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Metals + Chemical carcinogenesis (TOX 5)

38 important questions on Metals + Chemical carcinogenesis (TOX 5)

What are the physico-chemical properties of metals?

Positively charged
Different valences (Fe2+, Fe3+, Fe4+)
Occur naturally in the environment in low concentrations

How are humans exposed to metals?

Direct exposure: through air, water, soil
Indirect exposure: eating contaminated food

Did people get Mad Hatters disease via direct or indirect exposure?

Direct exposure, the inhalation of mercury.

Give an example of speciation, also describe how the different 'species' are transmitted and how toxic it is.

Metallic mercury, via food poor absorption so not very toxic but via air (inhalation) very toxic.
Insoluble mercury salts, via food poor absorption so not very toxic
Free mercury ions, through food poor absorption but very toxic
Alkylated mercury compounds, via food high absorption so very toxic

What happens with alkylated mercury compounds?

It accumulates in the brain.

In what way is the physical state important for absorption?

If it is a liquid, it will go via food resulting in low absorption. If it is damp, it will be inhaled resulting in high absorption.

What is the Mad hatter's disease? What causes it?

The Mad hatter's disease is caused after inhalation of mercury. People who produced felt from beaver skin got this disease because mercury ions from the beaver skin ended up as particles in the air.

What happened in 1956?

In 1956 the Minamata case occurred. Mercury came in the environment, bacteria methylation in sediment ended up in the water. This accumulated in fish that was eaten by human, causing malformation in babies.

Describe the graph for essential compounds.

Left to the optimum is deficiency. The optimum is efficient. Right to the optimum is toxic.

What are two examples of metal-protein complexes?

Metallotionines
Ferritin

How can metals bind to macromolecules?

Protein binding
DNA binding
Oxidative stress

What is oxidative stress?

Oxidative stress is an imbalance between antioxidants and reactive oxygen species (ROS).

What are reactive oxygen species (ROS)?

ROS are oxygen containing molecules that have an uneven number of electrons.

What are mechanisms of protein binding between metals and macromolecules?

Blocking of ion channels
Binding to proteins
Replacement of essential metals
Inhibition of enzymes

What are examples of toxic metals?

Lead
Arsenic
Chromium
(Mercury)

What is the toxicity mechanism of lead?

Lead inhibits ALAD, it induces heme formation. But it also has some neurological effects, Pb replaces Ca and Na having effects on cognition.

Is arsenic defined as acute or chronic toxicity?

Arsenic is defined as both acute and chronic toxicity. It can be acute when used as a murder weapon. But also chronic when it is groundwater and thus exposure happens all the time.

What is the toxicity mechanism of Chronium VI?

Chronium VI is reduced to Cr (V) to Cr (IV) to Cr (III). Cr (V) causes ROS (oxidative stress), Cr (III) binds to DNA.

What is the toxicity mechanism of arsenic?

Arsenite (As3+) and MeAs(OH)2 bind to SH groups of thiol-containing enzymes. Many proteins contain cysteined methionine so there are effects on many organ systems.

By what is cancer characterized? What are the two forms?

Cancer is characterized by unlimited cell division (proliferation). It can be either concentrated (tumor, neoplasm, mass) or diffused (leukemia).

What are the two different types of tumors? What are their properties?

Benign; encapsulated, differentiated cells, slow growth
Malign; dedifferentiated cells, invasive, metastasis

What are risk factors for cancers?

Genetic factors (pre-disposition)
Environmental factors (migrant-studies)
Hormonal and reproduction factors

What is the consequence of different risk factors?

There is variation between individuals and populations.

What are the stages of cancer?

Initiation: change in DNA
Promotion: dedifferentiation, increased proliferation
Progression: invasion, metastasis

What are mutagenic compounds?

Compounds that cause an inheritable change in the nucleotide order of the DNA.

What are electrophilic compounds?

Electrophilic compounds bind the base (DNA-adduct). This causes indirect or direct mutagens.

What are intercalating agents?

Intercalating agents do not bind to the DNA but they fit between the nucleotides causing stress.

What are the types of mutations?

Base-pair substitution
Frame-shifts

What is a base-pair substitution? What are the two forms?

A base-pair substitution is the change of a nucleotide. It can be missense or silent. In a missense substitution the DNA codes for a different protein. In a silent substitution the DNA still codes for the same protein.

What is a frame shift mutation? What are the two forms?

A frame shift mutation can be either a deletion or an insertion. It can be missense, causing a different protein to be encoded, or nonsense, coding for a stop protein.

How can you measure mutagenic potency?

Using an Ames assay.

Not every DNA-binding ultimately leads to a mutation. How is this possible?

There are several repair mechanisms.

What kind of repair mechanisms are present for DNA repair?

Nucleotide excision
Recombination
Error prone repair

How can you measure the tumor promoting potency of compounds?

Intercellular communication

What happens during the progression stage?

There is karyotypic instability, this can cause aneuploidy and polyploidy. There can also be extra mutations. The proto-oncogenes are turned on, the tumor-supressor genes are turned off causing the cell to go into cell division. So there is more cell division (proliferation).

In what way does dimethyl sulfate cause cancer?

It is a methylating substance, causing methylations that can cause mutations.

What causes oxidative stress?

Smoking (nicotin).

In what way does benzo-α-pyrene cause cancer?

Benzo-α-pyrene adds a PAH group to the DNA, causing the DNA not to be read correctly anymore.

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Toxicology

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