Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine.

Abstract

Folate deficiency in Swiss mice increased the incidence of micronuclei in peripheral blood erythrocytes, indicating increased chromosomal damage in nucleated erythrocyte precursors. Caffeine enhanced the incidence of micronuclei in blood and bone marrow by up to 5-fold in folatedeficient mice at doses that did not significantly alter the micronucleus frequency in the presence of adequate dietary folate. The lower dose of caffeine used in this study (75 mg/kg) approaches doses received by humans who consume large amounts of caffeinated beverages. Since folate deficiency and caffeine consumption are highly prevalent in the human population, the potential for a similar interaction in man should be evaluated.The occurrence of micronuclei in peripheral blood and bone marrow erythrocytes has been used as an indicator of cytogenetic damage in laboratory animals and man (1-3). Two recent studies indicate that folate deficiency and caffeinatedbeverage consumption may elevate the frequency of micronucleated erythrocytes in man. Caffeinated-coffee consumption was associated with an elevated frequency of micronucleated erythrocytes in a cross-sectional study of genotoxic risk factors (4), and folate supplementation lowered micronucleus frequency to normal in an individual with a marginal folate deficiency and an abnormally high micronucleus frequency (5). These studies suggest that folate status and caffeinated-beverage consumption may be risk factors for cytogenetic damage in man.Mild-to-moderate folate deficiency (6-9) and caffeinatedbeverage consumption (10) are both highly prevalent in the general population. Folate deficiency affects up to 60% of low-income and elderly persons (8,11) and is also common in subpopulations, such as alcoholics (12) Folate deficiency in pregnant women has been reported to range from 2% to 50%, depending on the population studied (25). Folate deficiency during pregnancy is associated with an elevated incidence of birth defects (26).Severe folate deficiency induced by antifolate drugs has been shown to increase the frequency of micronuclei in mouse bone marrow erythrocytes (27, 28), but we are not aware of previous reports of increased micronucleus frequencies induced by dietary folate deficiency in laboratory animals.Fragile-site expression induced in vitro by conditions of limiting folate is known to be strongly enhanced by caffeine, leading to micronucleus formation and increased frequencies of chromosome breaks (18,29). Under these conditions, caffeine increases folate-related breakage events, often by more than an order of magnitude. There appear to be no data indicating whether a similar interaction occurs in mammals in vivo. Although earlier studies of caffeine effects in animals and man have failed to demonstrate significant genotoxic effects in vivo at doses near those that would result from the consumption of caffeinated beverages (30-33), the recent report by Chen et al. (34) that chromosomal fragility in human lymphocytes cultured under low-folate conditions is linearly ...

A Prospective Study of Dietary Folate Intake and Risk of Colorectal Cancer: Modification by Caffeine Intake and Cigarette Smoking

“…Animal data have suggested that caffeine might act synergistically with folate deficiency to cause cytogenetic damage (8). On this basis, we hypothesized that an association between folate intake and risk of colon cancer might vary according to caffeine intake.…”

“…MacGregor et al (8) reported that folate deficiency causes cytogenetic damage in mice and that caffeine acts synergistically with inadequate folate status to augment this damage. Additionally, consumption of coffee and tea has been directly related to chromosome fragility (9) and chromosomal damage (10) in peripheral lymphocytes and erythrocytes.…”

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

“…The phenotype of PCFT-mutant mice presented in this report largely recapitulated the hematologic phenotype of dietary folate deficiency in mice and closely resembles the type of anemia reported in folate-deficient humans. 22,23 In mice, the key features of folate deficiency are growth retardation, anemia associated with a marked, progressive macrocytosis, and pancytopenia 22,24 accompanied by ineffective hematopoiesis in the BM and spleen. 22,25 In humans, the disease of folate malabsorption is characterized as macrocytic/megaloblastic anemia because of the accumulation of large immature erythroid progenitors, which undergo apoptosis before complete maturation resulting from impaired DNA synthesis.…”

Nutritional treatment of genome instability: a paradigm shift in disease prevention and in the setting of recommended dietary allowances

“…The reticulocyte is distinguishable from the erythrocyte by its larger size and much higher RNA content. Micronucleus frequencies in reticulocytes and erythrocytes are usually recorded separately (for a more detailed explanation, see MacGregor et al 1990;Abramsson-Zetterberg et al 2000).…”