NUTR*4510 Toxicology Unit 4: Chemical Carcinogens

NUTR*4510 Toxicology, Nutrition & Food - Unit 4: Chemical Carcinogens in Foods

• This unit covers chemical carcinogens found in foods.

Neurotoxicity Perspective

• Adverse effects affect brain, central nervous system, and peripheral nervous system functions
• Effects can be permanent or reversible
• Lipophilic xenobiotics accumulate in lipid-rich regions like the brain and spinal column
• Potential issues include problems with cognition, nerve transmission (action potentials and synaptic function), neurotransmitter function, sensory/perception, motor function, and behaviour/emotions

Neurotoxicity Phenotypic Manifestations/Characteristics

• Confusion, poor concentration, and memory loss are among the common symptoms
• Personality changes, behavioral changes, and pain (headache or localized)
• Numbness, hyperesthesia, and paraesthesia
• Loss of sensation, muscle weakness, loss of coordination
• Difficulty with speech/communication, swallowing
• Paralysis, involuntary muscle jerks or spasms, seizures
• Dizziness or vertigo; changes in sensory function (visual, auditory, taste, smell, touch)
• Changes in levels of consciousness, respiratory distress (rapid/slowed breathing/shallow breaths/asphyxiation), coma
• Cardiovascular effects (tachycardia, bradycardia, hypotension, pulmonary edema) and gastrointestinal effects (abdominal pain, diarrhea, vomiting)

Grading of Common Neurotoxicity Symptoms

• Grades I-IV categorize severity based on limiting activities of daily living (ADLs) and disorientation
• Grade I is mild limiting of ADLs and mild disorientation
• Grade II limits instrumental ADLs, and disorientation levels rise further
• Grade III severely limits self-care ADLs, and disorientation is severe
• Grade IV involves life-threatening consequences and urgent intervention
• This table serves to understand the varying grades of severity

Common Neurotoxicity Manifestations

• Encephalopathy is damage or malfunction in the brain causing an altered mental state, possibly with physical changes.
• Dysphasia leads to the inability to verbalize or understand speech
• Somnolence is the feeling of sleepiness or drowsiness
• Seizures are uncontrolled electric disturbances in the brain, manifesting as changes in behaviour, movement/spasms, or consciousness.

Basic Information about Cancer

• Cancer involves abnormal cell morphology (structure) and cell growth (proliferation)
• Many cells replicate continuously and unpredictably in cancer
• Cancer cells have variations in their sizes and shapes.
• The nucleus of a cancer cell is larger and darker than a normal cell nucleus.
• Clustered cancer cells lack a defined boundary.

What is Cancer?

• Cancer is a group of diseases with diverse types in varying tissues
• Cell growth and proliferation are controlled and highly regulated in healthy tissues
• Benign or malignant tumors can form, either of which can be either benign or malignant

Precancerous (Premalignant) Definitions

• Hyperplasia: An abnormal increase in cell numbers.
• Atypia (Atypical): Cells appear slightly abnormal under a microscope
• Metaplasia: Cells appear normal under microscopy, differing from normal tissue type
• Dysplasia: Cells exhibit abnormal organization and appearance, which might evolve into cancer over time

Metastasis

• Cancer cells spreading to other parts of the body to form new tumors
• Three methods of metastasis are invasion (direct extension), through the bloodstream (hematogenous spread), and through the lymphatic system

In Cancer

• Increased cell proliferation and decreased or blocked apoptosis are key characteristics
• This leads to the formation of long-lived, rapidly dividing cells, leading to tumors that grow in size and potentially metastasize

Examples of Types DNA Damage

• Base mismatch
• Point mutation (specific example provided)
• Single strand breaks
• Abasic sites
• 8-oxoguanine (mismatched base pairing)
• Double-strand breaks
• Cross-links (intrastrand and interstrand)
• Bulky adducts
• Small adducts
• Various types are identified

DNA Repair Mechanisms

• Primarily focuses on the base excision repair mechanism.
• Includes enzymes, stages, and mechanisms involved in the repair process

Examples of DNA Damage or Mutations Leading to Cancer

• Mutations in DNA repair mechanisms impede cells from fixing DNA damage.
• Example mutations in tumor suppressor genes, cell cycle genes, and apoptosis genes
• Changes in genes responsible for cell proliferation can result in an increased rate of replication.

Chemical Carcinogenesis Process

• Involves initiation (irriversible), promotion (encourages cell division), and progression (additional mutations, permanent changes) that lead to invasion and metastasis
• Specific examples of inducers are HCA, PAH, NA
• Ethanol is a weak inducer
• Accumulation of additional mutations are favored by heightened multiplication.

Examples of Types DNA Damage (continued)

• Focus on different types of DNA damages and repair mechanisms

Examples of Types DNA Damage (continued)

• Further detailed explanation of various DNA damages and repair processes.

Mycotoxins

• Toxic metabolites produced by molds/fungi; mycotoxins are a significant issue in many food sources
• Molds can grow before/after harvest or during food storage
• Often seen in warm, damp, or humid conditions
• Exposure is through eating infected foods or consuming animals that have consumed contaminated feed.
• Mycotoxins can significantly impact health both in humans and livestock, ranging from acute poisoning to long-term issues like immune deficiency and cancer,

Multistep Hepatocarcinogenesis

• Describes a stepwise development of liver cancer through hepatocytes, adenomas, and carcinomas
• Details methods of identifying and studying this process experimentally.

Examples of Dietary Carcinogens (perspective of xenobiotic metabolism)

• Mycotoxins
• Polycyclic aromatic hydrocarbons (PAHs)
• Heterocyclic amines (HCAs)
• Nitrosamines

PAH

• Polycyclic aromatic hydrocarbons are a class of over one hundred chemical compounds formed from incomplete combustion.
• These compounds form when burning various substances like food fats, carbohydrates, wood chips, tobacco, etc.
• They form at temperatures greater than 250 C
• PAH cause cancer in various parts of the gastrointestinal tract, primarily.
• Certain phytochemicals, like those found in many fruits and vegetables, compete with PAHs to prevent activation by the CYP family and binding to AhR.

HCA

• Heterocyclic amines, or HCAs, are a group of 20+ chemical compounds that contain heterocyclic and amine rings.
• They form during cooking processes like grilling, roasting, baking, and frying, resulting in high temperatures.
• The main source is the reaction between amino acids, sugars, and high temperatures within the cooking process.

HMF

• 5-Hydroxymethylfurfural (HMF)
• Potentially carcinogenic to humans, this material is a flavoring agent in several foods.
• HMF forms during Maillard reactions and caramelization via sugar dehydration.
• higher cooking temperature leads to higher HMF concentration.
• HMF concentration can be a marker to measure the quality of processed foods
• Intake range is 30 to 150 mg per day/person

Acrylamide

• Formed when certain amino acids (e.g., asparagine) react with reducing sugars during high temperature cooking
• Found in several different food items (e.g., potato chips, french fries, and other starchy/baked goods)
• Has been linked to neurotoxic properties in animals, but the association with humans is less clear.

PhIP

• PhIP (2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), a heterocyclic amine that is formed during cooking of meat, fish, or chicken in the conditions of higher temperatures.
• PhIP can trigger enzymes called CYPs (Cytochrome P450) and AhR activation to increase the formation of reactive intermediates, ultimately promoting DNA damage.
• Vegetables can competitively prevent PhIP from binding to the AhR.

BaP Metabolism

• Metabolism involves a series of reactions starting from the intake of a chemical to various steps of excretion.
• The CYP1A1/2 family are key in the metabolism of BaP. This is related to their expression response to environmental factors or diet (many products and foods can induce).

Tobacco Xenobiotics & Review

• Describes the effects of nicotine and other toxins from tobacco.
• The effect is on the body's systems due to the intake or exposure.
• Nicotine is an insecticide and neurotoxin often present in tobacco.
• Nicotine-derived nitrosamine ketone (NNK) is a secondary carcinogen.
• Nitrate converts into nitrite, which can react with amines and form nitrosamines

Nitrosamines

• Formed by reaction of secondary or tertiary amines and nitrosating agents, like nitrite
• Common in processed meats, and some other food products (e.g., cured bacon, processed meats, non-fat dry milk, beer and certain types of fish).
• These compounds are linked to increased cancer risk as they cause mutations after interacting with DNA.
• Elevated risks associated with this compound are esophageal and gastric cancers.

Review Cytochrome P450 (CYP) enzymes

• Different types of CYPs are outlined based on their locations in the body and their specific function
• The table summarizes the tissue distribution, specific inducers (e.g., certain chemicals), nuclear receptors involved, and substrates/products.

This quiz explores Unit 4 of NUTR*4510, focusing on chemical carcinogens found in foods. It also examines neurotoxicity, discussing adverse effects on the brain and nervous system. Understand the phenotypic manifestations of neurotoxicity, including cognitive impairments and sensory dysfunction.