Impacts of endocrine disruptors, teratogens and pollutants on health

Question 1

What is a teratogen?

Answer 1

A chemical or biological agent which can cause non-heritable (somatic tissues not germline changes) developmental malformations in an embryo or foetus following exposure during development

Question 2

What is a carcinogen?

Answer 2

A chemical or biological agent that can cause cancer

Question 3

What is an endocrine disruptor?

Answer 3

An exogenous substance that interferes with any aspect of hormonal action by disrupting, modifying or mimicking endocrine signals in the body

Question 4

What are examples of teratogens? (3)

Answer 4

• Cyclopamine
• Alcohol
• Thalidomide

Question 5

What is cyclopamine? (3)

Answer 5

• Teratogen which causes midline defects
• Discovered when lambs in fields with corn lilies were born with cyclopia
• Inhibitory effect on the sonic hedgehog signalling pathway

Question 6

What is thalidomide? (3)

Answer 6

• Was sold as a morning sickness drug
• Racemic mixture of 2 enantiomers, 1 of which is teratogenic
• Inhibits limb bud angiogenesis and outgrowth resulting in severe limb defects

Question 7

What are examples of endocrine disruptors? (2)

Answer 7

• DDT
• Oestrogen mimics

Question 8

What is DDT? (4)

Answer 8

• Endocrine disruptor
• Powerful insecticide which caused eggshell thinning in wild birds
• Exposure to DDT in early infancy greatly increases breast cancer risk
• Oestrogen mimic which blocks oestrogen function

Question 9

What are oestrogen mimics? (3)

Answer 9

• Similar structure to oestrogen
• Some mimics block oestrogen function and some enhance oestrogen function
• Oestrogen diffuses into cells, binds to oestrogen receptor, enters nucleus and causes gene transcription

Question 10

What are examples of oestrogen mimics? (2)

Answer 10

• Bisphenol A (BPA)
• Diethylstilbestrol (DES)

Question 11

What kind of biological agent is tobacco smoke?

Answer 11

Teratogen and carcinogen because it contains at least 70 compounds with known defect and disease-causing impacts

Question 12

What disease-causing compounds are in tobacco smoke? (6)

Answer 12

• Nicotine
• Nitrosamines
• Benzene
• Aromatic amines
• Acetaldehyde
• Polyaromatics

Question 13

What is the effect of Cytochrome P450 enzymes on polyaromatic hydrocarbons? (3)

Answer 13

• CYP1A1 and CYP1A2 convert polyaromatic hydrocarbons to highly reactive DNA-damaging epoxides
• Forms DNA adducts which prevents faithful DNA replication
• Benzopyrene is converted to BPD epoxide by CYP1A1 which binds to DNA forming BPDG (adduct)

Question 14

What is the aryl hydrocarbon receptor family (AHR)? (2)

Answer 14

• Transcription regulators
• Bind to aryl hydrocarbons like benzopyrene

Question 15

What are the members of the AHR family? (3)

Answer 15

• AhR
• ARNT
• AhRR

Question 16

What is the structure of the AHR family? (4)

Answer 16

• AhR has a DNA binding domain, protein binding domain, ligand binding domain (aryl hydrocarbon) and a transcriptional regulation domain
• The protein binding domain is for dimerisation either with another AhR or a different member
• ARNT has a similar structure to AhR so they can dimerise and work together
• AhRR doesn’t have a ligand binding domain

Question 17

What is the role of AhRR? (2)

Answer 17

• Interferes with AHR and ARNT activity
• Limits production of P450 enzyme CYP1A1 and inhibits DNA adduct formation

Question 18

What is the role of AHR? (3)

Answer 18

• AHR binds to benzopyrene
• AHR binds to DNA to cause transcription of P450 enzyme CYP1A1
• CYP1A1 metabolises polyaromatic hydrocarbons to reactive epoxides which cause mutagenic DNA adducts and cancer

Question 19

What happens to AHRR gene in response to smoking? (4)

Answer 19

• Hypomethylation of CpGs within AHRR gene
• Correlates with increased AHRR expression to counteract exposure to carcinogens
• Epigenome wide CpG differential methylation persists for many years after cessation of smoking but diminishes over time
• Differential methylation of some genes persists (never goes back to normal) which includes AHRR hypomethylation

Question 20

What is the effect of smoking during pregnancy on offspring? (2)

Answer 20

• AHRR is significantly hypomethylated in offspring cord blood
• Increased smoking duration correlates with greater level of hypomethylation

Question 21

Why does AHRR CpG hypomethylation persist after cessation of smoking? (2)

Answer 21

• Could be an epigenetic adaptation to promote AHRR expression in order to function as a tumour suppressor
• Early life exposure could confer some sort of epigenetic adapative advantage

Question 22

What are the types of pigmentation in the agouti mouse? (3)

Answer 22

• Black (eumelanin)
• Yellow (pheomelanin)
• Normal hairs are black with a band of yellow (Agouti and pseudo-Agouti phenotype)

Question 23

What is the Agouti viable yellow mutation? (2)

Answer 23

• Mutant allele which is transcriptionally unstable so offspring with this allele have a range of coat phenotypes
• Example of a metastable epiallele

Question 24

What is a metastable epiallele? (2)

Answer 24

• Alleles that are variably expressed in genetically identical individuals due to epigenetic modifications established during early development
• Thought to be particularly vulnerable to environmental influences

Question 25

How does methylation vary in the IAP promoter of the Avy locus? (2)

Answer 25

- Pseudo-agouti is most heavily methylated - Yellow has lowest methylation

Question 26

What is BPA? (2)

Answer 26

- Bisphenol A - Oestrogen mimic which is ubiquitous in many plastics in food and drink packaging

Question 27

What is the effect of BPA on the Avy phenotype? (2)

Answer 27

- Shifts the coat colour distribution towards the yellow phenotype - BPA causes hypomethylation of Avy regulatory elements

Question 28

What is the effect of BPA on the epigenome? (2)

Answer 28

- Changes DNA methylation of metabolic genes - Health impacts unknown