Benzo[a]pyrene (BP) DNA adduct formation in DNA repair-deficient p53 haploinsufficient [Xpa(-/-)p53(+/-)] and wild-type mice fed BP and BP plus chlorophyllin for 28 days

Abstract

We have evaluated DNA damage (DNA adduct formation) after feeding benzo[a]pyrene (BP) to wild-type (WT) and cancer-susceptible Xpa(-/-)p53(+/-) mice deficient in nucleotide excision repair and haploinsufficient for the tumor suppressor p53. DNA damage was evaluated by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ES-MS/MS), which measures r7,t8,t9-trihydroxy-c-10-(N (2)-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG), and a chemiluminescence immunoassay (CIA), using anti-r7,t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA antiserum, which measures both BPdG and the other stable BP-DNA adducts. When mice were fed 100 ppm BP for 28 days, BP-induced DNA damage measured in esophagus, liver and lung was typically higher in Xpa(-/-)p53(+/-) mice, compared with WT mice. This result is consistent with the previously observed tumor susceptibility of Xpa(-/-)p53(+/-) mice. BPdG, the major DNA adduct associated with tumorigenicity, was the primary DNA adduct formed in esophagus (a target tissue in the mouse), whereas total BP-DNA adducts predominated in higher levels in the liver (a non-target tissue in the mouse). In an attempt to lower BP-induced DNA damage, we fed the WT and Xpa(-/-)p53(+/-) mice 0.3% chlorophyllin (CHL) in the BP-containing diet for 28 days. The addition of CHL resulted in an increase of BP-DNA adducts in esophagus, liver and lung of WT mice, a lowering of BPdG in esophagi of WT mice and livers of Xpa(-/-)p53(+/-) mice and an increase of BPdG in livers of WT mice. Therefore, the addition of CHL to a BP-containing diet showed a lack of consistent chemoprotective effect, indicating that oral CHL administration may not reduce PAH-DNA adduct levels consistently in human organs.

Mechanistic relationships between hepatic genotoxicity and carcinogenicity in male B6C3F1 mice treated with polycyclic aromatic hydrocarbon mixtures

“…It was reported (Shi et al 2004) that women with reduced DNA repair capacity were at an increased risk for developing breast cancer. Attenuation of DNA repair and apoptosis could increase the formation of carcinogen-DNA adducts (John et al 2012) followed by DNA mutations and tumor formation. Our results indicate that proteins involved in cell cycle regulation showed both upregulation and downregulation.…”

“…Initial recognition of DNA adducts is a key event regulating DNA damage repair (Sugasawa 2011) and this includes nucleotide excision repair (NER). BaP-DNA adducts in liver and esophagus were significantly increased in DNA repair deficient mice compared to wild-type mice (John et al 2012). It was reported that apoptosis may also be associated with decreased BaP adduct levels (Zhou et al 2010) and failure to induce apoptosis in human bronchial epithelial cells exposed to cigarette smoke resulted in enhanced neoplastic transformation (Du et al 2012).…”

Role of nucleotide excision repair and p53 in zidovudine (AZT)‐induced centrosomal deregulation

“…Transgenic Xpa (−/−) p53 (+/−) C57BL/6J mice have previously been shown to be more susceptible to DNA damage [John et al, ] and cancer induction by benzo[ a ]pyrene, than their WT counterparts [Hoogervorst et al, ]. These mice (provided by H. van Steeg of the Laboratory of Toxicology, Bilthoven, The Netherlands) were originally generated on a C57BL/6 background [de Vries et al, ; van Steeg et al, ; Divi et al, ].…”

3,4-Dihydroxyphenylethanol (DPE or Hydroxytyrosol) Counteracts ERK1/2 and mTOR Activation, Pro-Inflammatory Cytokine Release, Autophagy and Mitophagy Reduction Mediated by Benzo[a]pyrene in Primary Human Colonic Epithelial Cells

“…B[a]P, besides being a lung carcinogen [ 6 ], can be considered a carcinogen for the colon [ 7 ]. As one of the underlying mechanisms leading to B[a]P-driven tumorigenesis, it is known that its metabolites can directly induce the formation of DNA adducts [ 8 ]. Of note, carcinogens may cooperate with inflammation to promote carcinogenesis [ 9 ] and may themselves trigger an inflammatory response [ 10 ].…”