Chapter 7: Cellular and Tissue Targets of Toxicity

Question 1

What is the target molecule concept in toxicology?

Answer 1

The target molecule concept in toxicology refers to the idea that somewhere in the body is a molecule that a toxicant can affect, and the adverse effect only happens if the toxicant is at a sufficient concentration at the target.

Question 2

What is toxicodynamics in toxicology?

Answer 2

Toxicodynamics in toxicology refers to what happens after the target molecule is altered by a toxicant, which can result in all types of molecular, cellular, and organ damage.

Question 3

How can exposure to toxicants result in alterations in gene expression?

Answer 3

Exposure to toxicants can result in alterations in gene expression. If a toxicant has high affinity to certain cellular receptors, it may directly alter the expression of certain genes through receptor complexes (ie: bifenthrin). Alternatively, if a toxicant binds to certain types of receptors, it may activate a cell signaling pathway(s) that can lead to altered gene expression.

Question 4

What are reactive oxygen species (ROS)?

Answer 4

Reactive oxygen species (ROS) are free radicals, which are atoms or molecules that have a single unpaired electron, such as O2˙, HO˙, and H2O2.

Question 5

How do cells deal with reactive oxygen species (ROS)?

Answer 5

Cells deal with reactive oxygen species (ROS) by removing superoxide radical (O2-) through enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT). However, no enzyme eliminates HO* due to its extremely short half-life (10-9 s).

Question 6

What can some toxicants cause?

Answer 6

Some toxicants can cause destruction of target molecules.

Question 7

What is an example of a toxicant that can cause destruction of target molecules?

Answer 7

An example of a toxicant that can cause destruction of target molecules is reactive oxygen species (ROS).

Question 8

What is Step 1 in the process of lipid peroxidation?

Answer 8

Step 1 is when a hydroxyl radical reacts with an unsaturated lipid to form a lipid radical.

Question 9

What can stop the chain reaction of lipid peroxidation?

Answer 9

Tocopherol (Vitamin E) can stop the chain reaction of lipid peroxidation by donating an electron.

Question 10

What happens after Tocopherol donates an electron to stop the chain reaction of lipid peroxidation? (Step 3)

Answer 10

After passing on the electron, the peroxyl radical is turned into a lipid peroxide, that forms aldehydes that can bind with biomolecules, trigger apoptosis, etc. This is Step 3.

Question 11

What is Step 2 in the process of lipid peroxidation?

Answer 11

Step 2 is when the lipid radical combines with O2 to form a peroxyl radical, which can pass on the free electron to another unsaturated lipid. This occurs again and again!

Question 12

What is the effect of some toxicants on cell function?

Answer 12

Some toxicants cause dysregulation of cell function.

Question 13

How do toxicants bind and alter the function of a target molecule?

Answer 13

Toxicants bind to and alter the function of a target molecule, but there is a lot of variation in how this can happen.

Question 14

What are the three critical ways that toxicants can disrupt cell function?

Answer 14

The three critical ways that toxicants can disrupt cell function are ATP depletion, sustained rise in intracellular Ca2+, and overproduction of ROS (and RNS).

Question 15

How does ATP depletion affect cell function?

Answer 15

Any toxicant that interferes with aerobic metabolism will decrease the overall levels of ATP in the cell. Without enough ATP, cells cannot carry out normal functions, such as active transporters (ion pumps) and maintaining homeostasis.

Question 16

What are the effects of sustained rise in intracellular Ca2+ on cell function?

Answer 16

Increased cytosolic Ca2+ can disrupt the cytoskeleton, cause membrane instability, and activate certain hydrolytic enzymes that break down integral membrane proteins and membrane lipids.

Question 17

What happens when there is overproduction of ROS and RNS?

Answer 17

High Ca2+ levels in the mitochondria activate the TCA cycle, causing more electrons to flow through the electron transport chain to ATP synthase. If ATP synthase is inhibited, the electron transport chain gets overwhelmed, and electrons mistakenly get transferred to oxygen or nitrogen, forming ROS and RNS species.

Question 18

What is apoptosis and how is it triggered?

Answer 18

Apoptosis is programmed cell death, which is a natural process that occurs all the time. It is often triggered by Cytochrome C (a protein involved in oxidative phosphorylation) leaking from the mitochondria. Cytochrome C associates in the cytoplasm with caspases and activates them. The ‘executioner’ caspases signals to the nucleus to begin the apoptosis process.

Question 19

What happens to the membranes and organelles when there is mitochondrial damage?

Answer 19

With mitochondrial damage, membranes and organelles get broken down and engulfed by phagocytes.

Question 20

What is the worst case scenario in terms of cell death and what is the process that leads to it?

Answer 20

The worst case scenario in terms of cell death is necrosis, which occurs when damage cannot be repaired. The process that leads to necrosis involves mitochondrial permeability transition (MPT), an abrupt increase in inner mitochondrial membrane permeability that leads to opening a pore and the contents leaking out into the cytosol. This immediately ceases all aerobic ATP production and actually causes ATP synthase to spin in reverse and consume any remaining ATP. Excess free radicals wreak havoc in the cytosol and the plasma membrane becomes permeable. The cell swells and bursts.

Question 21

What is the main determinant of whether a cell undergoes necrosis or apoptosis?

Answer 21

The main determinant of whether a cell undergoes necrosis or apoptosis is the extent of mitochondrial damage.

Question 22

What is the secondary determinant of whether a cell undergoes necrosis or apoptosis?

Answer 22

The secondary determinant of whether a cell undergoes necrosis or apoptosis is whether DNA is damaged, which sets off another cascade of events.

Question 23

What is carcinogenesis and what are the two types of genes involved in cancer development?

Answer 23

Carcinogenesis is the process of cancer development. The two types of genes involved in cancer development are oncogenes and tumor suppressor genes.

Question 24

How does cancer develop?

Answer 24

Cancer develops through a multi-stage process. A normal cell can pick up a mutation or two to become an initiated cell, which begins dividing and becomes a focal lesion. The transition through progression is irreversible and leads to full-on cancer. This can take a long time to develop.

Question 25

How can mutagens be carcinogens?

Answer 25

Mutagens can be carcinogens by altering DNA either through binding to DNA as adducts or directly damaging the DNA.

Question 26

How can binding of mutagens to DNA as adducts cause a change in the DNA code?

Answer 26

Binding of mutagens to DNA as adducts can cause a change in the DNA code when the cell repairs the adducts by a mechanism that isn’t perfect and a different nucleotide base is accidentally used to fix the DNA strand.

Question 27

What is an example of a mutagen that can lead to mutations in a DNA strand by forming a DNA adduct?

Answer 27

Benzopyrene is an example of a mutagen that can lead to mutations in a DNA strand by forming a DNA adduct.

Question 28

How can mutagens directly damage the DNA?

Answer 28

Mutagens can directly damage the DNA through ROS or radiation. Repairing this type of damage is error-prone and can cause a change in the DNA sequence.

Question 29

Are all mutagens carcinogens?

Answer 29

No, not all mutagens are carcinogens.

Question 30

What is carcinogenesis?

Answer 30

Carcinogenesis is the process by which normal cells transform into cancer cells.

Question 31

How can toxicants contribute to carcinogenesis?

Answer 31

Toxicants that cause cell death (especially in rapidly dividing cells) can be carcinogens. Hormone mimics that signal for a cell to divide when it should not can also contribute.

Question 32

Why can a person “randomly” get cancer?

Answer 32

A person can “randomly” get cancer because mistakes (i.e., mutations) can be introduced into DNA every time a cell copies its DNA prior to mitosis. More cell turnover = more “chances” for errors in replication to occur = higher probability that one of the “important” genes gains a mutation.

Question 33

What is an example of a carcinogen that isn’t a mutagen?

Answer 33

Asbestos is an example of a carcinogen that isn’t a mutagen. It causes cell death in the lungs, leading to lung cancer.