title: Prenatal exposure to flavonoids: implication for cancer risk.
abstract: Flavonoids are potent antioxidants, freely available as high-dose dietary supplements. However, they can induce DNA double-strand breaks (DSB) and rearrangements in the mixed-lineage leukemia (MLL) gene, which are frequently observed in childhood leukemia. We hypothesize that a deficient DSB repair, as a result of an Atm mutation, may reinforce the clastogenic effect of dietary flavonoids and increase the frequency of Mll rearrangements. Therefore, we examined the effects of in vitro and transplacental exposure to high, but biological amounts of flavonoids in mice with different genetic capacities for DSB repair (homozygous/heterozygous knock-in for human Atm mutation [Atm-ΔSRI] vs. wild type [wt]). In vitro exposure to genistein/quercetin induced higher numbers of Mll rearrangements in bone marrow cells of Atm-ΔSRI mutant mice compared with wt mice. Subsequently, heterozygous Atm-ΔSRI mice were placed on either a flavonoid-poor or a genistein-enriched (270 mg/kg) or quercetin-enriched (302 mg/kg) feed throughout pregnancy. Prenatal exposure to flavonoids associated with higher frequencies of Mll rearrangements and a slight increase in the incidence of malignancies in DNA repair-deficient mice. These data suggest that prenatal exposure to both genistein and quercetin supplements could increase the risk on Mll rearrangements especially in the presence of compromised DNA repair.
authors.affiliation: Department of Health Risk Analysis and Toxicology, Nutrition and Toxicology Research, Institute Maastricht, Maastricht University, 6200 MD Maastricht, The Netherlands. kimberly.vanhees@maastrichtuniversity.nl
authors.forename: Kimberly
authors.initials: K
authors.lastname: Vanhees
authors.forename: Laura
authors.initials: L
authors.lastname: de Bock
authors.forename: Roger W L
authors.initials: RW
authors.lastname: Godschalk
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: van Schooten
authors.forename: Sahar Barjesteh
authors.initials: SB
authors.lastname: van Waalwijk van Doorn-Khosrovani
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001772:Blood Cell Count; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics; D002478:Cells, Cultured; D002869:Chromosome Aberrations / Q000139:chemically induced; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005419:Flavonoids / Q000633:toxicity*; D019833:Genistein / Q000633:toxicity; D006579:Heterozygote; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009369:Neoplasms / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011794:Quercetin / Q000633:toxicity; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005419:Flavonoids; D025521:Tumor Suppressor Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011794:Quercetin; D019833:Genistein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases