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anat 322 > endocrine disruptors > Flashcards

endocrine disruptors Flashcards

1
Q

how did we become concerned about edcs

A
  1. genes, poor diet and sedentary lifestyle alone couldn’t explain obesity epidemic
  2. sharpest rise in human obesity coincides with expansion of chemical and pharmaceutical industry
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2
Q

what does DDT do (2)

A
  1. mimics estrogen effects
  2. reduces fertility
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3
Q

what sexual impacts are thought to be caused by edcs (4)

A
  1. changes in sex determination
  2. sexual dysfunctions
  3. impaired sexual behavior of aquatic species
  4. changes in mate preference in mammals
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4
Q

ex of edcs (5)

A
  1. pharmaceuticals (DES or EE2)
  2. dioxin
  3. PCBs
  4. pesticides (DDT)
  5. plasticizers (BPA)
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5
Q

ex of objects/products where edcs can be found (6)

A
  1. plastic bottles
  2. detergents
  3. flame retardants
  4. food
  5. toys
  6. cosmetics
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6
Q

where are edcs found in the body (3)

A
  1. accumulate in fat tissue
  2. can be transferred across placenta
  3. in breast milk
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7
Q

characteristics of edcs that make them act like hormones (5)

A
  1. act via hormone receptors (abnormal receptor function)
  2. some act at low doses
  3. non-linear DR relationships
  4. tissue-specific and life stage-specific effects
  5. developmental effects permanent
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8
Q

why can edcs bind to hormone receptors

A

their structure resembles that of hormones like estrogen or thyroid hormone

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9
Q

edc moa (2)

A
  1. mimic hormone (agonist)
  2. block hormone (antagonist)
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10
Q

concerns about edcs (5)

A
  1. adverse effects at low levels
  2. ubiquitous exposure in environment
  3. more hormonal systems involved (not just estrogen or reproductive system)
  4. more compounds involved
  5. fetal exposure impact on adult health
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11
Q

why would fetal exposure to edcs lead to problems

A

normal development of fetus requires certain amounts of hormones at precise times

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12
Q

what kind of problems would a change in amount or timing of hormones to fetus create (4)

A
  1. behavior
  2. immune function
  3. neurological development
  4. gender development
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13
Q

nuclear mechanisms of edcs (4)

A
  1. agonist
  2. co-activator
  3. co-inhibitor/repressor
  4. allosteric modulation
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14
Q

where are edcs mostly found

A

ocean

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15
Q

wildlife in which area have the highest concentrations of edcs in their tissues

A

regions of high chemical use

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16
Q

sources of edcs

A

everywhere, but water is central

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17
Q

routes of exposure to edcs

A

everywhere; everyday articles

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18
Q

how do edcs affect reproduction and sex determination (DNA level)

A

affect germ cell re-methylation -> altered germline DNA methylation -> altered testis transcriptome -> spermatogenic defect

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19
Q

how do edcs affect reproduction success in fish

A

increased vitellogenin in male fish -> feminization of fish (oocytes in testis) -> decreased male fertility -> decreased reproduction

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20
Q

how do edcs affect reproductive success in birds

A

eat contaminated worms -> increased volume of HVC -> more complex songs -> females prefer male with complex songs (preferentially mate with them)

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21
Q

human health impacts of edcs (7)

A
  1. hormone related cancers
  2. metabolic disorders
  3. reproductive health
  4. immune function and disease
  5. thyroid-related disorders
  6. bone disorders
  7. neurodevelopmental disorders in children
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22
Q

effect BPAs have on health (2)

A
  1. glucose intolerance
  2. hyperinsulinaemia
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23
Q

how do organotins lead to metabolic syndrome

A

increased adipocyte differentiation and adipose tissue -> increased leptin -> (leptin resistance?) -> increased appetite -> increased chance of developing metabolic syndrome

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24
Q

where do BPAs act on metabolic pathways to influence body weight (6)

A
  1. inhibit insulin release
  2. inhibit insulin receptor
  3. activate PI3-kinase
  4. inhibit PDK -> Akt
  5. inhibit internalization of glucose via GLUT4 (transporter)
  6. activate glucose uptake
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25
Q

metabolic syndrome

A
  1. obesity
  2. CVD
  3. insulin resistance
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26
Q

how do edcs contribute to manifestation of metabolic disorder (2)

A
  1. inflammatory processes via cytokines/adipokines
  2. producing effects of metabolic imbalance
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27
Q

risk factors for metabolic syndrome (6)

A
  1. obesity
  2. diabetes
  3. hypertension
  4. decreased HDL
  5. elevated triglyceride levels
  6. hypercoagulable states
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28
Q

what is DES

A

synthetic estrogen prescribed to pregnant women to avoid miscarriages

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29
Q

children exposed in utero to DES have higher risk of (6)

A
  1. reproductive malformations
  2. infertility
  3. testicular cancer
  4. vaginal carcinoma
  5. obesity
  6. metabolic disorder
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30
Q

how do estrogenic edcs (like DES) affect development (gene level)

A

program gene activity via epigenetic changes during critical periods of development

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31
Q

what type of agonist are organotin compounds

A

peroxisome proliferator activated receptor (PPAR) gamma and retinoid X receptor (RXR) agonists

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32
Q

what do organotin compounds stimulate

A

differentiation of preadipocytes into adipocytes and increase fat deposition (at low doses)

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33
Q

effects of organotin compounds at (a) low doses, (b) moderate doses, (c) high doses

A

(a) increase fat deposition
(b) inhibits activity of 11b-HSD2 -> increase in local active GC levels
(c) inhibits aromatase activity and downregulates ER

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34
Q

how can edc-induced mitochondrial dysfunction lead to obesity

A

poor development of mitochondria promotes inflammation

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35
Q

how can edc-induced physiological changes in adipose tissue promote cancerogenesis (2)

A
  1. dysfunctional adipose tissue leads to changes in signaling pathways (such as insulin signaling pathway) which results in cell proliferating/survival pathway activation
  2. edcs induce mutations and epigenetic changes in stem cells that lead to tissue-specific tumors
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36
Q

bpa levels in humans (2)

A
  1. most of general population has measurable level of bpa in bodily fluids
  2. all human fetuses have measurable blood concentrations of bpa
37
Q

which receptors does bpa bind to (4)

A
  1. ERa
  2. ERb
  3. mERs (rapid, non-genomic changes)
  4. antagonist to ARs
38
Q

bpa suppresses transcription of which receptor

A

thyroid hormone receptor

39
Q

transformation of bpa

A

transformed in liver through oxidation into several metabolites

40
Q

effect of bpa metabolites

A

can affect binding affinity of ERa to other proteins

41
Q

bpa degradation

A

can be degraded by some types of bacteria, fungi or algae

42
Q

cellular mechanism of bpa action

A

affects all hormone signalling pathways (except maybe GR) (affects binding of receptor dimers to HRE in DNA, affecting transcription)

43
Q

tdi of bpa in usa and europe

A

usa = 50 ug/kg bw/day
europe = 10 ug/kg bw/day

44
Q

how are tdis established

A

according to toxicological risk assessments

45
Q

effects of edc doses below tdi and why

A

can still have significant effects in animal models (and humans) because edcs can have negative effects at very low doses

46
Q

how do toxicological risk assessment

A

test at high doses and extrapolate effects to predict low dose effects -> assumes high dose predicts low dose effects (assumes linearity)

47
Q

how do endocrinology (risk assessment)

A

test over wide range of doses and assume that different effects will be observed in low or high dose conditions (doesn’t assume linearity)

48
Q

what is td50

A

dose at which 50% of animals die

49
Q

do edcs show monotonic or non-monotonic DR curve/response

A

non-monotonic: don’t act like typical DR patterns (effect doesn’t necessarily increase with the dose)

50
Q

what might be a mechanism of bpa accelerating cancer initiation

A

bpa alters epigenetic programming in early development: changes in methylation and in amount of non-coding RNAs

51
Q

early exposure to bpa is linked with which cancers (3)

A
  1. prostate cancer
  2. breast cancer
  3. hepatic cancer
52
Q

what can limit dna hypomethylation induced by bpa exposure

A

maternal diet supplemented with methyl donors like folic acid and genistein

53
Q

transgenerational effect of F0 dams exposed to bpa and dioxin during pregnancy

A

sperm epigenetic mutations in F3 generation even in absence of edcs after initial exposure

54
Q

some of reported effects of low dose bpa in animal experiments (5)

A
  1. obesity in adults following in utero exposure
  2. early puberty
  3. reduced sperm count
  4. prostate disease
  5. cellular causes of spontaneous miscarriage and downs syndrome
  6. increased embryo mortality
  7. abnormal mammary gland development
  8. impaired immune function
  9. decreased anti-oxidant enzyme levels
  10. changes in brain chemistry
  11. changes in formation of synapses in brain
  12. changes in behavior
55
Q

what are organotin compounds used as (3)

A
  1. disinfectants
  2. pesticides
  3. anti-fungal agents in anti-fouling paints (boats)
56
Q

potential adverse effects on animal and human health of organotin compounds include (4)

A
  1. promotion of reproductive dysfunction
  2. disruption of endocrine function such as hypothalamo-pituitary axis
  3. alteration of hormone synthesis and direct damage to endocrine glands
  4. alteration of bioavailability and activity of hormone receptors in target cells
57
Q

how do organotin compounds promote reproductive dysfunction (2)

A
  1. disruption of estrous cyclicity in females
  2. disruption of spermatogenesis in males
58
Q

how get exposed to organotin compounds

A

paint on ships -> get into water -> bioaccumulation in fish/food -> absorption & contamination

59
Q

organotin compound effects on (a) CNS, (b) HPG axis, (c) adrenal cortex, (d) pancreas, (e) ovaries, (f) testicles, (g) adipose tissue

A

(a) obesogenic effects
(b) abnormal HPG axis
(c) increased cortisol
(d) impaired glucose homeostasis
(e) altered estrous cycle and fertility
(f) altered steroidogenesis and sexual development
(g) adipogenesis and obesity

60
Q

effects of edcs on thyroid function (4)

A
  1. hypothyroidism
  2. hyperthyroidism
  3. thyroid neoplasm
  4. affects fetal brain development
61
Q

edcs have effect on what aspects of hormone life (5)

A
  1. synthesis
  2. secretion
  3. transport
  4. binding action
  5. elimination
62
Q

edcs cause hormones to alter which processes (3)

A
  1. homeostasis
  2. reproduction
  3. developmental process
63
Q

obesogens act on (2) and cause (1)

A
  1. adipose tissue
  2. brain
  3. cause obesity
64
Q

diabetogens act on (4) and cause (6)

A
  1. adipose tissue
  2. muscle
  3. liver
  4. pancreas
    cause:
  5. hyperinsulinemia
  6. hypoinsulinemia
  7. glucose intolerance
  8. insulin resistance
  9. fatty liver
  10. dyslipidemia
65
Q

immune system acts on which organs to increase risk of metabolic disorder (6) and how

A
  1. liver -> activate macrophages (kupffer cells) + proinf cytokine prod + insulin resistance
  2. pancreas -> b-cell death (less insulin)
  3. intestine -> dysbiosis + increased gut permeability
  4. circulation -> increased atherosclerosis
  5. adipose tissue -> proinf cytokine prod + insulin resistance
  6. skeletal muscle -> proinf cytokine prod
66
Q

activators of the inflammasome (6)

A
  1. lysosomal rupture
  2. altered metabolites
  3. autophagy (ER stress)
  4. mitochondrial dysfunction/ROS
  5. altered ion flux
  6. microbial substance
67
Q

what does the inflammasome produce and what does it do

A

caspase-1: induces apoptosis

68
Q

possible edc effects contributing to metabolic disorders (5)

A
  1. receptor mediated (estrogen)
  2. gut microbiota alteration (dysbiosis)
  3. mitochondrial dysfunction (ROS)
  4. ER stress (ROS)
  5. circadian disruption
69
Q

effects of increasing estrogen and androgen concentration in zebra fish

A

estrogens -> increasing concentrations lead to increased female fish
androgens -> increasing concentrations lead to increased male fish

70
Q

what population of neuron is especially vulnerable to estrogenic edcs and why

A

both populations of kisspeptin neurons because are highly sensitive to early life estrogen exposure

71
Q

differentiation of the male reproductive system and effect of inhibiting its steps

A
  1. undifferentiated gonads
  2. XY karyotype -> SRY gene -> sertoli cell differentiation
  3. sertoli cells produce AMH -> mullerian duct degeneration (apoptosis)
  4. male differentiation
    *inhibiting any step of the pathway will cause the animal to be female (even if the karyotype is XY)
72
Q

effects of edcs on leydig cells (4)

A

decreased leydig cell function -> androgen insufficiency -> cryptorchidism + hypospadias + hypogonadism + reduced semen quality

73
Q

effect of edcs on male germ cells (2)

A

impaired germ cell differentiation -> reduced semen quality + testicular cancer

74
Q

effects of edcs on sertoli cells (2)

A

disturbed sertoli cell function -> impaired germ cell differentiation -> reduced semen quality + testicular cancer

75
Q

mechanisms of how edcs disrupt sperm quality (6)

A
  1. disruption of testicular gonadotropin receptors (LH and FSH can’t act on testis)
  2. disruption of leydig cell steroidogenesis (testosterone prod)
  3. sertoli cell damage
  4. inhibition of spermatocyte development
  5. disruption of mature sperm
  6. disruption of epididymal sperm modification
76
Q

what do edcs affect in term of male fertility (9)

A
  1. sperm motility/morphology
  2. [sperm] or sperm count
  3. semen volume
  4. DNA integrity
  5. steroid action
  6. acrosome action
  7. embryo quality
  8. time to pregnancy
  9. miscarriage
77
Q

what do edcs affect in terms of female fertility (9)

A
  1. cycle length/age at menopause
  2. oocyte number/quality
  3. fertilisation
  4. blastocyst formation
  5. implantation
  6. embryo quality
  7. steroid action
  8. time to pregnancy
  9. miscarriage
78
Q

effects of edcs on estradiol biosynthesis

A

every step of synthesis can be affected (block or boosted)

79
Q

effect of DES on uterine weight

A

low doses have worst effects -> enhance estrogen responses (increased uterine weight)

80
Q

effects of edcs on the ovary

A

affect all stages of follicle/oocyte development (reduction or increase)

81
Q

effects on mammary gland from exposure to edcs during (a) gestation, (b) early life, (c) puberty, (d) pregnancy/lactation, (e) adulthood

A

(a) x
(b) altered growth and development; altered carcinogen susceptibility
(c) altered growth and development; altered carcinogen susceptibility
(d) lactational impairment
(e) breast cancer

82
Q

what protein can edcs bind to other than hormone receptors

A

plasma binding proteins (like albumin)

83
Q

what can edc impact by affecting the thyroid gland

A

brain development (neuronal migration)

84
Q

actions of edcs on HPT axis (5)

A
  1. th synthesis
  2. bind to th receptors
  3. bind to serum binding proteins and deiodinases in blood
  4. act on liver (target of th)
  5. act on brain (target of th)
85
Q

where do edcs act produce thyroid-disrupting effects in brain (8)

A
  1. hypothalamus
  2. pituitary
  3. thyroid gland
  4. serum binding proteins
  5. liver
  6. th transporters
  7. th receptors
  8. deiodinases
86
Q

effect of edcs on hpa axis

A

adrenocortical hyperplasia (also hypoplasia probably)

87
Q

effect of ddt on adrenal cortex

A

irreversible binding of ddt derivative to adrenal cortex -> forms adducts and affects function

88
Q

how reduce/reverse adverse effects of edcs

A

reduce edcs in environment (birds are coming back after banning of ddt)

anat 322 (7 decks)

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