☣️Toxicology Unit 6 – Carcinogenesis and mutagenesis

Key Concepts and Definitions

• Carcinogenesis involves the transformation of normal cells into cancer cells through a multistage process
• Mutagenesis refers to the induction of permanent changes in the DNA sequence of an organism
• Mutagens are physical or chemical agents that increase the rate of mutations above the spontaneous rate
• Carcinogens are substances or agents that can cause cancer by inducing cellular and molecular changes
• Oncogenes are genes that have the potential to cause cancer when activated or overexpressed
• Tumor suppressor genes normally regulate cell growth and division and can contribute to cancer development when inactivated or underexpressed
• Apoptosis is a programmed cell death process that plays a crucial role in maintaining tissue homeostasis and eliminating damaged or abnormal cells
• Angiogenesis involves the formation of new blood vessels and is essential for tumor growth and metastasis

Mechanisms of Carcinogenesis

• Chemical carcinogenesis occurs when chemical agents interact with DNA, causing mutations and cellular alterations
  • Initiators are carcinogens that cause irreversible DNA damage and initiate the carcinogenic process (benzene)
  • Promoters are agents that enhance the growth and proliferation of initiated cells (phorbol esters)
• Physical carcinogenesis can be caused by exposure to ionizing radiation (X-rays) or ultraviolet radiation (UV light)
  • Ionizing radiation induces DNA damage through direct ionization or the formation of reactive oxygen species
  • UV radiation causes the formation of pyrimidine dimers and other DNA lesions
• Viral carcinogenesis involves the integration of viral DNA into the host genome or the expression of viral oncogenes
  • Human papillomavirus (HPV) is associated with cervical cancer
  • Hepatitis B virus (HBV) is a risk factor for liver cancer
• Chronic inflammation can contribute to carcinogenesis by creating a microenvironment that promotes cell proliferation and survival
• Epigenetic alterations, such as DNA methylation and histone modifications, can alter gene expression patterns and contribute to cancer development

Types of Mutagens and Carcinogens

• Direct-acting mutagens and carcinogens can interact with DNA without requiring metabolic activation (alkylating agents)
• Indirect-acting mutagens and carcinogens require metabolic activation to become reactive and cause DNA damage (polycyclic aromatic hydrocarbons)
• Physical mutagens include ionizing radiation and ultraviolet radiation
• Chemical mutagens can be classified based on their mechanism of action
  • Base analog mutagens are incorporated into DNA in place of normal bases (5-bromouracil)
  • Intercalating agents insert between DNA base pairs and distort the DNA structure (ethidium bromide)
  • Alkylating agents add alkyl groups to DNA bases, causing mispairing and mutations (dimethyl sulfate)
• Biological mutagens include viruses and certain bacteria that can integrate their genetic material into the host genome

Cellular and Molecular Changes

• Mutations in proto-oncogenes can convert them into oncogenes, leading to uncontrolled cell growth and division
  • Point mutations can alter the function of the encoded protein (RAS gene mutations)
  • Gene amplification can increase the copy number of an oncogene (HER2 amplification in breast cancer)
• Inactivation of tumor suppressor genes can occur through mutations, deletions, or epigenetic silencing
  • The p53 gene is frequently mutated in various types of cancer, leading to a loss of its tumor-suppressive functions
• Dysregulation of cell cycle checkpoints can allow cells to bypass normal growth control mechanisms and continue dividing
• Evasion of apoptosis enables cancer cells to survive and proliferate despite the accumulation of genetic abnormalities
• Acquisition of immortality through the activation of telomerase allows cancer cells to maintain telomere length and avoid senescence
• Induction of angiogenesis provides a blood supply to support tumor growth and metastasis

DNA Damage and Repair Processes

• DNA damage can occur through various mechanisms, including oxidation, alkylation, and hydrolysis
• Endogenous sources of DNA damage include reactive oxygen species generated during cellular metabolism
• Exogenous sources of DNA damage include exposure to UV radiation, ionizing radiation, and chemical mutagens
• DNA repair mechanisms are essential for maintaining genomic integrity and preventing the accumulation of mutations
  • Base excision repair (BER) corrects small base modifications and single-strand breaks
  • Nucleotide excision repair (NER) removes bulky DNA adducts and repairs UV-induced pyrimidine dimers
  • Mismatch repair (MMR) corrects base mismatches and small insertion/deletion loops
  • Double-strand break repair mechanisms, such as homologous recombination and non-homologous end joining, repair double-strand breaks
• Defects in DNA repair genes can increase the risk of cancer development (BRCA1 and BRCA2 mutations in breast and ovarian cancer)

Genetic and Epigenetic Factors

• Inherited genetic mutations can predispose individuals to certain types of cancer (familial adenomatous polyposis)
• Single nucleotide polymorphisms (SNPs) can influence an individual's susceptibility to carcinogens and cancer risk
• Epigenetic modifications, such as DNA methylation and histone acetylation, can alter gene expression without changing the DNA sequence
  • Hypermethylation of tumor suppressor gene promoters can lead to gene silencing and contribute to cancer development
  • Histone deacetylation can result in a closed chromatin structure and reduced gene expression
• Epigenetic changes can be influenced by environmental factors, such as diet and exposure to toxicants
• Epigenetic alterations can be reversible and potentially targeted by epigenetic therapies (DNA methyltransferase inhibitors)

Detection and Testing Methods

• In vitro assays are used to assess the mutagenic and carcinogenic potential of substances
  • Ames test utilizes bacterial strains to detect mutations caused by chemical agents
  • Mammalian cell-based assays, such as the mouse lymphoma assay, evaluate mutagenicity in eukaryotic cells
• In vivo animal models are used to study the carcinogenic effects of substances and assess tumor development
  • Rodent bioassays involve the administration of a substance to rats or mice and monitoring for tumor formation
  • Transgenic animal models, such as the p53 knockout mouse, are used to study specific genetic alterations in cancer development
• Epidemiological studies investigate the association between exposure to carcinogens and cancer incidence in human populations
  • Cohort studies follow a group of individuals over time to assess cancer risk based on exposure
  • Case-control studies compare the exposure history of individuals with cancer to those without cancer
• Biomarkers can be used to detect early signs of carcinogenesis or assess the risk of cancer development
  • DNA adducts can serve as biomarkers of exposure to genotoxic agents
  • Mutations in specific genes, such as KRAS or EGFR, can be used as biomarkers for certain types of cancer

Risk Assessment and Prevention Strategies

• Risk assessment involves evaluating the potential hazards and exposure levels of carcinogens to estimate cancer risk
  • Hazard identification determines whether a substance has the potential to cause cancer
  • Dose-response assessment examines the relationship between exposure levels and cancer incidence
  • Exposure assessment estimates the extent and duration of human exposure to a carcinogen
  • Risk characterization integrates the information from the previous steps to estimate the overall cancer risk
• Regulatory agencies, such as the International Agency for Research on Cancer (IARC), classify substances based on their carcinogenic potential
• Prevention strategies aim to reduce exposure to known carcinogens and promote healthy lifestyles
  • Occupational safety measures, such as personal protective equipment and ventilation systems, can reduce workplace exposure to carcinogens
  • Public health campaigns promote awareness of cancer risk factors and encourage behaviors that reduce cancer risk (smoking cessation)
  • Vaccination against cancer-causing viruses, such as HPV and HBV, can prevent certain types of cancer
  • Chemoprevention involves the use of natural or synthetic compounds to prevent or delay the development of cancer (tamoxifen for breast cancer prevention)
• Early detection and screening programs aim to identify precancerous lesions or early-stage cancers when treatment is most effective
  • Mammography for breast cancer screening
  • Colonoscopy for colorectal cancer screening
  • Pap smear for cervical cancer screening