Msh2 deficiency increases susceptibility to benzo[a]pyrene-induced lymphomagenesis.
DNA mismatch repair (MMR) is essential for repair of single-base mismatches and insertion/deletion loops. MMR proteins also participate in cellular response to DNA damaging agents such as various alkylating agents. Mice deficient in the MMR gene Msh2 develop tumors earlier after exposure to alkylating agents when compared to unexposed mice. The interaction between the MMR system and polycyclic aromatic hydrocarbons such as benzo[a]pyrene (B[a]P) has not been investigated in vivo. Here, we show that treatment of Msh2-deficient mice with B[a]P enhances susceptibility to lymphomagenesis. Carrying at least one intact copy of the Msh2 gene had a protective effect. B[a]P treatment only induced lymphomas in 3 of the 40 (7.5%) mice with at least one intact copy of the Msh2 gene as compared to 13 of the 17 (76.5%) Msh2-deficient mice and occurs only after a much longer time period. The B[a]P-DNA adduct levels measured in lung, liver, spleen and forestomach of B[a]P-treated Msh2-/- mice were not significantly different from B[a]P-treated Msh2+/+ mice. In summary, the results suggest that B[a]P accelerates lymphomagenesis in Msh2-deficient mice. Furthermore, Msh2 deficiency does not have any significant effect on B[a]P-DNA adduct levels.
Zienolddiny
Shanbeh
S
Department of Toxicology, National Institute of Occupational Health, Oslo, Norway.
Ryberg
David
D
Svendsrud
Debbie H
DH
Eilertsen
Einar
E
Skaug
Vidar
V
Hewer
Alan
A
Phillips
David H
DH
te Riele
Hein
H
Haugen
Aage
A
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D018736:DNA Adducts; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D008223:Lymphoma / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000502:physiology
D018736:DNA Adducts; D001564:Benzo(a)pyrene; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein