Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH); this ubiquitous environmental carcinogenic agent is found in tobacco smoke, charcoal-grilled foods, and PAH-contaminated surfaces of roofs, playgrounds, and highways. Cytochrome P450 1 wild-type, Cyp1a2(-/-), Cyp1b1(-/-), or Cyp1a2/1b1(-/-) knockouts, and mice with Cyp1a1 expression deleted in hepatocytes can ingest large oral BaP doses (125 mg/kg/d) without apparent toxicity. Cyp1a1(-/-) and Cyp1a1/1a2(-/-) knockouts and mice with Cyp1a1 expression deleted in gastrointestinal (GI) tract epithelial cells develop immunotoxicity and die within 32 days, indicating that GI tract inducible CYP1A1 is absolutely required for detoxication of oral BaP. Cyp1a1/1b1(-/-) and Cyp1a1/1a2/1b1(-/-) mice are rescued from immunosuppression and early death due to absent metabolic activation of BaP by CYP1B1 in immune cells. Ten-fold lower oral BaP doses result in adenocarcinoma of the proximal small intestine (PSI) in Cyp1a1(-/-) mice; Cyp1a1/1b1(-/-) double-knockout mice show no PSI cancer but develop squamous cell carcinoma of the preputial gland duct (PGD). BaP-metabolizing CYP1B1 in the PSI and CYP3A59 in the PGD are the most likely candidates to participate in tumor initiation in the epithelial cells of these two tissues; oncogenes and tumor-suppressor genes upregulated and downregulated during tumorigenesis are completely different between these tissues. This "oral BaP Cyp1" mouse paradigm represents a powerful teaching tool, showing that gene-environment interactions depend on route-of-administration: the same oral, but not intraperitoneal, BaP exposure leads to dramatic differences in target-organ toxicity and tumor type as a function of dose and Cyp1 genotype.

<h4>Background</h4>The association between gastrointestinal cancer and types of meat consumption, including red meat, processed meat, or a combination of both, remains disputable. Therefore, we performed a systematic review and meta-analysis of prospective cohort studies to estimate the association between meat consumption and gastrointestinal cancer risk.<h4>Methods</h4>PubMed, EmBase, and the Cochrane library databases were searched systematically for eligible studies that investigated the relation between meat consumption and the risk of developing gastrointestinal cancers, including esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), colon cancer (CC), rectal cancer (RC), pancreatic cancer (PC), and hepatocellular carcinoma (HCC) throughout February, 2023. The pooled relative risk (RR) with 95% confidence interval (CI) was assigned as an effect estimate and calculated using a random-effects model with inverse variance weighting.<h4>Results</h4>Forty cohorts comprising 3,780,590 individuals were selected for the final quantitative analysis. The summary results indicated that a higher red meat consumption was associated with an increased risk of CRC (RR: 1.09; 95% CI: 1.02-1.16; P = 0.007) and CC (RR: 1.13; 95% CI: 1.03-1.25; P = 0.011). Moreover, a higher processed meat consumption was associated with an increased risk of CRC (RR: 1.19; 95% CI: 1.13-1.26; P < 0.001), CC (RR: 1.24; 95% CI: 1.13-1.26; P < 0.001), and RC (RR: 1.24; 95% CI: 1.08-1.42; P = 0.002). Furthermore, a higher total consumption of red and processed meat was associated with an increased risk of CRC (RR: 1.13; 95% CI: 1.06-1.20; P < 0.001), CC (RR: 1.17; 95% CI: 1.04-1.33; P = 0.012), and RC (RR: 1.20; 95% CI: 1.04-1.39; P = 0.016). Finally, the strength of higher consumption of total red and processed meat with the risk of GC, and higher consumption of red meat with the risk of RC in subgroup of high adjusted level was lower than subgroup of moderate adjusted level, while the Abstract Background The association between gastrointestinal cancer and types of meat consumption, including red meat, processed meat, or a combination of both, remains disputable. Therefore, we performed a systematic review and meta-analysis of prospective cohort studies to estimate the association between meat consumption and gastrointestinal cancer risk. According to the International Agency for Research on Cancer (IARC), mortality caused by gastrointestinal cancers accounts for 45% of all cancer-related mortality in China [ 2 ]. The standard treatment strategies for gastrointestinal cancers include surgery, endoscopy, chemotherapy, Studies have found that several diseases could be caused by unhealthy diets, including cancer, and nearly 930,000 cancer-related mortality were induced by poor diet in 2017, especially breast and colorectal cancer (CRC) [ 5 , 6 ]. The IARC classified red meat as a probable carcinogen based on CRC, pancreatic cancer (PC), and prostate cancer evidence, while processed meat was regarded as carcinogenic to humans based on CRC evidence [ 7 ]. Moreover, the World Cancer Research Fund and American Institute for Cancer Research suggest that red meat consumption should be less than three portions per week [ 8 ]. Prospective cohort studies that assessed the association of red and processed meat consumption with gastrointestinal cancer risk were included in this study, and the publication language and status without restriction. Subgroup analyses indicated no significant association between red meat, processed meat, and total red and processed meat with GC risk in all subsets (Table 2 ). No significant publication bias was observed for red meat ( P value for Egger: 0.095; P value for Begg: 0.536), processed meat ( P value for Egger: 0.395; P value for Begg: 1.000), and total red and processed meat consumption ( P value for Egger: 0.388; P value for Begg: 0.806) (Supplementary file 2 ). Fig. 3 Association of meat consumption with the risk of gastric cancer. Subgroup analyses revealed that higher consumption of red meat intake was associated with an increased risk of RC when pooled studies were conducted in Western countries, and pooled studies with moderately adjusted levels, and the strength of relation in the subgroups of studies with higher adjusted levels was significantly lower than those of studies with moderate adjusted levels (RRR: 0.50; 95% CI: 0.28–0.91). Furthermore, higher processed meat consumption was associated with an increased risk of RC when pooled studies were conducted in Western countries, follow-up duration < 10.0 years, and irrespective of the adjusted level, while the strength of the relationship in the subgroup with longer follow-up duration was significantly lower than that in the subgroup with shorter follow-up duration (RRR: 0.77; 95% CI: 0.60–1.00) (Table 2 ). Our study found that meat consumption plays an important role in the risk of CRC, CC, and RC, which is consistent with prior meta-analysis [ 11 ]. There were varies molecular pathways contributed the carcinogenesis across the regions of colon and rectum. The microsatellite instability, a CpG island methylator phenotype, and KRAS mutations were more evident for proximal colon cancers than rectal and distal colon tumors, whereas TP53 and APC mutations were more evident for rectal and distal colon tumors [ 103 ]. The potential mechanism could be high levels of cholesterol and saturated fat in red meat is significantly related to the progression of cancer. Moreover, subgroup analyses revealed that processed meat was associated with a reduced risk of HCC when the follow-up duration was < 10.0 years. These results could be explained by the fact that HCC progression is significantly related to socioeconomic status, which could affect meat consumption [ 108 , 109 ]. Other influencing factors included selection bias, random errors, and various adjusted levels. Some limitations of this study should be acknowledged.

On October 26, 2015, IARC published a summary of their findings regarding the association of cancer with consumption of red meat or processed meat (IARC 2015; The Lancet Oncology 2015). The Working Group concluded that there is limited evidence in human beings for carcinogenicity from the consumption of red meat and inadequate evidence in experimental animals for the carcinogenicity of consumption of red meat. Nevertheless, the working group concluded that there is strong mechanistic evidence by which ingestion of red meat can be linked to human colorectal cancer and assigned red meat to Group 2A "probably carcinogenic to humans". The Working Group cited supporting mechanistic evidence for multiple meat components, including those formed from meat processing, such as N-nitroso compounds (NOC) and heterocyclic aromatic amines, and the endogenous compound, heme iron. The mechanism of action for each of these components is different and so it is critical to evaluate the evidence for each component separately. Consequently, this review critically examined studies that investigated mechanistic evidence associated with heme iron to assess the weight of the evidence associating exposure to red meat with colorectal cancer. The evidence from in vitro studies utilized conditions that are not necessarily relevant for a normal dietary intake and thus do not provide sufficient evidence that heme exposure from typical red meat consumption would increase the risk of colon cancer. Animal studies utilized models that tested promotion of preneoplastic conditions utilizing diets low in calcium, high in fat combined with exaggerations of heme exposure that in many instances represented intakes that were orders of magnitude above normal dietary consumption of red meat. Finally, clinical evidence suggests that the type of NOC found after ingestion of red meat in humans consists mainly of nitrosyl iron and nitrosothiols, products that have profoundly different chemistries from certain N-nitroso species which have been shown to be tumorigenic through the formation of DNA adducts. In conclusion, the methodologies employed in current studies of heme have not provided sufficient documentation that the mechanisms studied would contribute to an increased risk of promotion of preneoplasia or colon cancer at usual dietary intakes of red meat in the context of a normal diet.

Colorectal cancer is one of the leading causes of cancer-related death worldwide, and part of its risk is linked to modifiable dietary factors. This integrative review examined studies published between 2013 and 2023 in PubMed, SciELO, ScienceDirect and LILACS addressing the relationship between red and processed meat intake and intestinal cancer. Overall, cohort studies and meta-analyses consistently show an increased risk of colorectal cancer among individuals with higher consumption of these foods, particularly processed meats. Proposed mechanisms include the formation of N-nitroso compounds, heterocyclic amines and polycyclic aromatic hydrocarbons during high-temperature cooking, as well as the effects of heme iron, gut dysbiosis and chronic inflammation on the colonic epithelium. It is concluded that limiting red meat intake, avoiding processed meats and adopting dietary patterns rich in fiber and plant-based foods are key strategies for colorectal cancer prevention. RCMOS – Revista Científica Multidisciplinar O Saber. ISSN: 2675-9128. São Paulo-SP. Este é um artigo publicado em acesso aberto (Open Access) sob a licença CreativeCommons Attribution, que permite uso, distrib uição e reprodução em qualquer meio, sem restrições desde que o trabalho original seja corretamente citado. Ano III, v.2 2023 | submissão: 04/12/2023 | aceito: 06/12/2023 | publicação: 08/12/2023 Consumo de carne vermelha e risco de câncer colorretal: uma revisão integrativa da literatura internacional Red meat consumption and colorectal cancer risk: an integrative review of the international literature Kathleen Coelho Vieira Moreno Resumo O câncer colorretal figura entre as principais causas de morte por câncer no mundo, e parte desse risco está associada a fatores dietéticos modificáveis. Esta revisão integrativa analisou estudos publicados entre 2013 e 2023 nas bases PubMed, SciELO, Scien ceDirect e LILACS sobre a relação entre consumo de carne vermelha/processada e câncer intestinal. De forma consistente, coortes e metanálises indicam aumento do risco de câncer colorretal em indivíduos com maior ingestão desses alimentos, especialmente car nes processadas. Mecanismos propostos incluem a formação de compostos N -nitrosos, aminas heterocíclicas e hidrocarbonetos aromáticos policíclicos durante o preparo em altas temperaturas, além do papel do ferro heme, da disbiose intestinal e de processos inflamatórios crônicos no epitélio colônico. Conclui -se que a limitação do consumo de carne vermelha, a evitação de carnes processadas e a adoção de padrões alimentares ricos em fibras e alimentos de origem vegetal constituem estratégias relevantes de prevenção do câncer intestinal. Palavras-chave: carne vermelha; câncer colorretal; carcinogênese intestinal; carne processada; dieta. Abstract Colorectal cancer is one of the leading causes of RCMOS – Revista Científica Multidisciplinar O Saber. ISSN: 2675-9128. São Paulo-SP. Este é um artigo publicado em acesso aberto (Open Access) sob a licença CreativeCommons Attribution, que permite uso, distrib uição e reprodução em qualquer meio, sem restrições desde que o trabalho original seja corretamente citado. Ano III, v.2 2023 | submissão: 04/12/2023 | aceito: 06/12/2023 | publicação: 08/12/2023 Referências BOUVARD, V. et al. Carcinogenicity of consumption of red and processed meat. Lancet Oncology, London, v. 16, n. 16, p. 1599-1600, 2015. INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. Red meat and processed meat . IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, v. 114. Lyon: IARC, 2018. WORLD CANCER RESEARCH FUND; AMERICAN INSTITUTE FOR CANCER RESEARCH. 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Dietary exposure to carcinogenic compounds generated during meat processing represents a critical yet underexplored component of the African cancer exposome. Traditional high-temperature cooking methods, including smoking, grilling (braai), and singeing, are deeply embedded in African culinary culture and food security systems. However, these practices promote the formation of polycyclic aromatic hydrocarbons (PAHs), heterocyclic aromatic amines (HCAs), and N-nitroso compounds (NOCs), which undergo enzymatic bioactivation to form DNA-reactive metabolites. This chapter examines the multifaceted carcinogenic risks associated with thermally processed meats in African contexts, emphasizing the synergistic effects of dietary carcinogens and environmental co-exposures, including heavy metals and persistent organic pollutants from inappropriate fuel sources. Molecular mechanisms linking these exposures to colorectal, esophageal, hepatic, and gastric cancers are elucidated through the lens of cytochrome P450-mediated metabolism, oxidative DNA damage, and disrupted cellular signaling. Critically, this analysis demonstrates how the African exposome, characterized by the intersection of traditional food practices, environmental contamination, and socioeconomic constraints, creates unique carcinogenic exposure profiles. Evidence-based mitigation strategies are presented, including antioxidant marinades, temperature moderation, clean fuel adoption, and improved smoking technologies. These interventions must be implemented within a One Health framework that integrates food safety policy, community engagement, and environmental health protection. By reconciling traditional culinary heritage with contemporary cancer prevention science, this chapter charts a pathway toward culturally respectful yet health-protective dietary practices across African communities.