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Abstract
Maintenance of genome integrity is important for preventing mutagenic events and preserving overall cell functionality. DNA damaging agents induce DNA double strand breaks (DSBs) that are repaired through repair pathways non-homologous end-joining (NHEJ) and homologous recombination (HR). DSB-induced inter-chromosomal HR repair can lead to mutagenic events including the translocations associated with infant acute myeloblastic leukemia (AML) and infant acute lymphoblastic leukemia (ALL). It has been cited that a specific translocation associated with AML involving the human MLL gene at the 11q23 chromosome position is associated with exposure to topoisomerase II (Top2) poison etoposide.. The natural compounds known as bioflavonoids have cardioprotective, cytoprotective, anti-inflammatory, anti-viral, and anticarcinogenic properties at low doses and are added to many over the counter supplements. However, they are also biochemically similar to etoposide and inhibit Top2 and cause DNA DSBs in a dose-dependent manner in cultured cells. Previous work supports the potential for in vivo exposure to bioflavonoid genistein to cause DNA damage in mice and rats, and is associated with a dose-dependent increase of cells in S phase hypothesized to be associated with frozen Top2 cleavage complexes halting the cell cycle. Further, bioflavonoids are capable of crossing the placental barrier and may pose a threat to a developing fetal genome. This work utilized a unique transgenic reporter mouse model to be the first study to evaluate genistein for its direct potential to promote DSB-induced inter-chromosomal homologous recombination in vivo. It was observed that genistein induces inter-chromosomal HR at readily detectable frequency in the kidney, uterus, testes, and placenta but minimally or undetectable in the bone marrow, liver, or in utero in developing whole fetus or fetal liver. This work is the first demonstration that genistein supplementation in vivo can cause inter-chromosomal HR. This implies a more mutagenic role of genistein has previously been described and serves as important evidence that genistein supplementation should be moderated.