Mycotoxins and Chemical Carcinogenesis Quiz

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Questions and Answers

What is the primary effect of genotoxic substances on DNA?

Repair DNA strands

Stabilize genetic material

Damage DNA (correct)

Enhance protein synthesis

How do mycotoxins potentially alter protein function?

By promoting protein folding

By enhancing lysine residues

By binding to lysine residues (correct)

By hydrolyzing protein structures

Which consequence can result from widespread mycotoxin impact within a tissue?

Cell apoptosis (correct)

Enhanced tissue repair

Improved tissue function

Maintained cellular homeostasis

Which region of DNA is associated with mycotoxin binding and damage?

Guanine/cytosine-rich regions Signup and view all the answers

What is the significance of undergoing a Phase II reaction for mycotoxin metabolites?

It promotes excretion in urine Signup and view all the answers

What is the outcome of mutations in cell cycle genes?

Cells continue to divide and proliferate. Signup and view all the answers

What occurs as a result of mutations in apoptosis genes?

Cells that cannot undergo apoptosis survive longer. Signup and view all the answers

Which of the following best describes the process of initiation in chemical carcinogenesis?

It is a permanent change to the DNA. Signup and view all the answers

During progression in cancer development, what is primarily favored by rapid cell division?

Accumulation of additional mutations. Signup and view all the answers

What characterizes the process of metastasis in cancer progression?

Invasive behavior and ability to spread to distant sites. Signup and view all the answers

What is the consequence of the initial metabolic step in adipose tissue concerning the fetal brain?

It produces a reactive electrophile that can be toxic. Signup and view all the answers

How may reactive epoxide electrophiles be excreted from the body?

Conjugation to GSH via GST to form a mercapturic acid. Signup and view all the answers

What happens to the nucleophile diol intermediate in the metabolic process?

It quickly converts into a reactive diol epoxide electrophile. Signup and view all the answers

Which characteristic of the reactive diol epoxide electrophile contributes to its carcinogenic potential?

The 'bay region' induces steric hindrance, making detoxification difficult. Signup and view all the answers

What challenge is presented by the availability of GSH in the context of reactive electrophile metabolism?

GSH is limited and impacts the conjugation process negatively. Signup and view all the answers

What is the primary area of the body affected by lipophilic xenobiotics?

Brain Signup and view all the answers

Which of the following is a possible manifestation of neurotoxicity?

Memory loss Signup and view all the answers

Which neurotoxicity symptom is characterized by excessive sensitivity of the skin?

Hyperesthesia Signup and view all the answers

Which of the following symptoms may indicate a severe manifestation of neurotoxicity?

Seizures Signup and view all the answers

Which term describes the damage or malfunction in the brain resulting in an altered mental state?

Encephalopathy Signup and view all the answers

Which of the following symptoms relates to changes in levels of consciousness?

Dizziness or vertigo Signup and view all the answers

What type of function can be affected by neurotoxicity?

Motor function Signup and view all the answers

Which symptom is characterized by an inability to maintain balance and coordination?

Ataxia Signup and view all the answers

What is the role of the CYP1A family in BaP metabolism?

To metabolize BaP into reactive epoxide electrophiles Signup and view all the answers

What effect does steric hindrance have on BaP metabolism?

It limits enzyme access to the 'bay region' Signup and view all the answers

What does the term 'metastasis' refer to in cancer biology?

The spreading of cancer cells to form new tumors in different parts of the body Signup and view all the answers

Why is BaP considered a stable secondary carcinogen?

It does not damage DNA directly Signup and view all the answers

Which of the following accurately describes how cancer cells evade cell death mechanisms?

They develop resistance to apoptotic signals Signup and view all the answers

What results from the binding of BaP to the AhR?

Induction of CYP1A1 and CYP1A2 gene expression Signup and view all the answers

What is a consequence of BaP being lipophilic?

It accumulates in lipid-rich tissues Signup and view all the answers

Which option describes one way cancer cells can spread to distant organs?

By breaking away from the primary tumor and entering the bloodstream Signup and view all the answers

What is a significant effect of increased angiogenesis in tumors?

It supports the growth and sustenance of the tumor Signup and view all the answers

Which of the following statements is true regarding BaP metabolism?

GSH/GST is involved in conjugating BaP metabolites Signup and view all the answers

What is one way tumor cells achieve increased cell proliferation?

By blocking pro-apoptotic signals Signup and view all the answers

What does the formation of DNA adducts from BaP indicate?

Mutations and potential cancer initiation Signup and view all the answers

Which type of DNA damage is commonly associated with reactive oxygen species (ROS)?

Point mutations, particularly G→T transitions Signup and view all the answers

How does the presence of GSH/GST affect BaP metabolism?

It aids in the conjugation of metabolites Signup and view all the answers

What characterizes the cells in a cancerous tumor over time?

They divide rapidly while evading normal cell death Signup and view all the answers

How do tumor cells typically respond to growth factors compared to normal cells?

They become unresponsive to anti-growth signals Signup and view all the answers

Study Notes

NUTR*4510: Toxicology, Nutrition & Food

Course focusing on the unit of chemical carcinogens in food

Neurotoxicity Perspective

Adverse effects on the structure and function of the brain, central nervous system, and peripheral nervous system
Can be permanent, or reversible.
Lipophilic xenobiotics accumulate in lipid-rich parts of the body, including the brain and spinal column.
Problems can occur in cognition, nerve transmission, synaptic function, neurotransmitter function, sensory and motor function, behavior, and emotions.

Possible Neurotoxicity Manifestations

Confusion
Poor concentration
Memory loss
Changes in personality
Headaches
Pain elsewhere in the body
Numbness
Hyperesthesia (excessive skin sensitivity)
Paraesthesia (“pins and needles”)
Loss of sensation
Muscle weakness
Loss of coordination
Difficulty communicating (speaking, swallowing)
Paralysis
Muscle spasms
Seizures
Dizziness, vertigo
Sensory changes (visual, auditory, taste, smell, touch)
Changes in the levels of consciousness
Respiratory distress showing shallow, rapid, or slowed breathing; asphyxia
Coma
Cardiovascular problems, such as tachycardia, bradycardia, hypotension, and pulmonary edema.
Gastrointestinal problems, such as abdominal pain, diarrhea, and vomiting.

Grading of Common Neurotoxicity Symptoms

A grading assessment system (CTCAE 4.03) exists for severity levels of neurotoxic symptoms.
Grade levels categorize the intensity of neurotoxicity.
Symptoms include encephalopathy, dysphasia, seizures, and somnolence.

Common Neurotoxicity Manifestations

Encephalopathy- brain damage/malfunction leading to altered mental states and physical changes.
Dysphasia- issues with speech, including difficulty verbalizing or problems with comprehension of speech.
Somnolence- feeling sleepy or drowsy
Seizures- uncontrolled electric disturbances in the brain can manifest as changes in behaviour, activity, or consciousness.

Basic Cancer Information

Cancer involves abnormal cell growth (proliferation) and morphology (structure)
Normal cells divide and grow at controlled rates, while the cells in a cancerous tumor divide and grow uncontrollably.
Nucleus in cancerous cells is larger and darker than normal nuclei.
Chromosomes in cancerous cells are arranged in a disorganized fashion, as opposed to the organized form in normal cells.
A cancerous tumor doesn't have a defined boundary; it will grow larger as it develops a distinct boundary.

What is Cancer?

A group of more than 100 diseases affecting tissues in the body.
Characterized by abnormal cell growth and division.
Tumors can be benign or malignant.
Precancerous conditions (premalignant cells) can develop into cancer if not treated. These conditions are often seen in the colon as polyps.
Cancer cells can develop from genetic changes and abnormalities that can occur over time.

Precancerous (premalignant) Definitions

Hyperplasia- abnormal increase in the number of cells
Atypia (atypical)- cells that slightly appear abnormal under a microscope.
Metaplasia- cells that appear normal under a microscope but are not the typical cells found in a specific tissue.
Dysplasia- cells develop abnormally in both appearance (phenotypically) and organization.

Metastasis

Cancer cells spreading to different parts of the body to form new tumors
Three ways this occurs: invasion (direct extension); through the bloodstream (hematogenous spread); through the lymphatic system.
Cancer cells travel through bloodstream or lymphatic vessels to any organ or lymphoid.

In Cancer

Increased cell proliferation due to the accelerated cell division.
Decreased or blocked cell apoptosis- cancer cells become non-responsive to pro-apoptotic signals leading to long-lived, rapidly dividing transformed cells that contribute to a growing tumor.

DNA Damage Examples

Base mismatch, insertions, deletions (point mutations).
Single-strand breaks, abasic site, and 8-oxoguanine (affecting guanine and pairing nucleotides).
Double-strand breaks and interstrand crosslinks.
Bulky adducts (intrastrand crosslinks) and small adducts (reverse/release).

DNA Repair Mechanisms

Base excision repair ("most common"), nucleotide excision repair, mismatch excision repair, and double-strand break repair are mechanisms to fix DNA damage.

DNA Damage or Mutations Leading to Cancer

Mutations that lead to impaired function in DNA repair mechanisms.
Mutations in tumor suppressor genes, cell cycle genes, and apoptosis genes.
Mutations that promote cell proliferation.

Chemical Carcinogenesis Process

Initiating damage to DNA where it leads to irreversible changes.
Promotion where more cells divide enabling accumulation of mutated cells.
Progression, where mutations accumulate producing permanent changes; these result in a tumor with distinct boundaries.
Invasion, where additional mutations happen, angiogenesis, and loss of cell-cell contact occur creating a malignant, invasive tumor.

Multistep Hepatocarcinogenesis

A process where the liver undergoes a series of changes that lead to the formation of hepatocellular carcinoma.
Collect tissue samples (biopsy) from animals or humans to study the process under a microscope.
A step-by-step process starting in the liver, through hepatocytes, to hepatocellular adenoma to hepatocellular carcinoma.

Dietary Carcinogens

Mycotoxins (produced by molds and fungi).
Polycyclic aromatic hydrocarbons (PAHs)
Heterocyclic amines (HCAs)
Nitrosamines

Mycotoxins

Toxic metabolites produced by molds or fungi in food.
Stable; can survive food processing.
Exposure can occur directly by eating contaminated foods or eating contaminated meat.

General Paradigm for Mycotoxin Effects

Mycotoxins can form DNA adducts, leading to strand breaks in the DNA.
Mycotoxins can affect protein function.
Mycotoxins can cause cell death/apoptosis in tissues.
Mycotoxins can affect cellular pathways like cytochrome P450.
Mycotoxins can damage and alter the balance of cellular pathways, to cause issues with protein function and cellular apoptosis.

Specific Food Products and Mycotoxin Toxicity

Aflatoxins (produced by Aspergillus)- hepato-carcinogen.
Fumonisin (produced by Fusarium spp.)- neurotoxic; hepatotoxic; possible esophageal and liver cancers.
Ochratoxin (produced by Aspergillus/Penicillium)- nephrotoxic; possibly carcinogenic.
Fusariotoxins (produced by Fusarium spp.)- possible gastrointestinal issues, as well as other potential issues.

Aflatoxin Exposures (Similar for Other Mycotoxins)

AFB1, AFM1, B1, G1 and G2 forms of aflatoxins all have implications on toxicity.
Inhaling contaminated crops, direct contact with it or consumption of products that animals consumed while eating crops can all introduce toxicity.
Acute aflatoxicosis; nausea, vomiting, abdominal pain, and acute liver injury.
Liver cancer, growth failure in children, and immune suppression are common outcomes.

Aflatoxin Metabolism

AFB1 and AFM1 are both metabolized to form a reactive epoxide intermediate through CYP450 and GSH/GST.
The reactive epoxide leads to DNA damage resulting in mutations which can cause various issues, including immune suppression.
Aflatoxin B1-N7-guanine adducts are formed. They bind to DNA, and affect protein function.

Polycyclic Aromatic Hydrocarbons (PAHs)

Formed through the incomplete combustion of carbon-containing compounds at temperatures above 250 degrees celsius.
PAH are large and lipophilic compounds. Examples such as Benzo[a]Pyrene (BaP).
Carcinogenic for several types of gastrointestinal (GI) cancers.
Induce the production of CYP1A enzymes.
Metabolism of PAH by CYP1A creates reactive electrophiles and the resulting DNA damage leading to mutations and cancer.

Phytochemicals and Competition for CYP Activation and AhR Binding

Phytochemicals, such as indole-3-carbinol, curcumin, and quercetin, can competitively inhibit the BaP reaction.
This prevents the accumulation of the reactive epoxide electrophile and results in slower phase I reactions allowing for more reactions that will remove the metabolite before it can cause serious damage.

Dietary Influences on Phase 1 Metabolism

Some phytochemicals (e.g., isothiocyanates (ITCs)) bind to the AhR and block the large induction of CYP1A1 and CYP1A2.
This can serve as an AhR antagonist via competitive inhibition, while being present at higher concentrations in the diet than other xenobiotics.

Examples of PAHs

Many different types of PAHs can be derived from chemical ring structures.

BaP Metabolism

BaP can be metabolized into a highly reactive epoxide product through CYP1A1/2.
Leading to DNA adducts and mutations.
Other phase II metabolic steps can take place that converts it into an excretable byproduct.

BaP Metabolism With Phytochemicals

Certain Phytochemicals can prevent BaP accumulation due to slower phase I reactions.
Slower phase I reactions can lead to less production of DNA damaging electrophile, and less damaging metabolites enter pathways that ultimately remove it from the body.

Grilled Meats + Phytochemicals

Grilled meats, with a high content of carcinogens (e.g., PAHs, HCAs) can have harmful effects.
Eating vegetables and fiber with meals containing grilled meats can help lower the potential harms due to the phytochemicals competing with carcinogens.

Heterocyclic Amines (HCAs)

Form from the reaction of amino acids, creatine, and sugars during high temperature cooking.
Examples include 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).
PhIP can induce the expression of CYP1A enzymes.
PhIP is metabolized by the CYP1A family into reactive electrophiles leading to DNA damage and mutations.
Fruits and vegetables contain phytochemicals (e.g., indole-3-carbinol) that interact with HCAs and can reduce the risk of DNA damage.

PhIP in Grilled Meats

PhIP concentrations increase as cooking time increases.
Higher cooking temperatures (e.g., very well-done/extra well-done) can result in more PhIP formation.

PhIP Metabolism

CYP1B1 and other enzymes (e.g., CYP1A2) are involved in the initial metabolism of PhIP to a reactive intermediate.
The reactive intermediate undergoes further processing, via phase II enzymes (e.g., UDPGA or GSH/GST), and is excreted in the urine.
Polymorphisms in NAT1 and NAT2 enzymes can influence the rate and efficiency of this metabolism.

PhIP Metabolism and Phytochemicals

Vegetables and similar phytochemicals compete with PhIP for binding to the AhR, which, in turn, affects CYP1A/2 activity.
These vegetables can lower the formation of highly mutagenic metabolites.

Acrylamide

Formed from asparagine and reducing sugars during cooking of foods, particularly at high heat temperatures.
High levels of acrylamide found in foods like potato chips, French fries, and certain types of baked goods.
Acrylamide is a neurotoxin in humans and animals. It is also a reproductive toxicant (mutagenic in germ cells).
Can bind to proteins and DNA causing adducts and mutations.

Acrylamide Metabolism

Absorbed and distributed throughout the body.
Acrylamide is converted into more biologically active products by CYP1A2 and CYP2E1 enzymes, leading to a highly reactive intermediate leading to DNA damage and mutations.
Acrylamide-Hb and glycidamide-Hb levels are used to show exposure levels.

Mechanisms to Reduce Acrylamide Content in Food

Reducing cooking time, blanching potatoes before frying, or draining them after cooking can lower acrylamide formation and levels.
Soaking the food in water can help.
Lower cooking temperatures (below roughly 120°C) will significantly lower acrylamide formation.

Cytochrome P450 (CYP) Enzymes

Induction of gene expression.
Different CYP enzymes, e.g., CYP1A1/2, CYP2E1, CYP1B1, and CYP2A6, have different roles in metabolizing different compounds (e.g. PAH, HCA's, mycotoxins, and other dietary compounds.)

Tobacco Xenobiotics

Nicotine, stored in tobacco leaves, is a neurotoxin with neuroexcitatory effects.
Nitrogen can be converted to Nitrates and then Nitrite, which play a role in the formation of NNK.
NNK, a tobacco specific nitrosamine, is a potent secondary carcinogen.

Nitrosamines

Formed from the reaction of secondary or tertiary amines with a nitrosating agent (usually nitrite) during food processing.
Nitrosamines, like DMN, are potent carcinogens, especially in the esophagus and stomach.
Can be found in processed meats, beer, and other certain foods processed in similar conditions.
CYP2E1 plays a role in the activation of DMN.

Dimethylnitrosamine (DMN)

A highly toxic nitrosamine found in various foods.
Primary carcinogen, causing mutations and liver fibrosis.
DMN's methylation of macromolecules in DNA and RNA damage those molecules leading to adverse impacts.

HMF (5-Hydroxymethylfurfural)

A potential carcinogen formed during the Maillard reaction and from the dehydration of sugars.
Forms in many cooked foods.
Higher temperatures result in higher HMF concentration.
Used as an indicator of improper processing or high heat in food.

Simplified Metabolism of HMF

Main metabolites are 5-hydroxymethyl-2-furoic acid (HMFA) and 5-sulfoxymethylfurfural (SMF).
Removal of the sulfate from SMF results in a genotoxic ester.
HMF is converted to various metabolites in the body, which can potentially damage DNA and proteins.

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This quiz explores the effects of genotoxic substances and mycotoxins on DNA and protein function, highlighting their roles in cancer development and progression. Participants will answer questions related to the biochemical mechanisms underpinning these processes and their consequences on cellular functions. Dive into the world of toxicology and cancer biology through these thought-provoking questions.