endocrine tox READY TO REVIEW! Flashcards
what are endocrine disrupting chemicals
exogenous compounds that disturb hormonal regulation and the normal endocrine system
is there only one mech of action by which EDCs act? What are the different ways they can act?
- mimic natural hormones – bind to hormone receptors and trigger similar effects
- block hormone receptors – prevent hormones from binding and exerting their effects
- interfere with hormone synthesis
- alter hormone metabolism
- affect hormone delivery to target tissues
t/f: you need a high level of EDCs for them to lead to effects
false! even very low doses can have a profound effect on exposed organisms
t/f: EDC mixtures will act the same as the EDC alone
false! mixtures can lead to compounded/synergistic effects
t/f: it doesn’t matter whether you give the EDC before, during, or after development
false! the timing relative to development and reproduction is critical
what is the DOHaD Premise
IN UTERO environmental interaction with genomic factors influences the risk of health and disease LATER! in life.
what is the main challenge of studying endocrine toxicity?
dont know whether the observed toxic response is a cause or a consequence of the endocrine dysfucntion
what are the 3 key players of the endocrine system
- the endocrine glands that produce and secrete the hormones
- the circulating hormones
- the target tissues that respond to the circulating hormones
whats the difference between primary and secondary endocrine organs
primary the main function is excreting hormones. secondaries have other functions besides excreting hormones.
what are the primary endocrine organs
pineal gland, hypothalamux, pituitary, thyroid parathyroid, adrenal gland, testes, overies, placenta, pancreas
what are the secondary endocrine organs
skin, heart, liver, stomach, kidney, small intestine.
whats is a hormone
substance produced by a ductless endocrine gland.
what are the three categories of hormones (what does each include)
peptides + proteins (neurohoromones in the post pit, tropic hormones in the ant pit, pancreatic hormones)
steroids (adrenal cortex, testes, ovaries, placenta hormones)
amino acid derivatives (catecholamines)
whats the dif between hydrophobic and hydrophillic hormones wrt
- storage
- secretion
- transport in blood
- target receptors
hydrophillic - stored in the endocrine gland cells, need secretory vessels for secretion, free transport in blood, target the plasma membrane receptors
hydrophobic - not stored in the endocrine gland cells, secreted via passive diffusion, bound to proteins to be transported in the blood, target nuclear receptors.
the ___ pituitary receives peptide releasing hormones from the hypothal, and stimulates the release of hormones
anterior
the ___ pituitary is innervated by axons with cell bodies in the hypothalamus. nerve stimulation results in hormone release
posterior
whats the difference between the ant and post pituitary
ant synthesises and releases, post just releases
what are the dif cell types in the ant pit; what do they do
somatotrophs – release GH
lactotrophs – release prolactin
corticotrophs – release adenocorticotropic hormone
thyrotrophs – release thyroid stim
gonadotrophs – release LH and FSH
what does GnRH lead to
gonadotropin releasing leads to release of LH, FSH from gonads
what goes GHRH lead to
leads to release of GH in muscle, liver
what does GHIH (somatostatin) lead to
inhibits growth hormone
what does TRH lead to
increases thyroid stimulating hormone, which acts on thyroid
also increases prolactin
what does PIH (dopamine) lead to
inhibits prolactin
what does CRH lead to
stimulates adenocorticotropic
what are four categories of pituitary toxins
heavy metals, peticides, PCBs and PBDEs, dioxin (TCDD)
how do heavy metals like cadmium, mercury, and lead affect the endocrine system
they inhibit LH, FSH secretion from the gonadotrophs
mercury in the ant pit can also lead to age related decline in growth hormone levels
how do pesticides like DDT, methoxychloride affect the endo system
they inhibit dopamine, so increase prolactin
how does endosulfan impact the endo system? what kind of toxin is this?
endo sulfan is a pesticide, and is a pituitary toxin.
it downregulates FSH, LH, and GH
how do PCBs and PBDEs impact the endo system
they reduce the release of LH and FSH from gonadotrophs
they also reduce TSH secretion from thyrotrophs
how does dioxin (TCDD) impact the endo system
reduces GH expression
also redcues LH, FSH release from gonadotrophs
what is the molecular mech of dioxin toxicity
its mediated by Ahr, binding at specific DREs leads to toxic effects like (endo disruption, teratogenesis, tumorigenesis, thymic atrophy, liver atrophy, steatohepatitis).
there is a speciifc mutation A375 that has higher sensitivity for TCDD than V375. so, A375 mutations lead to higher toxicity
how does dioxin affect LH, FSH
reduces LH, FSH
what is the role of the adrenal gland
plays a major role in stress management
has two sections: the cortex and the medulla, which have dif roles
what is the function of the adrenal cortex vs medulla
cortex: synthesizes and releases steroid hormones that regulate salt/fluid balance glucose homeostasis, long term stress
medulla: synthesizes and secretes catecholamines to regulate immediate stress repsonses.
t/f: the adrenal cortex ONLY makes cholesterol
false. cholesterol is the precursor. its cleaved to make a bunch of other things. some key molecules are:
- aldosterone
- cortisol
- estriol (most potent!)
describe the HPA axis pathway
the hypothalamus releases CRH.
the CRH trigges the anterior pituitary to release ACTH
the ACTH stimulates the adrenal cortex to secrete cortisol
cortisol activates glucocoricoid receptor.
the cortisol negative feebacks on the ACTH by blocking both the hypothal and the ant pit.
which endo region are arsenic and DEHP toxins of
HPA axis.
how is arsenic toxic to the HPA axis
perinatal arsenic exposure: increased CRH in hypothal. alters glucocortocid receptor distribution (too much GR activity!)
describe the pathway by which DEHP interferes with the HPA axis
7 ways it can interfere!
1. deregulates potassium channel expression and decreases AT2 R expression. messes up control of aldosterone.
2. increases lipid import, biosyntehsis of cholesterol and storgae of cholesterol.
3. alters PPAR expression.
4. reduced downstream PPAR targets
5. increaeses MAPK pathway
6. reduced cholesterol to mito, decreased circulating aldosterone
7. less aldosterone, less minealcorticoid receptor expression, less testosterone production.
whats the function of the parathyroid glands
parathyroid: produces and secretes PTH.
PTH is needed to maintain normal plasma calcium levels.
whats the function of the thyroid glands
synthesize + secrete T4, T3
regulates overall body metabolic rate
describe the HPT axis
TRH from hypothalamus
TRH leads to TSH release from ant pit.
TSH leads to T3/T4 synthesis and release from thyroid
T3/T4 give negative feedback to ant pit.
how are thyroid hormones synthesized
iodine in the thyroid follicular cells combines with tyrosine this makes MIT (monoiodo) and DIT (di iodo)
DIT + DIT makes t4
MIT + DIT makes T3
whats the difference between T3 and T4
t3 is the active hormone.
t4 is the prohormone.
t4 gets converted to t3 by monodeiodenise enzymes.
reverse t3 (the other MD metabolite) is inactive
how does T3 act
enters the cell through thyroid hormone transporters, or generated locally by cytoplasmic MD enzymes.
binds to THR-RXR dimers
binds to TRE
regulate gene transcription
how does low dose vs high dose radioactive iodine impact the thyroid
remember that iodine is taken up into the thyroid follicular cells by the NIS
radioactive I emits Beta rays when it decays.
- low dose - mutates the cell - increases long term risk for thyroid cancer
- high dose - kills the cell - good for hyperthyroid treatement
how does butachlor impact the thyroid
its a thyroid toxin
it increases T3 and T4 levels
it biaccumulates and affects expression of genes in the HPT axis
how does PCB impact thyroid
inhibits thyroid hormone levels + activity
inhibits thyroid hormone synthesis, increases the phase 2 enzymes that metabolise thyroid hormones.
inhibits thyroid hormone binding to binding proteins, blocks thyroid hormones from binding to thyroid receptors.
overall leads to neurocog effects
what is PFAS; what are the two main types
PFOA and PFOS (has a sulfate)
whats the similarity and difference between polyfluro and perfluroralkyls
they are both non polymers
but they are within two dif subtypes (many fluoro vs 2 fluoro)
are short or long chain PFAS used more
short chain. long chain has been phased out.
what are long chain PFASs
theres are perfluoroalkyl sulfs with 6 or more carbons, perfluoroalkyl carbox with 7 or more. they bioaccumulate
what are short chain PFASs
shorter chains. high mobility. lower bioaccumulation.
where is PFAS found
many dif products! paints, nail polish, water resistant clothing, fast food packaging…
what does the PFAS cycle demonstrate
PFAS are made …then go in waster water…then get uptaken by plants and groung water,,,, get into drinking water…get into air….
they are everywhere!
what is seen about PFAS in northern indigenous communities
levels are elevated in northern indig communties! mainly due to diet
how do dietary differences affect PFAS levels
country food (hunted) has the most long chain PFAS; main source of exposure in arctic communties
how does PFAS affect developement
delayed mammary gland development, lowered vaccination response, lower birthweight…
what happens when exposed to PFAS during gestation
birth weight is much lower. but, at low conc, you saw more obesity over time
how did PFAS affect mice exposed during development
more obseity over time
whats the relevance of breast milk to PFAS exposure
as moms age increases, level or PFAS in breast milk increased. snacking, eating out, all lead to more maternal PFAS
what are the thyroid effects of PFAS
interacts with the NIS to inhibit iodine uptake.
alters synthesis of thyroglbulin which is needed for thyroid hormone storgae
alters activity of thyroid peroxidase
alters thyroid signalling pathway
BPA has a very close resemeblance to what endogenous molecule
estradiol
where can you find BPA
food and water, PCP, air and dust, thermal paper, dental materials, occupational exposure
what is polycarbonate made out of
linked BPA molecules!!
how does BPA get released into foods through plastic (think bonds)
polycarbonate weakens over time, BPA gets released into food, expecially increases with heating, acidic, and high fat foods.
the elimination half life of BPA is
4 hours
what is the primary metabolizer of BPA
UGT 2B1 *glucuronidation
does BPA bind to plasma binding porteins
limited binding.
where does BPA accumulate
fat, because its lipophillic.
what are the main toxic effects of BPA
acts like environmetal estrogen, antagonizes action of thyroid, antagnoizes most androgens, but agonizes mutant form of androgen foudn in prostate cancer
it binds to ERB, can have developmental effects, can lead to cancer.
what level of BPA is assumed to be safe
below 50 ug/kg/day.
how would BPA compare to estradiol in the e-screen assay
you’d expect to see proliferation similar to that seen with estradiol.
what are some chemical replacements for BPA
other bisphenols (BPF, BPS) but they have the same hormonal actions.
where are phthalates found
they are plasticizers, make vinyl plastic soft and flexy.
found in PVC
when do phtalates become a risk
if they leach out of soft vinyl ie during sucking/chewing/squeezing.
how do phtalates impact endo system
can disrupt reprod + development, increases testicular cancer, decreased sperm count, increased obseity, hypospadia
whats the dif between high weight and low weight phtalates
high weight: these are DEHP, DiNP, DnOP, found in vinyl flooring, wall covering, med devices
low: DEP, DBP, BBP - found in personal care products, laquers vasrnish and coatings…
health effects of DEP
reduced growth rate, reduced food condumption, increased organ weight.
health effects of DBP
liver and kindye effects dev and reprod effects, reduced fetal weight, hypospadia
health effects of BBP
testicular tox, teratogenesis, altered steroid hormones
health effects of DEHP
liver cancer, testicular tox, teratogen
how are phtalates biotransformed
an esterase makes it a monoester. then a UGT makes it a glucuronide.
fast metabolism; dont accumulate; excreted in urine. urine levels is a good biomarker for exposure.
how do phtalates interact with PPARs
activates all PPAR subtypes
what are parabens and where are they found
carboxylate esters of para hydroxybenzoic acid.
found in cosmetics, kids products,
how are we exposed to parabens / how are they absorbed / how detoxified / what do they activate
exposed through cosmetics, food
absorbed through skin and detectable in serum one hour after topical application!!
detoxified by being hydrolyses by skin esterases.
activates ERa and ERb weakly.
what products are parabens found in
pharmaceuticals, personal care, cosmetics, food
how do parabens impact the endo system
they are estrogenic
also have adv effects on sperm production, testosterone levels
how do parabens affect sperm
decreases sperm levels
what happens in the uterotrophic assay
remove ovaries from mouse. treat with the test compound. harvest the uterus. if there is estrogenic activity by the compound, the uterus increases in size.
how is paraben tox related to the ER and AR signalling pathways
agonises the ER, antagnzies the AR,
can also directly damage DNA
this system is a major target for BPA, phtalates, and parabens
reproductive.
