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TOX 412 > EDCs > Flashcards

EDCs Flashcards

1
Q

What is the EPA definition of EDCs?

A

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

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2
Q

major concerns with EDC?

A

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

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3
Q

what are the hypothesized effects of EDCs?

A
  • 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)
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4
Q

what biological processes are hormones involved in?

A
  • growth
  • development
  • energy homeostasis
  • reproduction
  • water/electrolyte homeostasis
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5
Q

types of hormones

A
  • peptide hormones
  • amino acid derivatives (catecholamines, thyroid hormones)
  • cholesterol derivatives (steroid hormones, vit D)
  • eicosanoids (prostaglandins)
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6
Q

what is the HPG axis?

A

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

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7
Q

general mechanisms of endocrine modulation?

A
  1. hormone synthesis
  2. hormone transport
  3. hormone degradation
  4. hormone action
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8
Q

what is StAR?

A

steroidogenic acute regulatory protein; moves cholesterol into mitochondria during steroidogenesis–> critical process

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9
Q

what are the targets in hormone synthesis?

A

availability of precursors– StAR, cholesterol
Altered enzyme activities in synthesis– P450scc, aromatase, 5a-reductase (all enzymes potential targets)
possible transcriptional and translational control

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10
Q

what are the targets for hormone transport?

A

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

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11
Q

what are the targets for hormone degradation?

A

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`

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12
Q

what are the targets for hormone action?

A
  • -nuclear receptor super family: ligand-activated transcription factors (alters gene expression)
  • -EDCs can mimic endogenous hormone–bind to receptors (agonist, partial agonist, antagonist)
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13
Q

what are the physio roles of endogenous estrogens?

A

repro; CV system, bone, thyroid hormone actions

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14
Q

why are XEs problematic in the environment?

A

stable in the enviro, potential to bioaccumulate;

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15
Q

what are the difficulties in risk assessment of XEs?

A

relative potentcy–> ER-binding affinity;
nonmonotonic DR relationships
additivity assumed in mixtures (i.e. we are exposed to mixtures of XEs)

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16
Q

what is relative potency?

A

biological activity of a test compound compared to the standard compound, estradiol (E2)–>assigns estrogen equivalency factor
– E2 - Eq = sum(EEF*[XE])

17
Q

describe Tier I assays, and what they find

A

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

18
Q

limitations of Tier I assay?

A

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
19
Q

describe the H295R steroidogenesis assay

A

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

20
Q

describe tier II assays

A
  1. mouse uterotropic assay–>measure uterine weight before and after exposure to XE
  2. full life-cycle test
      • fish, invertebrate
  3. two generation reproductive tox tests
    • fish, frog, bird, mammal
    • exposure animal before its mature–>let it repro–>follow offspring through life
21
Q

what is sex determination vs sex differentiation

A

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)

22
Q

what is teh Jost paradigm of sex diff?

A

Chromosomal sex–> gonadal sex–> phenotypic sex

23
Q

describe sex diff in mammals

A

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

24
Q

what are specific concerns to XE exposure?

A
  1. cryptorchidism–undescended testes
  2. hypospadias– occurs in both sexes; urethra opens in the wrong place
  3. decreases anogenital distance (AGD)– happens in mice and humans; sensitive marker of XE exposure
  4. altered sex ratio–
    some effects may actually be due to anti-androgenic compounds (DDE, vinclozolin)
25
Q

what was hte issue with DES exposure?

A

thought natural, so they didn’t not think there would be deleterious effects–> but exposure during organogenesis disrupted differentiation of estrogen responsive organs; also has effects of bones and immune system

26
Q

what were the effects of DES sons?

A

increased incidence of testicular cancer; repro tract abnormalities–> cryptorchidism, hypospadias, cysts of epididymis; decreased fertility

27
Q

DES mech of action?

A

some effects estrogen-receptor-mediated (especially through alpha isoform of ER);
gene imprinting effects–>epigenetic response; involves DNA methylation and histone modifications–> XEs effect these processes

28
Q

what is the difference between DES and endogenous estros?

A

DES does not strongly bind to sex steroid binding glob–>therefore it crosses the placental barriers; has a greater binding affinity to ER than E2; there are also non-ER-mediated effects (effects on other pathways)

29
Q

what is EE2, and main concerns?

A

17alpha-ethynylestradiol; potent synthetic estro; present as oral contraceptive
– released into enviro and wastewater effluents; main concern is effects of low conc in aquatic wildlife;

30
Q

what is VTG and its effects?

A

vitellogenin; yolk precursor protien in oviparous (yolk-bearing) vertebrates;
–VTG is an estro-dependent gene product; usually only expressed in females; however,males will express VTG after XE exposure; sensitive biomarker

31
Q

what is BPA, and how does it affect organisms?

A

monomer of plastics; found in epoxy resins and polycarbonate;
has structural similarities to DES and is a weak ER agonist; is about 2000-10000X weaker than E2;

32
Q

effects of BPA in lab animals?

A

Female repro tract:
–decreased uterine weight
–increased expression of Era and progesterone receptor;
–vaginal cell proliferation
–earlier time of vaginal opening
mammary glands
–major cell proliferation occurs normally during increasing E2 levels; in immature mice exposed to BPA, mammary glands resemble those of pregnant mice–>may cause breast cancer?

33
Q

what are phthalates used for, and what are the concerns?

A

used as plasticizers or “softeners”; ubiquitous in environments; the major phthalate is DEHP (di/bis2-ethylhexylphthalate)

34
Q

what is DEHP’s mechanism of action?

A

weak ER agonist; 50 000X less potent than E2; but estrogenic effects in humans not considered relevant;
however, DEHP is an agonist of PPARa; PPARa involved in cell diff and growth, abundant in the liver–> causes hepatocarcinoma in rats and mice (not humans), because we have 10X fewer PPARa receptors;
activation of PPARa leads to inhibition of apoptosis, increases production of ROS

35
Q

what are alkylphenols and what is the concern?

A

detergents and emulsifiers; present in soaps an ppc; degrade to nonylphenol ethoxylates–>sewage bacteria remove the ethoxylate groups, creating nonylphenol

36
Q

what is the concern with nonylphenol?

A

stable and lipophilic; much more soluble in fat than water, BCF = 100 (bioaccumulates in fish)

37
Q

nonylphenol effects and concerns

A

weak ER agonist, 30 000x less potent than E2; but present at very high levels; has effects in fish–> males: induction of VTG expression, intersex (eggs in testes); increases cell death in testes
females: fewer mature eggs
both sexes: delayed maturity, reduced hatching success, reduced success at swim up

38
Q

what is p,p’-DDE?

A

dichlorodiphenyldichloroethylene; metabolite of DDT; most common DDT metabolite in enviro samples bc it’s stable and resistant to enviro degradation;

39
Q

DDE mech of ac as an EDC?

A

weak ER agonist; 10 000X less potent than E2; similar to DDT; some other OCs are also estrogenic;
also an antagonist of androgen receptor;
causes eggshell thinning–> repro failure in bird pops, linked to reduced prostaglandin synthesis

TOX 412 (24 decks)

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