor cells and an elevation in the number of granulocytic precursor cells in the hematopoietic system of the offspring (Keller and Snyder, 1986, 1988), effects consistent with the ultimate development of leukemia.…”

Section: Dna Damagementioning

confidence: 99%

In utero–initiated cancer: The role of reactive oxygen species

Wan

Winn

2006

Birth Defect Res C

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It is becoming more evident that not only can drugs and environmental chemicals interfere with normal fetal development by causing structural malformations, such as limb defects, but that xenobiotic exposure during development can also cause biochemical and functional abnormalities that may ultimately lead to cancer later on in life. Fetal toxicity may be partly mediated by the embryonic bioactivation of xenobiotics to free radical intermediates that can lead to oxidative stress and potentially lead, in some cases, to carcinogenesis. Using a number of examples, this review will focus on the role of reactive oxygen species (ROS) in the mechanisms pertaining to in utero initiated cancers.

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In vivo rodent erythrocyte micronucleus assay. II. Some aspects of protocol design including repeated treatments, integration with toxicity testing, and automated scoring

Hayashi¹,

MacGregor²,

Gatehouse³

et al. 2000

Environ. Mol. Mutagen.

236

107

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An expert working group on the in vivo micronucleus assay, formed as part of the International Workshop on Genotoxicity Test Procedures (IWGTP), discussed protocols for the conduct of established and proposed micronucleus assays at a meeting held March 25–26, 1999 in Washington, DC, in conjunction with the annual meeting of the Environmental Mutagen Society. The working group reached consensus on a number issues, including: (1) protocols using repeated dosing in mice and rats; (2) integration of the (rodent erythrocyte) micronucleus assay into general toxicology studies; (3) the possible omission of concurrently‐treated positive control animals from the assay; (4) automation of micronucleus scoring by flow cytometry or image analysis; (5) criteria for regulatory acceptance; (6) detection of aneuploidy induction in the micronucleus assay; and (7) micronucleus assays in tissues (germ cells, other organs, neonatal tissue) other than bone marrow. This report summarizes the discussions and recommendations of this working group. In the classic rodent erythrocyte assay, treatment schedules using repeated dosing of mice or rats, and integration of assays using such schedules into short‐term toxicology studies, were considered acceptable as long as certain study criteria were met. When the micronucleus assay is integrated into ongoing toxicology studies, relatively short‐term repeated‐dose studies should be used preferentially because there is not yet sufficient data to demonstrate that conservative dose selection in longer term studies (longer than 1 month) does not reduce the sensitivity of the assay. Additional validation data are needed to resolve this point. In studies with mice, either bone marrow or blood was considered acceptable as the tissue for assessing micronucleus induction, provided that the absence of spleen function has been verified in the animal strains used. In studies with rats, the principal endpoint should be the frequency of micronucleated immature erythrocytes in bone marrow, although scoring of peripheral blood samples gives important supplementary data about the time course of micronucleus induction. When dose concentration and stability are verified appropriately, concurrent treatment with a positive control agent is not necessary. Control of staining and scoring procedures can be obtained by including appropriate reference samples that have been obtained from a separate experiment. For studies in rats or mice, treatment/sampling regimens should include treatment at intervals of no more than 24 hr (unless the test article has a half‐life of more than 24 hr) with sampling of bone marrow or blood, respectively, within 24 or 40 hr after the last treatment. The use of a DNA specific stain is recommended for the identification of micronuclei, especially for studies in the rat. In the case of a negative assay result with a non‐toxic test article, it is desirable that systemic exposure to the test article is demonstrated. The group concluded that successful application of automated scoring by...

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Benzene‐induced micronuclei formation in mouse fetal liver blood, peripheral blood, and maternal bone marrow cells

Cited by 25 publications

References 21 publications

Comparative metabolism of [ 14 C]benzene to excretable products and bioactivation to DNA-binding derivatives in maternal and neonatal mice

Comparative metabolism of [ 14 C]benzene to excretable products and bioactivation to DNA-binding derivatives in maternal and neonatal mice

In utero–initiated cancer: The role of reactive oxygen species

In vivo rodent erythrocyte micronucleus assay. II. Some aspects of protocol design including repeated treatments, integration with toxicity testing, and automated scoring

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