Teratogenesis, Mutagenesis, and Carcinogenesis

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Define teratogenesis, mutagenesis, and carcinogenesis. • Describe the relevance of replication, transcription, and translation to teratogenesis, mutagenesis, and carcinogenesis. • Summarize the mechanism of action for teratogenesis, mutagenesis, and carcinogenesis. • Discuss examples of known teratogens, mutagens, and carcinogens.

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Principles of Environmental Toxicology Learning Objectives • Define teratogenesis, mutagenesis, and carcinogenesis. • Describe the relevance of replication, transcription, Teratogenesis, Mutagenesis, and translation to teratogenesis, mutagenesis, and and Carcinogenesis carcinogenesis. • Summarize the mechanism of action for teratogenesis, mutagenesis, Principles of Environmental Toxicology and carcinogenesis. Instructor: Gregory Möller, Ph.D. • Discuss examples of known University of Idaho teratogens, mutagens, and carcinogens. 2 Principles of Environmental Toxicology Principles of Environmental Toxicology Molecules of Life The Cell • Toxicants can react with or modify DNA or RNA. replication – Can lead to heritable change in offspring or changes in cellular growth and development. DNA • Replication → perpetuate genetic nucleus transcription information. RNA • Transcription and translation → express genetic information. translation ribosomes Proteins cytoplasm 3Hughes 4 Principles of Environmental Toxicology Principles of Environmental Toxicology Protein Functions Endpoints • Antibodies. • Teratogenesis. – Recognize molecules of invading organisms. – Origin or production of malformed fetuses or offspring. • Receptors. • Mutagenesis. – Part of the cell membrane; recognize other proteins, or – Production of a mutation or change in the genetic code of chemicals, and inform the cell. an organism. • Enzymes • Carcinogenesis. – Assemble or digest. – Cancer formation including carcinoma and malignant • Neurotransmitters, hormones neoplasms. – Trigger receptors. • Channels and pores. 6 Hughes 5 Rothamsted 1
Principles of Environmental Toxicology Principles of Environmental Toxicology DNA Replication Replication • Duplicates cell DNA. • Structure implies replication • Mitosis - one somatic cell with 2n chromosomes • Occurs via multiple enzyme action divides to create two cells with 2n chromosomes • Helix unravels, strands part, DNA replicates (humans, n = 23). • Mitosis, meiosis • Number, quality and quantity of chromosomes per • Not always perfect cell is conserved. – Repair enzymes – Triggers for mitosis (receptors + proteins). • External signals. • Hormones. • Internal factors. • Growth factors. 8Hughes 7 Principles of Environmental Toxicology Principles of Environmental Toxicology Replication, 2 DNA Transcription • Meiosis - germ cells are cells that divide into gametes. • DNA is copied via expendable mRNA – 2 cell divisions. • mRNA codes for specific proteins – Four daughter cells. • Occurs in nucleus of cell • Each with a different set of chromosomes. • Each with 1 set that will be joined by another in fertilization. 9Hughes 10 Principles of Environmental Toxicology Principles of Environmental Toxicology DNA Translation Transcription and Translation • Occurs in the cytosol • DNA: double strand of nucleotides. – Nucleotide = nucleic acid, sugar and phosphate. • Interaction of mRNA, tRNA, – Cytosine, Thymine, Uracil; Adenine, Guanine. amino acids and enzymes – Base pairing = A-T, G-C. • tRNA has three-base codons – Gene: sequence of bases that code for a specific which correspond to different aa sequence of amino acids (protein). • AA are added one at a time to – Codon: sequence of 3 bases form chain - polypeptide that code for a single amino • Polypeptide corresponds to acid, i.e. • AGC → Serine. protein with a specific aa • AAA → Lysine. sequence Hughes 11 12 2
Principles of Environmental Toxicology Principles of Environmental Toxicology Transcription and Translation, 2 DNA Structure - Function • Transcription = copying. • Nucleotides form chains – DNA unzips and enzymes make RNA “copy”. • 3 nucleotides form a codon – Differences: • Multiple codons form genes • T → U (UA not TA). • Multiple genes form chromosomes • Deoxyribose → ribose. • Multiple chromosomes form DNA – mRNA formation; transport to cytoplasm. • Translation = protein formation. – mRNA (blueprint). – rRNA (support). – TRNA (a.a. transport). Hughes 13 14 Principles of Environmental Toxicology Principles of Environmental Toxicology DNA/RNA Complex DNA/RNA Complex, 2 15 16 Errors in DNA Replication, Principles of Environmental Toxicology Principles of Environmental Toxicology DNA/Chemical Interactions Transcription and Translation • Base pairing • Alkylation - covalent adduct between DNA and chemical • Repair enzymes and other enzymes • Intercalation - noncovalent • Regulatory genes, operons, binding of chemical between two termination sequences adjacent base pairs • Methylation patterns • Cross-linkage - Inter or • Post transcriptional/translational intrastrand covalent binding of processing chemical • Breakage - scission of one or both strands of DNA 17 18 3
Principles of Environmental Toxicology Principles of Environmental Toxicology Afltoxin B1 – DNA Adduct Teratogenesis • Teratology: the study of the frequency, causation, and development of congenital malformations. • Complex mechanisms and timing of disruptive interaction during embryogenesis. • Some natural “bad path” spontaneous abortion. – Humans: critical 1st 8 wks gestation. • Embryonic stage. • Morphological defects in specialized tissues and organs. – Fetal stage exposure. • Developmental or neoplastic endpoints. • Known human teratogens. 19 20 Principles of Environmental Toxicology Principles of Environmental Toxicology Example: Teratogenesis Example: Teratogenesis, 2 Five Legged Frog Ovine Cyclopia Veratrum Californicum W. False Helebore 21 22 Principles of Environmental Toxicology Principles of Environmental Toxicology Example: Teratogenesis, 3 Case Study: Lupine Alkaloid Birth Defects Crooked Calf • In September 1980, a baby boy born in the OH mountainous back-country of northwestern Disease California (Trinity County) was brought to the UC Medical Center in Sacramento with severe bone deformities in his arms and hands, including a partial absence of forearm bones (radial aplasia) N and absent thumbs. Lupine • Extensive medical histories and genetic analyses Quinolizidine alkaloids of his parents indicated that the probable cause Anagyrine was environmental rather than hereditary. • His mother feared that somehow exposure to herbicide spraying was responsible. Association of forest spraying and a reportedly high incidence of birth defects in northwestern California and southern Oregon has been highly publicized in recent years and has become controversial. Indeed, it appears likely that this herbicide had been applied to a forested ridge several miles distant from the mother's home more than a year before the child's conception. 23 24 4
Principles of Environmental Toxicology Principles of Environmental Toxicology Case Study: Lupine Alkaloid Birth Defects Mutagenesis • Somatic cell mutations → metabolic dysfunction; • The mother provided the evidence that her goats also gave birth to kids stillborn or with deformed legs during and after the period of her carcinogenesis. pregnancy, and that puppies born to a dog fed • Germ cell mutation → heritable change. the goat's milk during pregnancy were likewise deformed. • Local goat's milk has become a common food • Point mutation. item in the area, and the child's mother drank it – Base substitution (including analogues). regularly herself throughout pregnancy. • A thorough survey of nearby areas where the – Frame shift. goats had regularly browsed at the time of the mother's early pregnancy showed that a • Chromosomal aberration. perennial lupine, identified as the widely distributed Lupinus latifolius, often formed the – Structural anomaly. principal low-growing forage as well as wild tobacco (Nicotiana), poison hemlock (Conium), – Numerical anomaly. and skunk cabbage (Veratrum). • Circumstantial evidence. Hughes UC Davis Env Tox Newsletter 25 26 2:3 November 5, 1981 Principles of Environmental Toxicology Principles of Environmental Toxicology Karotypes Abberations • Aneuploidy/Polyploidy Patterns photographed • Loss or gain of complete chromosomes during metaphase help – Microscopically visible examine for chromosomal – Down’s Syndrome - (47,21+) trisomy 12 3 4 5 defects. 1 2 3 4 5 – Klinefelder’s Syndrome (47,XXY) trisomy – Turner’s Syndrome (45,XO) monosomy 67 8 9 10 11 12 6 7 8 9 10 11 12 13 14 15 16 17 18 13 14 15 16 17 18 19 20 21 22 X Y 19 20 21 22 X Y 27 28 Principles of Environmental Toxicology Principles of Environmental Toxicology Ames Test for Chemical Mutagenicity Carcinogenesis • Salmonella bacteria strain with histidine coding Procarcinogen (nonreactive) defect. Multi-step, • Mutagenic chemicals can change the defect to allow multi-factorial disease Carcinogen cell division and growth. • Add salmonella + test chemical + rat hepatocytes Carcinogen + DNA (for biotransformation). Mutation/ – Growth indicates Initiation mutagenic effect. Mutation Promoting agent Promotion 30 Cancer Cancer 29 5
Principles of Environmental Toxicology Principles of Environmental Toxicology Cancer Definitions Cancer Definitions, 2 • Cancer. NLM • Benign tumor. – A malignant tumor that has the ability to metastasize or – A tumor that does not invade into surrounding tissues. metastasize. • Tumor (Neoplasm). • Metastasis. – A general term for the uncontrolled growth of cells that – Ability to establish secondary becomes progressively tumor growth at a new location. worse with time. • Neoplasia. – The growth of new tissue with abnormal and unregulated cell proliferation. NLM 31 32 Copyright © 2006 Gary Carlson Principles of Environmental Toxicology Principles of Environmental Toxicology Cancer Definitions, 3 Multistage Carcinogenesis: Initiation NLM • Carcinoma. • Chemical-virus-spontaneous causes DNA lesion – Malignant tumor arising in the epithelium. • Cell division perpetuates DNA lesion – Most common form of cancer. • No outcome if not promoted – Usually spreads in the lymphatic system. – Some chemicals can initiate and promote • Sarcoma. – May remain indefinitely if not promoted – Malignant tumor in muscle • One hit or connective tissue. – No threshold; irreversible – Usually spread in the blood stream. – Frequently metastasizes to the lung. 33 34 Copyright © 2006 Gary Carlson Principles of Environmental Toxicology Principles of Environmental Toxicology Properties of Initiated Cells Multistage Carcinogenesis: Promotion • No phenotypic differences • Change in micro-environment of cells • Excess/deficiency of enzymes • Chemical, viral, spontaneous-induced clonal – e.g. δ-GT, G-6-P, Fe exclusion, ATPase proliferation of initiated cells • Growth control factors; receptors; immune • Resistance to cytotoxic chemicals function; endocrine control; – Faster or slower metabolism communication; metabolic; • Impaired cellular communication apoptosis • Enhanced response to • Multi-hit, high dose growth factors – Reversible • Resistance to terminal – Threshold differentiation 35 36 6
Principles of Environmental Toxicology Principles of Environmental Toxicology Multistage Carcinogenesis: Progression Classification of Carcinogens Hughes • Complete loss of growth control • Genotoxic. – Act directly on DNA or expression of DNA during • Karyotype instability translation. • Loss/gain of chromosomal fragments • DNA replication errors. • DNA demethylation/deregulation • Point mutations. • Chromosomal aberration. • Gene amplification • Epigenetic. • Error prone DNA repair – Non-DNA reactive. • Irreversible – Potentiators. • Same mechanisms as – Cell, hormone, immune promotion function modifiers. 37 38 Principles of Environmental Toxicology Principles of Environmental Toxicology Genotoxic Carcinogens Epigenetic Carcinogens Marquardt • Chemical capable of producing cancer by directly • Cytotoxic carcinogens. altering the genetic material of target cells. – Nitrillotriacetate, BHA, BHT. • Direct carcinogens (no metabolic activation). • Tumor promotors. – Alkylating agents. – DDT, Dioxin • Indirect carcinogens (metabolic activation). • Hormones. – Polycyclic aromatic hydrocarbons. – Estradiol, DES – Aromatic amines. • Immunosuppressants. – Nitrosamines. – Cyclosporin A – Natural substances. • Particulates. • Mycotoxins. – Asbestos. – Inorganic carcinogens. • Ni, Cr, Cd, As. 39 40 Marquardt Principles of Environmental Toxicology Principles of Environmental Toxicology PAH Carcinogenic Activation Proven Human Carcinogens Bay region Marquardt • Chemicals. 11 Marquardt 10 – Aflatoxins, 4-aminobiphenyl, As, benzene, benzidine, Be, 9 bis-chloroethylether, Cd, Cr(VI), soot, mineral oils, mustard gas, 2-naphthylamine, Ni, vinyl chloride. 8 7 • Substance abuse. O 7,8-Epoxide – Alcohol, betel nuts, cigarettes. • Dust and fiber. O – Asbestos, silica, soots, talcum, wood dust. HO HO • Chronic infection. OH OH – H pylori, Hepatitis B/C, HIV, 7,8-Diol 7,8-Diol-epoxide liverfluke, papilloma virus, (reactive) schistosomes. 42 41 DNA 7
Principles of Environmental Toxicology Principles of Environmental Toxicology Initiator Chemicals in Food Promoting Agents in Food • Most genotoxic chemicals • Butylated hydroxy toluene (BHT) • PAHs • Saccharin • Aromatic amines • Cholic acid • Heterocyclic amines • Tetrachloro-dibenzo-dioxin (TCDD) • Mycotoxins • Alcohol • Nitrosamines • Nitrosamides 43 44 Principles of Environmental Toxicology Principles of Environmental Toxicology Chemical Cancer Assessment Causes of Cancer Human carcinogen Sufficient human Group A • Diet, 35% • Infection, 10% NLM evidence • Tobacco, 30% • Occupational exposure, 4% Probable human Limited human Group B1 • Sexual behavior, 7% • UV/radiation, 3% evidence • Alcohol, 3% • Pollution, 2% Probable human Inadequate human Group B2 evidence Possible human Limited animal Group C evidence Not classifiable Inadequate animal Group D evidence No evidence 2 animal tests or Group F epidem. and animal 45 46 NLM Principles of Environmental Toxicology Principles of Environmental Toxicology 2006 Estimated US Cancer Cases* 2006 Estimated US Cancer Deaths* Lung & bronchus 31% 26% Lung & bronchus Prostate 33% 31% Breast Men Women Men Women Colon & rectum 10% 291,270 273,560 15% Breast Lung & bronchus 13% 720,280 679,510 12% Lung & bronchus Prostate 9% 10% Colon & rectum Colon & rectum 10% 11% Colon & rectum Pancreas 6% 6% Pancreas Urinary bladder 6% 6% Uterine corpus Leukemia 4% 6% Ovary Melanoma of skin 5% 4% Non-Hodgkin lymphoma Liver & intrahepatic4% 4% Leukemia Non-Hodgkin 4% bile duct lymphoma 4% Melanoma of skin 3% Non-Hodgkin Esophagus 4% lymphoma Kidney 3% 3% Thyroid Non-Hodgkin 3% 3% Uterine corpus Oral cavity 3% 3% Ovary lymphoma 2% Multiple myeloma Leukemia 3% 2% Urinary bladder Urinary bladder 3% 2% Brain/ONS Pancreas 2% 2% Pancreas Kidney 3% 23% All other sites All Other Sites 18% 22% All Other Sites All other sites 23% *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. 47 48 ONS=Other nervous system. Source: American Cancer Society, 2006. Source: American Cancer Society, 2006. 8
Lifetime ProbabilityPrinciples of Environmental Toxicology Principles of Environmental Toxicology of Developing Lifetime Probability of Developing Cancer, Cancer, by Site, Men, 2000-2002* by Site, Women, US, 2000-2002* Site Risk Site Risk * For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during All sites† All sites† 1 in 2 1 in 3 2000 to 2002. ‡ Includes invasive and in situ cancer cases Prostate 1 in 6 Breast 1 in 8 † All Sites exclude basal and squamous cell skin cancers and in situ cancers except Lung and bronchus 1 in 13 Lung & bronchus 1 in 17 urinary bladder. Source: DevCan: Probability of Developing or Colon and rectum 1 in 17 Colon & rectum 1 in 18 Dying of Cancer Software, Version 6.0 Statistical Research and Applications Branch, NCI, 2005. http://srab.cancer.gov/devcan bladder‡ Urinary 1 in 28 Uterine corpus 1 in 38 Non-Hodgkin lymphoma 1 in 46 Non-Hodgkin lymphoma 1 in 55 Melanoma 1 in 52 Ovary 1 in 68 Kidney 1 in 64 Melanoma 1 in 77 Leukemia 1 in 67 Pancreas 1 in 79 Urinary bladder‡ Oral Cavity 1 in 73 1 in 88 Stomach 1 in 82 Uterine cervix 1 in 135 49 50 Principles of Environmental Toxicology Principles of Environmental Toxicology Colorectal Colon Polyps Cancer Risk Factors – Over 50 – Previous occurrence – Family history – High fat/low fiber diet – Smoking – Alcohol consumption – Sedentary – Over weight 51 52 Principles of Environmental Toxicology Principles of Environmental Toxicology Stages of Colorectal Cancer Kidney Cancer NLM 53 54 9
Principles of Environmental Toxicology Principles of Environmental Toxicology Liver Cancer Basal Cell Carcinoma NLM NLM 55 56 Trends in Consumption of FivePrinciples of Recommended or More Environmental Toxicology Principles of Environmental Toxicology Vegetable and Fruit Servings for Cancer Prevention, Tobacco Use in the US, 1900-2002 Adults 18 and Older, US, 1994-2003 5000 100 35 4500 90 The American Cancer Age-Adjusted Lung Cancer Death 30 24.4 24.4 24.2 4000 80 24.1 Society recommends that 23.6 25 individuals eat five or more Per Capita Cigarette Consum 3500 70 20 Prevalence (% Per capita cigarette servings of vegetables and consumption 3000 60 15 fruits a day for cancer prevention. 2500 50 10 Male lung cancer 2000 40 5 death rate 1500 30 0 1994 1996 1998 2000 2003 1000 20 Year Female lung cancer 500 10 death rate Note: Data from participating states and the District of Columbia were 0 0 aggregated to represent the United States. 1900 1905 1910 1915 1920 1925 1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 Source: Behavioral Risk Factor Surveillance System CD-ROM (1984- 1995, 1996, 1998) and Public Use Data Tape (2000, 2003), National Center for Chronic Disease Prevention and Health Promotion, Centers for Year Disease Control and Prevention, 1997, 1999, 2000, 2001, 2004. *Age-adjusted to 2000 US standard population. Source: Death rates: US Mortality Public Use Tapes, 1960-2002, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2005. Cigarette consumption: US 57 58 Department of Agriculture, 1900-2002. 10