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Cell Bio & Developmental Genetics > Lecture 14 (8b) - Endocrine Disruptors > Flashcards

Lecture 14 (8b) - Endocrine Disruptors Flashcards

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1
Q

Exposure to endocrine disruptors results in

A

misreglatioin of the endocrine system

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2
Q

The endocrine disruptor hypothesis

A

hormonally active molecular compounds in the environment (endocrine disruptors) alter gene expression during early development in ways that have significant impact on the health of human and wildlife populations

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3
Q

Difference between teratogens and endocrine disruptors

A

• teratogens produce no obvious malformation
• major changes caused by the endocrine disruptors are physiological, and in many cases the aberrant phenotypes are not seen until adulthood
- you can have altered gene expression not easily detected

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4
Q

Hormone disrupting chemicals are everywhere in our technological society

A
  • plastics
  • cosmetics
  • pesticides
  • sun blocks
  • hair rinses
  • vinyl toys
  • air fresheners
  • chemical coating of clothes
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5
Q

Endocrine disruptors are

A

exogenous chemicals that interfere w/ the normal functions of hormones

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6
Q

Endocrine disruptors can be agonsists

A

mimicking the effect of a natural hormone and binding to its receptors
• eg DES (diethylstilbestrol) mimics the sex hormone estradiol binding to the estrogen receptors

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7
Q

Endocrine disruptors can also act as antagonists

A

either preventing the binding of a hormone to its natural receptor or blocking the hormone’s synthesis
• eg DDE (metabolic product of insecticide DDT) can act as an anti-androgen

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8
Q

Endocrine disruptors are

A

exogenous chemicals that interfere with the normal functions of hormones
• endocrine disruptors can increase hormone synthesis
• endocrine disruption can affect the elimination/transportation of a hormone w/i the body

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9
Q

Endocrine disruptors can increase

A

hormone synthesis

• eg herbicide atrazine - elevates levels of estrogen via induction of aromatase enzyme

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10
Q

Endocrine disruptors can affect the

A

elimination or transportation of a hormone within the body

• eg PCBs (polychlorinated biphenyls) interfere w/ the elimination and degradation of thyroid hormones

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11
Q

Endocrine disruptors can prime the organism to

A

be more sensitive to hormones later in life
• eg rat fetus exposed to bisphenol a
- embryonic mammary gland makes more estrogen receptors
- this alters mammary gland growth responses to natural estrogen later in life, predisposing breast tissue to cancer formation

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12
Q

The origin of the endocrine disruptor hypothesis dates back to

A

Rachel Carson’s 1962 book “Silent Spring”
• documents the effects of DDT and other insecticides on reproductive failures in birds and other wildslife
• first evidence in humans in 1970
- from about 1940-1970 DES was given to pregnant women in the mistaken belief that it would reduce the risk of pregnancy complications and losses
- DES daughters showed reproductive abnormalities and rare form of vaginal carcinoma

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13
Q

The endocrine disruption hypothesis had a difficult time being accepted in mainstream medical articles

A
  • no major visible morphological changes
  • endocrine disruption can be a functional change in a tissue that superficially appears normal
  • causes difficult to detect
  • variations in sensitivity
  • additive or synergistic effect
  • the effects can be transgenerational
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14
Q

Endocrine disruption hypothesis - causes difficult to detect

A

the symptoms/disease are likely to result from altered gene expression, resulting in altered morphogenesis leading to dysfunctional physiology

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15
Q

Endocrine disruption hypothesis - variations in sensitivity

A

sensitivity to disruptive agent depends on stage of development, dose, and even sex of exposed individual

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16
Q

Endocrine disruption hypothesis - additive or synergistic effect

A

endocrine disruptors may be additive or synergistic with nutritional influence and is influenced by the exposed organism’s genetic background

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17
Q

Endocrine disruption hypothesis - the effect can be transgenerational

A

changes in gene expression can affect the germ cells and effect can be transmitted to next generation

18
Q

Endocrine disruptor - DDT

A
  • an insecticide that can’t be broken down and eliminated by vertebrates
  • therefore, DDT builds up (bioaccumulation), in particular in carnivores that feed on DDT containing animals
  • even though not legally used since 1972, most of us will have DDT in our bodies
19
Q

Bioaccumulation of DDT was especially pronounced in some

A

birds of prey

• peregrine falcons and bald eagles became endangered because of DDT-induced fragility of their eggshells

20
Q

How does DDT affect development?

A

• DDT acts as an estrogenic compound, while DDE (metabolic product of DDT) inhibits androgens such as testosterone from binding to the androgen receptor

21
Q

Eggshell thinning is caused by several actions of DDT

A
  • hens with high DDT levels have poorly developed shell glands which lack CARBONIC ANHYDRASE - an enzyme critical for the deposition of shell-strengthening calcium carbonate in the egg
  • high DDE levels in the shell gland also prevent calcium carbonate deposition by downregulating the synthesis of prostaglandins
22
Q

Endocrine disruptor - Estrogens

A
  • estrogens are a family of steroid hormomes that regulate growth, differentiation, and function of reproductive organs but also of bones, brain, and cardiovascular organs
  • both sexes need estrogen for proper bone and connective tissue development
23
Q

We are continuously exposed to estrogens (xenoestrogens)

A
  • food, water, plastic
  • exposure to estrogenic compounds early in development can cause both men and women to experience fertility problems, cancer, and obesity later in life
  • xenoestrogens not endogenous
24
Q

Estrogen or endocrine disruptor binds

A

plasma membrane receptor or nuclear estrogen receptor
• plasma membrane receptor - binding of estrogen leads eg to opening of calcium channels
• nuclear estrogen receptors are transcription factors, bind to estrogen responsive element (ERE)
• disruptors can inhibit or activate

  • enhancer in all genes activated by estrogen = ERE
  • estrogen receptors that bound estrogen bind to enhancer = genes activated

• 2 ways for estradiol to bind
(here = transcription factor)

• estrogen binds to receptor (transcription factor ) –> releases protein

25
Q

Diethylstilbesrol (DES) is one of the best studied xenoestrogens

A

• agonist (same as endogenous), mimics estrofunction
• DES was advertised as a “miracle drug” shortly after WWII
• treatment for suppressing lactation, balance, hormones in menopause and for prevention of premature termination of pregnancies
- doesn’t work
- latch to reproductive abnormalities in daughters
–>

26
Q

Genital abnormalities occurred in

A

DES daughters
• T-shaped constricted uterus = ectopic pregnancy
• adenosis of cervix and vagina (abnormal tissue)
• tissue “hood” of cervix
• cervical dysplasia (precancerous growth)

27
Q

Comparison of gonad development in males and females

A

• germline cells migrate to area of testis or ovaries, surrounded by somatic cells

  • in males - sertoli cells in testis cord secrete the anti-Mullerian hormone which blocks the development of female ducts
  • in females - each individual germ cell is surrounded by somatic cells. The Mullerian duct is maintained
  • in males - Leydig cells produce testosterone, the Wolffian duct (tube through which the sperm passes into the urethra) is maintained
  • in females - due to the lack of testosterone, the Wolffian duct degenerates. The Mullerian duct develops into the oviduct, uterus, etc
28
Q

DES interferes with

A

sexual development
• cell type changes
• loss of boundary between oviduct and uterus

29
Q

Regions of reproductive tract are specified by

A

Hox genes
• DES represses HOXA 10 expression in Mullerian duct

• Mullerian duct - Hox 10 expression reduced
- no Hox 10 in exposed mouse

30
Q

Wnt genes and Hox genes communicate with each other during

A

specification of reproductive tissue
Wnt7a –> Hox 10, Hox11 –> cell specification –> normal glandular tissue and smooth muscle

in presence of DES - improper cell specification, disorganized smooth muscle tissue

31
Q

DES causes

A

obesity in mice
• DES sensitizes mouse embryos
- large concentrations of estrogen during sexual maturation - mice become obese

• DES –> more estrogen receptors

32
Q

Soy estrogens can act as

A

estrogen disruptors in mice
• mice treated with Genistein, the estrogenic compound found in soy develop aberrant reproductive systems and mammary glands
• no data available showing that soy has the same effects in humans

33
Q

Decrease in sperm count and increase in testicular cancer during the past decade

A
  • average sperm has fallen 113million per ml to 66million in industrialized world
  • the average weight of the men’s testis has decreased, while the proportion of fibrous testicular tissue has increased
34
Q

Spermatogenesis in mammals

A
  • PCGs became incorporated intot he sex cords in the testis
  • the sex cords then hollow out and form the seminiferous tubules
  • the epithelium of the tubules differentiates into the sertoli cells (protect and nourish)

sperm epithelium –> lumen, collect in lumen
- seminiferous tubules in mice show less sperm (tails fill lumen)

35
Q

Maturating sperm progresses towards the

A

lumen of the seminiferous tubule

36
Q

Sharpe and Shakkebaek suggest testicular dysgenesis syndrome due to

A

endocrine disruptors
• testicular dysgenesis syndrome can be induced in lab animals (rats) by a group of endocrine disruptors - the PHTHALATES
• there’s also evidence from human males exposed to high levels of phthalate in utero
• phthalates are widely used in cosmetics, air fresheners, vinyl plastic

37
Q

Pesticides cause infertility in males

A
  • lower sperm count in men living in agricultural regions compared to men in urban areas
  • in toads, the frequency of testicular abnormalities and intersex gonads increases linearly with the amount of agricultural activity
  • in highly agricultural sites, testosterone production in male toads has declined so significantly that the sexual dimorphism in skin color has vanished
38
Q

BPA causes

A

meiotic defects in maturing oocytes

• BPA = estrogen agonist

39
Q

The age at which girls begin to express adult female sexual characteristics has

A

declined over the past years
• this is due to nutrition but also possibly also to endocrine disruptors
• female mice exposed to low doses of BPA reach sexual maturity faster
• female mice show altered mammary development

40
Q

Most endocrine disruptors show a

A

non-linear dose effect
“inverted U response”
• not linear link in teratogens (dosage-dependent)

41
Q

The molecular effects of BPA

A
  • BPA inactivates the nuclear estrogen receptor Erbeta (oocyte)
  • BPA also binds to the estrogen receptor in the plasma membrane - opening of calcium channels - activation of calcium dependent responses in the cell
  • BPA interferes with microtubuli polymerization (could explain oocyte defect)

Cell Bio & Developmental Genetics (27 decks)

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