Endocrine Disruptors Flashcards
Endocrine disruptors(EDC)
Alter function of endocrine system and produce disruption in development and repro
Stores for years in body fat, bioaccumulate?
Links to obesity, type 2 diabetes, metabolic syndrome-obesity,diabetes,hi BP
Ex. Pesticides:
Organochloride, DDT: have estrogenic or antiestrogenic and antiandrogenic effect depending on cell type
Window of susceptibility
Usually in development-womb(very sensitive)
Repair/protection mech not fully formed in developing animals
Altered epigenetic programming of somatic cells
Change in early life may not manifest until later in life
FeBAD: fetal basis of adult disease: some disease in adults result of early exposures
Polyfluoroalkyl compounds(PFAs)
Carbon backbone with C-F bonds resist biological and chemical degradation
Ex. polyfluorooctanoic acid(PFOA)
Hydrophobic core of C-F but philic tail-carboxylic acid or sulfonic
t1/2 = 4-5 yrs
Bisphenol A(BPA)
Used in plastic, precursor to flame retardant-make pliable plastic
Meant to form polymer, unbound monomer remain and leach out
Widespread human exposure even though non-persistent
95% around have
Alter sexual, brain and behavioural development in animal models
Similar structure to diethylstilbestrol(synthetic Estrogen supplement), BPS used now
Brominated flame retardants
Polybrominated biphenyls
Endocrine disruption and neurotoxicity in animals
Linked with type 2 diabetes and metabolic syndrome(U shaped association)
Found in human adipose and breast milk
Dose and effect?
EDCs show U-shaped dose-response curves-some are inverted
Lowest dose EDC appear to be active is far below the concentration experimentally tested
Reason for U-shape:
Property of receptor?
Two separate processes that appear to be a single?
Receptors desensitize at hi dose
EDC Mechanism
Membrane-bound receptors
Nuclear receptors(NRs)
Most evidence suggest majority if NRs for estrogen and androgens and the aryl hydrocarbon receptor
EDC Potential Mechanism
Acitaction or modulation: Direct recruitment of coativator or only some coactivators(mimic agonist)
Inhibition: Recruit corepressors=inhibit gene transcription
Squelching: Change the conformation of a NR so that it binds coactivators another NR needs
Synergism or inhibition: inhib or synergism btwn two NRs bound to neighbouring NREs
DNA-binding competition: competition btwn two NRs for NRE
Proteasome activation: Activation of one NR may promote degradation of another through proteasome activation
Metabolism and NRs
Two type of estrogen NRs: alpha and beta
Typically form homodimers after binding estrogen
Both bind same NRE, but have diff ligand affinity
Both found on preadipocytes-estrogen can increase number of mature adipocytes
Alpha knockout- increase insulin resistance and impaired glucose tolerance=diabetes
Alpha may be controlling neural networks responsible for food intake
EDC effects via estrogen receptor
BPA exposure shown to enhance adipocyte differentiation, adipocyte-specific gene expression and leptin synthesis
Brief BPA exposure has been seen to lead to chronic hyperinsulinemia via alpha ER in pancreas
BPA mimics estrogenic effects on insulin: human concentration is the concentration range of greatest effect
ALPHA ESTROGEN RECEPTOR RESPONSIBLE, BETA DOESN’T MATTER
Octylphenol: increase adipocyte resistin production
Resisitin: thought to cause insulin resistance and increase risk of type 2 diabetes
Effect via non-classical ER
Gpr30 is transmembrane G-protein(Gs) coupled receptor that binds estrogen
BPA is equipotent with estrogen as an agonist and will activate the receptor
Knockout GPR30 results in impaired glucose tolerance, reduction in bone growth
Epigenetic mechanism
Can change in two points: before maturation(Stem cells) or after maturation in normal cells
Change in methylation pattern during development= longlasting changes
Transgenerational epigenetic effect, therefore must study F3(4th generation rat)
Obesogens
Chemicals that promote weight gain by:
Directly acting on fat cells
Indirectly by altering mechanism of satiety, appetite
Altering energy balance to favour storage of calories
Interact with several receptors including RXR-PPAR-gamma heteromers
Tributyltin
Agriculture fungicide, plastic-an organotin
Tributyltin can decrease aromatase activity and increase testosterone levels
Transform female to male fish
AGONIST at both PPAR-gamma and RXR receptor
Result increase in adipose mass, even with normal diet and exercise, adult animals accumulate more fat
Adipocyte formation
Multipotent stromal cells(MSCs) are pluripotent cells which can differentiate into adipocytes-bone, cartilage, muscle, adipocytes
Exposure of preg mice to TRIBUTYLTIN resulted in differentiation into adipocyte and the loss of bone cell
