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

Abstract

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.

Low Folate Status Enhanced Benzene-Induced Cytogenetic Damage in Bone Marrow of Mice: A Relationship Between Dietary Intake and Tissue Levels of Folate

“…As shown in the results, a low folate status increased susceptibility to benzene-induced chromosomal damage. It has been shown that feeding of a folate deficient diet alone for 7 wk increased slight but significant chromosomal damage in bone marrow (9,10). In this study, we could not replicate the same findings even though we evaluated the damage using the same MN method.…”

A review on exposure and effects of arsenic in passerine birds

“…Rat and rabbit Mukherjee et al (2003Mukherjee et al ( , 2004 Cancer Liver, adrenal, ovarian and lung tumors Mouse Cui et al (2006); Waalkes et al (2003) Genotoxicity Somatic mutations and mitotic recombination, chromosomal aberrations (bone marrow cells), Drosophila melanogaster, rat and Das et al (1993); Datta et al (1986);McDorman et al (2002); Poddar et al (2000); Ramos-Morales and Rodríguez-Arnaiz (1995) (continued on next page) (Geens et al, 2010;Hofer et al, 2010). Moreover, breeding parameters such as clutch size, length of the incubation period or hatching and fledging success are evaluated to study the effects of As and metals in breeding performance.…”

Folate deficiency enhances arsenic effects on expression of genes involved in epidermal differentiation in transgenic K6/ODC mouse skin

“…Folate is a B vitamin that normally functions in DNA methylation, synthesis and repair (Choi and Mason, 2000). A number of experimental studies in rodents, and in human and rodent cell culture systems, have shown that folate deficiency can enhance the genotoxicities of arsenic and other chemicals (MacGregor et al, 1990;Branda et al, 2001;McDorman et al, 2002). Folate deficiency and other methyl deficient diets, in the absence of any known carcinogen exposure, have been associated with increased risks of cancer of the colorectum, esophagus, cervix, lung, brain, pancreas, breast and liver (Mikol et al, 1983;Ghoshal and Farber, 1984;Choi and Mason, 2000).…”