EDCs Flashcards
(39 cards)
What is the EPA definition of EDCs?
exogenous agents that interfere with the synthesis, secretion, transport, binding, action or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, repro, development, and/or behaviour
major concerns with EDC?
may have effects on developmental processes in the embryos/neonates resulting in subtle, long-term, irreversible effects;
effects may not manifest until long after exposure has stopped
what are the hypothesized effects of EDCs?
- impaired fertility
- delyaed development/malformation of repro organs
- cancer in hormone responsive organs (breast, ovary, etc)
- altered sex ratios/phenotypes
- neurobiological/behavioural alteration
- “ambiguous gender”
- epigenetic changes (mods to DNA)
what biological processes are hormones involved in?
- growth
- development
- energy homeostasis
- reproduction
- water/electrolyte homeostasis
types of hormones
- peptide hormones
- amino acid derivatives (catecholamines, thyroid hormones)
- cholesterol derivatives (steroid hormones, vit D)
- eicosanoids (prostaglandins)
what is the HPG axis?
hypothalamus-pituitary-gland axis; hypothal releases GnRH which acts on ant pit, which releases LH and FSH, which acts on ovaries and testes; ovaies produce estrogen and progesterone–either can act +/- on AP or hypothal; in males, testes release testosterone–>act negatively on AP or hypothal
general mechanisms of endocrine modulation?
- hormone synthesis
- hormone transport
- hormone degradation
- hormone action
what is StAR?
steroidogenic acute regulatory protein; moves cholesterol into mitochondria during steroidogenesis–> critical process
what are the targets in hormone synthesis?
availability of precursors– StAR, cholesterol
Altered enzyme activities in synthesis– P450scc, aromatase, 5a-reductase (all enzymes potential targets)
possible transcriptional and translational control
what are the targets for hormone transport?
CBG, SSBG, and transthyretin– bind corticosteroid, sex steroid, and thyroxines; if these are bound by a EDCs, then more hormone is able to diffuse into cells and bind to receptors
what are the targets for hormone degradation?
biotransformative enzymes– eg phase I hydroxylation, demethylation, and deamination enzymes; phase II glucuronidation, sulfation enzymes; inhibition/induction of these enzymes can alter levels of circulating hormones`
what are the targets for hormone action?
- -nuclear receptor super family: ligand-activated transcription factors (alters gene expression)
- -EDCs can mimic endogenous hormone–bind to receptors (agonist, partial agonist, antagonist)
what are the physio roles of endogenous estrogens?
repro; CV system, bone, thyroid hormone actions
why are XEs problematic in the environment?
stable in the enviro, potential to bioaccumulate;
what are the difficulties in risk assessment of XEs?
relative potentcy–> ER-binding affinity;
nonmonotonic DR relationships
additivity assumed in mixtures (i.e. we are exposed to mixtures of XEs)
what is relative potency?
biological activity of a test compound compared to the standard compound, estradiol (E2)–>assigns estrogen equivalency factor
– E2 - Eq = sum(EEF*[XE])
describe Tier I assays, and what they find
Use Yeast reporter gene (YES) assay–> transcriptionally activate a reporter gene construct via an ERE; E screen assay– induce prolif of E2-responsive human MCF-7 breast cancer cells;
Classical ER competitive binding assay–tests for ER affinity
limitations of Tier I assay?
most assays focus on ER binding and direct receptor-mediated effects; but not all effects are receptor-mediated
- -e.g. altered enzyme activity - -changes in signal transduction pathways
describe the H295R steroidogenesis assay
adapted tier I assay; use a human adrenocortical cancer cell line–>expresses entire steroid biosynth pathway, therefore you can detect non-R mediated effects;
also no animal use–>big advantage
describe tier II assays
- mouse uterotropic assay–>measure uterine weight before and after exposure to XE
- full life-cycle test
- fish, invertebrate
- two generation reproductive tox tests
- fish, frog, bird, mammal
- exposure animal before its mature–>let it repro–>follow offspring through life
what is sex determination vs sex differentiation
sex determination
–dependent upon genetics or temps; signals to initiate male or female development
sex diff
–embryonic process of DEVELOPING into a male or female (sex already decided)
what is teh Jost paradigm of sex diff?
Chromosomal sex–> gonadal sex–> phenotypic sex
describe sex diff in mammals
early embryo development is identical– bipotential gonads
–having a Y chrom drives male development–> SRY gene in “tue mammals”
Males secret AMH, anti-mullerian hormone; testosterone, which causes the mullerian duct to refree and the wolfian duct to form; testosterone is tehn converted to DHT (dihydrotestosterone) by 5alpha-reductase–>causes masculinization of the bipot gonads
what are specific concerns to XE exposure?
- cryptorchidism–undescended testes
- hypospadias– occurs in both sexes; urethra opens in the wrong place
- decreases anogenital distance (AGD)– happens in mice and humans; sensitive marker of XE exposure
- altered sex ratio–
some effects may actually be due to anti-androgenic compounds (DDE, vinclozolin)
