Lecture 14 (8b) - Endocrine Disruptors Flashcards
Exposure to endocrine disruptors results in
misreglatioin of the endocrine system
The endocrine disruptor hypothesis
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
Difference between teratogens and endocrine disruptors
• 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
Hormone disrupting chemicals are everywhere in our technological society
- plastics
- cosmetics
- pesticides
- sun blocks
- hair rinses
- vinyl toys
- air fresheners
- chemical coating of clothes
Endocrine disruptors are
exogenous chemicals that interfere w/ the normal functions of hormones
Endocrine disruptors can be agonsists
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
Endocrine disruptors can also act as antagonists
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
Endocrine disruptors are
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
Endocrine disruptors can increase
hormone synthesis
• eg herbicide atrazine - elevates levels of estrogen via induction of aromatase enzyme
Endocrine disruptors can affect the
elimination or transportation of a hormone within the body
• eg PCBs (polychlorinated biphenyls) interfere w/ the elimination and degradation of thyroid hormones
Endocrine disruptors can prime the organism to
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
The origin of the endocrine disruptor hypothesis dates back to
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
The endocrine disruption hypothesis had a difficult time being accepted in mainstream medical articles
- 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
Endocrine disruption hypothesis - causes difficult to detect
the symptoms/disease are likely to result from altered gene expression, resulting in altered morphogenesis leading to dysfunctional physiology
Endocrine disruption hypothesis - variations in sensitivity
sensitivity to disruptive agent depends on stage of development, dose, and even sex of exposed individual
Endocrine disruption hypothesis - additive or synergistic effect
endocrine disruptors may be additive or synergistic with nutritional influence and is influenced by the exposed organism’s genetic background
Endocrine disruption hypothesis - the effect can be transgenerational
changes in gene expression can affect the germ cells and effect can be transmitted to next generation
Endocrine disruptor - DDT
- 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
Bioaccumulation of DDT was especially pronounced in some
birds of prey
• peregrine falcons and bald eagles became endangered because of DDT-induced fragility of their eggshells
How does DDT affect development?
• DDT acts as an estrogenic compound, while DDE (metabolic product of DDT) inhibits androgens such as testosterone from binding to the androgen receptor
Eggshell thinning is caused by several actions of DDT
- 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
Endocrine disruptor - Estrogens
- 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
We are continuously exposed to estrogens (xenoestrogens)
- 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
Estrogen or endocrine disruptor binds
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
Diethylstilbesrol (DES) is one of the best studied xenoestrogens
• 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
–>
Genital abnormalities occurred in
DES daughters
• T-shaped constricted uterus = ectopic pregnancy
• adenosis of cervix and vagina (abnormal tissue)
• tissue “hood” of cervix
• cervical dysplasia (precancerous growth)
Comparison of gonad development in males and females
• 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
DES interferes with
sexual development
• cell type changes
• loss of boundary between oviduct and uterus
Regions of reproductive tract are specified by
Hox genes
• DES represses HOXA 10 expression in Mullerian duct
• Mullerian duct - Hox 10 expression reduced
- no Hox 10 in exposed mouse
Wnt genes and Hox genes communicate with each other during
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
DES causes
obesity in mice
• DES sensitizes mouse embryos
- large concentrations of estrogen during sexual maturation - mice become obese
• DES –> more estrogen receptors
Soy estrogens can act as
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
Decrease in sperm count and increase in testicular cancer during the past decade
- 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
Spermatogenesis in mammals
- 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)
Maturating sperm progresses towards the
lumen of the seminiferous tubule
Sharpe and Shakkebaek suggest testicular dysgenesis syndrome due to
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
Pesticides cause infertility in males
- 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
BPA causes
meiotic defects in maturing oocytes
• BPA = estrogen agonist
The age at which girls begin to express adult female sexual characteristics has
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
Most endocrine disruptors show a
non-linear dose effect
“inverted U response”
• not linear link in teratogens (dosage-dependent)
The molecular effects of BPA
- 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)
