Biochemistry of Endocrine Disruptors and Metabolic Disorders Flashcards
Endocrine Disruptor
- Exogenous substance that causes health effects in an intact organism,
or its progeny, consequent to changes in endocrine function - Effects aquatic and terrestrial wildlife, birds, humans
- Affects oestrogens, androgens, thyroid hormones, glucocorticoids etc
What are consequences observed?
- Reproductive abnormalities
- Thyroid and adrenal dysfunction
- Disorders of immune system
- Cardiovascular disease
- Bone disorders
- Obesity
- Diabetes
What are the routes of exposure of endocrine disruptors?
- Oral
- Inhalation
- Dermal absorption
- Workplace environment
- Air quality
- Diet => Contaminants of food and water, fungi
- Personal lifestyle choices => Personal care products, Synthetic hormones (contraceptive pill, hormone replacement therapy)
- Living environment => pesticides, plastics, detergents
How do endocrine disruptors interfere with endocrine function?
- By mimicking the action of a naturally-produced hormone and thereby setting off similar chemical reactions in the body
- By blocking the hormone receptors in cells, thereby preventing the action of normal hormones
- By affecting the synthesis, transport, metabolism and excretion of hormones, thus altering the concentrations of natural hormones.
Disruption of control of metabolic pathways by endocrine disruptors
Disruption of hormone synthesis
- By altering levels of key enzymes or altering enzymatic activities
Disruption of Thyroid hormone synthesis
Alter levels of T3 and T4
Thyroid hormones regulate:
- Metabolism of vitamins
- Metabolism of protein, fat, carbohydrate
- Basal metabolic rate
Control growth and development
What is the mechanism in which aromatase is increased in cells?
- Aromatase is a cytochrome P450 enzyme
- Many xenoestrogens bind to aryl hydrocarbon receptor (AhR) which acts to regulate expression of cytochrome P450 genes
- This heterodimerises with Arnt (arylhydrocarbon nuclear translocator)
- Dimer binds to dioxin response elements (DRE) in the DNA
- Transactivation of gene expression (cytochrome P450 genes)
What are the consequences of disruption of steroid synthesis?
Disruption of Hormone bioavailability
- Steroid hormones are hydrophobic and so have to be carried in the blood either bound to protein or conjugated
- It is the unbound, unconjugated “free” steroid (bioavailable steroid) which is biologically active
Disruption of Hormone Action
- By binding to relevant receptors and causing inappropriate responses
- Steroid/Thyroid hormones act at a target cell by binding to intracellular receptors
1) Ligand binds to receptor
2) L-R complex binds to DNA
3) Alters expression of specific genes
Parabens
Environmental chemicals which interfere in oestrogen action
Preservatives in foods, pharmaceuticals and cosmetics
- Bind to oestrogen receptors
- Enable expression of oestrogen-regulated genes
- Enable proliferation of oestrogen-regulated cells
Disruption of Glucose metabolism
- Altering levels of key enzymes
- Altering enzyme activities
- Altering substrate availability by interfering with glucose uptake by tissues
- Consequences => Type 2 diabetes
EDC interference in homeostatic control of blood glucose
- EDCs may cause insulin resistance and maintenance of hyperglycaemia
What are obesogens?
Environmental chemicals are now suspected to trigger weight gain
Obesogenic activity & lipophilic properties of EDCs
