Transcript Don’t Drink the Water Don’t Breathe the Air

Don’t Drink the Water
Don’t Breathe the Air
Environmental Estrogens,
Endocrine Disruptors, and Human
Reproduction
Kirtly Parker Jones MD
Learning Objectives
Each Participant should:
1. Understand the potential mechanisms by
which endocrine disruptors may effect an
organism
2. Identify chemicals which are suggested to
be potential endocrine disruptors
3. Evaluate the evidence suggesting that
environmental estrogens or endocrine
disruptors play a role in human disease
Endocrine Disruptors
• For over 50 years, there have been
reports concerning chemicals in the
environment with hormone-like effects on
wildlife
• Silent Spring
Definitions
Endocrine Disruptors
• Environmental compounds that
interfere with the normal function of
endogenous hormones - may
stimulate or block the actions of
hormones, or can interfere with their
metabolism.
Endocrine Disruptors
• They have been recognized to
include a diverse range of chemicals
including pesticides, plasticizers,
flame retardants, industrial
byproducts, pharmaceuticals, and
plant-derived compounds
Definitions
Epigenetic
• DNA modifications that do not involve
changes in the sequence of DNA.
Epigenetic changes can affect gene
expression (phenotype) and can be
transmitted from one generation to the
next
Vallombrosa Consensus Statement
Definition
DES
• Synthetic estrogen given as a feed
additive to livestock and prescribed for
pregnant women 1947-1971 to prevent
miscarriages (experiments started in 1942)
– interferes with normal development of
the reproductive tract and fertility of sons
and daughters
Vallombrosa Consensus Statement
Definitions
Bisphenol A
• Building block of polycarbonate plastics
used in food containers, water bottles,
baby bottles, CD cases, eye glass lenses,
lining of food cans and as dental sealants.
Binds with nuclear and extracellular
estrogen receptors
Vallombrosa Consensus Statement
Definition
Dioxins
• A class of highly persistent chemicals,
some of which are highly toxic, that result
from industrial combustion/incineration,
burning of household trash, chlorine
bleaching of pulp/paper and some kinds of
chemical manufacturing – also contained
in cigarette smoke
Vallombrosa Consensus Statement
Definitions
Alkylphenol Ethoxylates
• APEs are high-volume chemicals that
have been used for more than 40 years as
detergents, emulsifiers,. Some uses
include ingredients in spermicides,
cosmetics, and detergents and as inert
ingredients in pesticides. Some are
endocrine disruptors, particularly as
contaminants in aquatic environments.
Vallombrosa Consensus Statement
Definitions
Perfluorinated Compounds
• PFCs are persistent, bioaccumulative
chemicals found in a wide array of
products including stain resistant coating
for carpets and clothing, non stick
cookware (Teflon) and insecticides.
Widespread contamination of human
tissues has been documented with highest
levels in the US
Vallombrosa Consensus Statement
Definitions
Phthalates
• Chemicals added to personal care
products to enhance penetration and hold
scent/color and as plasticizers in rigid
plastics to increase flexibility. Found in
vinyl flooring, plastic shower curtains,
cosmetics and fragrances, shampoos and
lotions, toys, pharmaceutical and herbal
pill coatings, and in hospital equipment
including IV bags and tubing
Definitions
Polybrominated diphenyl ethers
• PBDEs are persistent, bioaccumulative
chemicals added to electronics, upholstery
foam, textiles and other materials to make
them flame resistant. Chemical structure
is similar to PCBs and have been rapidly
accumulating in wildlife and human tissues
Vallombrosa Consensus Statement
Definitions
Polychlorinated Biphenyls
• PCBs are persistent, bioaccumulative
compounds banned in the US in the late
1970s, although widespread
contamination still exists. PCBs were
used in hundreds of commercial and
industrial applications including lubricants,
plasticizers, insulators, caulking, and paint
Vallombrosa Consensus Statement
Endocrine Disruptors
• Studies in 1960s and 1970s characterized
the estrogenicity of DDT, kepone, and
PCBs
• In 1990s - new plasticizers (phthlates,
bisphenol) and new pesticides
• Phytoestrogens and mycoestrogens
• Human estrogen contaminants
Endocrine Disruptors and Human
Fertility
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•
•
•
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•
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Declining sperm counts?
Declining male/female birth ratios?
Increasing hypospadias?
Increasing testicular cancer?
Increasing breast cancer?
Increasing premature thelarche?
Decreasing Fertility?
Endocrine Disruptors
• Late exposure may effect mature adults
• Early exposure may have effect on fetus
or embryo with adult consequences
• Epigenetic effects may effect DNA for
several generations
Endocrine Disruptors
The Challenge
• Identify xenoestrogens among synthetic
chemicals and natural estrogens in the
environment
• Develop a methodology to assess
interactions among mixtures of
xenoestrogens and naturally occuring
estrogens
• Discover markers of exposure
Endocrine Disruptors
Mechanism of Action
• Mimic the effect of endogenous hormones
• Antagonize endogenous hormones
• Disrupt synthesis and metabolism of
endogenous hormones or their receptors
• Change structure of DNA which may effect
transcription
• None of the above
Endocrine Disruptors:
The Wake Up Call
• In 1949 crop dusters spraying DDT were
found to have reduced sperm counts
• Workers at a kepone (insecticide) plant
had low sperm counts and decreased
libido
• The demasculinization of alligators
exposed to DDE
Sonnenschein and Soto, J Steroid Biochem Mol Biol, 1998
Endocrine Disruptors:
Amphibian Model
• Amphibians may be very sensitive to
environmental estrogen disruptors
• Exposed to chemical effluents in water
environment
• Frog hepatocytes competively bind
estrogens and estrogenic activity can be
assessed in industrial chemicals
Lutz, Sci Total Environm.1999
Xenoestrogens
• Frog hepatocyte model can rank affinity for
chemicals that bind to estrogen receptor
• E2>tetrachlorobiphenyl>diethylphthlate>
bisphenol A
5 industrial effluents tested: 3 showed>50%
estradiol in this assay
Confounding Factors
• Natural estrogen production varies with
age, gender, and reproductive cycles.
Women produce more estrogen than men,
estrogen is high in fetal life, low in
childhood, high in reproductive ages, low
in menopause. Environmental estrogens
may have differing effects depending on
gender and time of life and genetics
Confounding Factors
• Natural hormones are more potent than
any known environmental estrogens
(phytoestrogens or mycoestrogens) or
industrial xenoestrogens
• Industrial pollutants (DDT and PCBs)
accumulate in fat over time and have
extremely long half-lives (10 years or
more) and accumulate up food chain
Confounding Factors
• Combinations of certain synthetic
compounds may have a synergistic effect
– two compounds may be more potent
than either by itself
• Environmental estrogens may antagonize
others effects
• Environmental estrogens bind differently to
different estrogen receptors
Dietary Estrogen Equivalents
10000
1000
100
estrogen equivalents
in food products
10
1
OC
red wine
white
wine
cabbage
Organochlorine
Compounds –
pesticides
Safe SH, Environ Health Persp, 2000
Wildlife Studies
• PCBs and DDT found extensively in the
Great Lakes thought to have decreased
fertility in fish and birds
• PCBs and DDT were restricted and then
banned in the 1970s – still are abundant
though in decreased concentrations
• After ban of DDT, dramatic increase in
gulls, cormorants, terns and eagles
Wildlife Studies
British Fish and Men
• Alkyphenol ethoxylate surfactants (AEs) –
industrial detergents and degradation
products of polystyrene are found in high
concentrations in industrial effluents and
sediments in lakes and rivers in Europe
• Found to be “estrogenic” – induced
vitellogenin (an egg protein) in male fish
Wildlife Studies
British Fish and Men
• Nonyphenol (an AE – emulsifier, solvent)
thought to be linked to declines in Atlantic
salmon
• Nonyphenols are estrogenic in the lab
• Widespread estrogenized fish populations
in British rivers and estuaries initially
linked to nonyphenols and related
compounds…..
Wildlife Studies
British Fish and Men
• Identification of estrogens in sewage
treatment effluents that received mainly
domestic human wastes showed that the
major estrogenic compounds were
estradiol, estrone, and minor components
of ethinyl estradiol (the estrogen in the
“pill”) in sufficient quantities to estrogenize
fish
Routledge et al. Environmental Science and Technology 1998
Endocrine Disruptors
Sperm Counts
• Meta analysis BMJ 1992 – “genuine
decline in semen quality over the past 50
years.”
• Subsequent studies show great regional
and temporal variability in populations, but
no clear declines in the industrial world
(sperm donor from NYC highest, LA
lowest)
Endocrine Disruptors
Correlation between levels of PCBs and
phthlates and semen quality – highest
levels associated with lowest semen
quality
Endocrine Disruptors
Hypospadias
• Hypospadias and cryptorchidism observed
in rodents exposed in utero to estrogenic
and antiandrogenic compounds
• Significantly increased incidence of
crytporchidism observed in male offspring
of female (but not male) gardeners – no
chemical exposure specifically
documented
Weidner et al. Environ Health Persp, 1998
Endocrine Disruptors
Hypospadias
• Hypospdias increased in more affluent
areas of the world up to 1985, then has
declined in most areas of the world
• No specific environmental estrogen
exposure identified
Endocrine Disruptors
Testicular Cancer
• Increasing in most countries
• DDE associated as it is antiandrogen?
• Testicular cancer higher in Denmark
(14/10000) than Finland (3/10000) but
DDE in mothers the same
• DDE concentrations falling as testicular
cancers are rising
Endocrine Disruptors
Sex Ratios
• Accidental exposure to dioxin in Italy let to
decrease in sex ratio – this area has also
been noted for increased exposure to
other plastic byproducts and insecticides
Dioxin Exposure and Sex Ratios
0.6
0.5
0.4
0.3
sex ratio
0.2
0.1
0
unexposed
31-60
Mocarelli et al, Lancet, 2000
118-264
Dioxin in
ppt
Dioxin Exposure and Sex Ratio
0.6
0.5
0.4
0.3
sex ratio
0.2
0.1
0
unexposed
<19
>19
Dioxin Exposure and Sex Ratio
• Mechanism of action of dioxin exposure
and sex ratio is not clear
• Males exposed at puberty had children
with the lowest sex ratios
• Similar findings noted in rats exposed to
dioxin
Endocrine Disruptors
Phthlates
• Used to soften plastics – medical supplies,
cosmetics, plastic wraps, beverage
containers
• Cause spontaneous abortion in rats,
prolong estrous phase and delay ovulation
• Act as an estrogen to the rat endometrium
• Adverse actions in women not clearly
known
Endocrine Disruptors
Phthlates
• Puerto Rico has this highest incidence of
premature thelarche ever reported
• Increase has been noted over the past 2
decades
• Defined as the growth of breast tissue
prior to 8 years without other
manifestations of puberty
Colon, I. Environmental Health Perspectives, 2000
Phthalates
Premature Thelarche
• Average incidence of premature thelarche
(breast development in girls 6-24 months)
is 8/1000
• This is 18.5 times higher than a similar
study in Minnesota
Phthlates
Premature Thelarche
• Dairy and meat products are contaminated
by estrogenic chemicals – but 800
samples were tested with no abnormal
levels
• Genetic predisposition of Puerto Rican
girls? But a similar population in
Philadelphia had no increase and other
ethnic groups in PR have increased rates
Endocrine Disruptors
Phthlates
• Serum from 41 patients with premature
thelarche and 35 controls assayed for
pesticides and phthalates
• Hi levels of phthalates found in 35% of
cases and only 1/35 of controls
Endrocrine Disruptors
Phthalates
• Are phthalates acting as estrogens to
stimulate breast development?
• Are Puerto Rican girls with premature
thelarche different in dietary or other
habits, or are phthalates markers of other
life styles which may predispose to early
breast development in a culture with
relatively early puberty?
Endocrine Disruptors
Phytoestrogens
• Act as an estrogen in the prostate of
rodents
• Australian sheep developed infertility after
grazing in clover high in coumestrol (a
phytoestrogen)
• Newborn rats exposed to genestein or
coumestrol have altered puberty, females
did not ovulate, males fewer ejaculations
Phytoestrogens
Confounding factors
• Phytoestrogens may produce opposing
effects: at high amounts, some create
infertility in quail, mice, and sheep. Others
may protect against breast and
reproductive tract cancers in humans
• Phytoestrogens may act as estrogens,
antiestrogens, and antiandrogens
Endocrine Disruptors
Phytoestrogens
• No clear data in humans
• An uncontrolled study is being carried out
via health food stores
• Women (and men) are taking
phytoestrogens in doses 200X higher
than that found in a vegetarian diet
Endocrine Disruptors
• Still more heat than light
• Wash off your fruit – Coke tastes better in
glass than plastic
• What’s with all this water in plastic bottles?
• Better to microwave your kids food in
ceramics than plastic
• “Brown paper packages tied up with string”
Pulmonary Function and Air Fresheners
FEV1 – forced
Expiratory volume
At one minute
MMEFR – maximum
mid-expiratory flow
rate
Elliot L et al, Environmental Health Perspectives, 2006
by User
Endocrine Disruptors
Resources
• Working Group on Endocrine Disruptors –
US Government Science and Technology
Council. www.epa.gov/endocrine
• Journal: Environmental Health
Perspectives (free online)
• Vallombrosa Consensus Statement