toxicology c4.2 mutagenicity

Spontaneous vs. Induced mutations

spontaneous mutation

• occur naturally, without any mutagen exposure

• due to DNA replication errors(DNA polymerase sometimes inserts the wrong base)

• due to Spontaneous lesions

• due to Transposable elements (“Jumping genes”)

induced mutations

• caused on purpose or by known mutagen exposure.

• X-rays

• UV rays

• nitrosamines

How they cause mutation:

• Break DNA strands

• Cause wrong base pairing

• Insert or delete DNA pieces

list out chemical mutagens

1. alkylating agents (dimethyl nitrosamine and diethyl nitrosamine) Add alkyl groups → wrong base pairing

2. intercalating agents (ethidium bromide) slips between DNA base pairs (intercalates). This stretches and distorts DNA helix. During replication:DNA polymerase inserts extra bases OR skips bases—>Frameshift mutations

3. aromatic hydrocarbon (benzo a pyrene) DNA adducts → cancer

list out physical mutagen

1. x ray

2. uv ray

Breaks DNA or forms thymine dimers that Distorts DNA helix → DNA polymerase cannot replicate DNA properly, blocks cell division

list out biological mutagen

1. HPV

2. HBV

3. HCV

Insert viral DNA into genome

example of direct acting mutagens

Ethyl methane sulfonate (EMS)- an alkylating agent

example of Indirect-acting Mutagens

diethyl and dimethyl nitrosamines causes HCC by forming DNA adducts by reactive metabolites

4 types of macromutations

Type	Meaning	Outcome
Deletion	Part is lost	Missing genes
Duplication	Extra copy	Gene overload
Inversion	Segment flipped	Wrong orientation
Translocation	Piece moves to another chromosome	Misregulated genes

2 types of micromutations aka point mutation

Type	How It Happens	Effect
Frameshift	Addition or deletion of 1–2 bases	Changes reading frame → severe
Substitution: Transition	Purine ↔ purine or pyrimidine ↔ pyrimidine	Mild to moderate
Substitution: Transversion	Purine ↔ pyrimidine	More disruptive

3 mechanisms of induced mutations

• replace a base in the DNA

• alter a base so that it specifically mispairs with another base

• damage a base so that it can no longer pair with any base

Xeroderma Pigmentosum (XP)

• Normally, UV-damaged DNA (like thymine dimers) is repaired by nucleotide excision repair (NER).

• In XP patients:

  • NER gene is defected

  • DNA damage cannot be repaired

  • skin cancer

the mutagen that causes HCC

diethyl nitrosamine

• forms adducts by reactive metabolite