What is an Endocrine Distruptor?

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What is an Endocrine Distruptor?
Any chemical agent in the environment that can
alter normal endocrine system actions leading to
deleterious effects on an organism or its progeny.
Disruptors may act directly or indirectly.
Direct acting disruptors are usually hormone
agonists or antagonists that interfere with
hormone actions on target cells. Indirect acting
disruptors alter hormone dynamics in circulation,
change hormone metabolism, or interfere with
hormone regulation.
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Useful References
1. Silent Spring. R. Carson. 1962. 2. Our Stolen
Future. T. Colborn, D. Dumanoski, J.P. Myers.
1996. 3. Our Stolen Future - an activist
website 4. Hormonally Active Agents in the
Environment. National Research Council.
National Academy Press Washington, D.C.
1999. 5. Endocrine and Hormonal Toxicology. P.W.
Harvey, K.C. Rush, A. Cockburn. John Wiley
Sons Ltd. Chichester, UK. 1999. 6. Generations
at Risk Reproductive Health and the
Environment. T. Schettler, G. Solomon, M.
Valenti, A. Huddle. The MIT Press
Cambridge, MA. 1999. 7. Hormonal Chaos The
Scientific and Social Origins of the
Environmental Endocrine Hypothesis. S. Krimsky.
Johns Hopkins University Press Baltimore,
MD. 2000.
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Timeline for Endocrine Disruptors
1874 DDT synthesized 1881 PCB
synthesized 1930-77 Widespread PCB use in
transformers as cutting oils 1938 DES
synthesized 1942-72 Widespread DDT application
in malaria control agriculture 1941-54 FDA
USDA DES approved for use in humans
animals 1959 DES produces cancer in
experimental animals 1962 Publication of
Silent Spring by Rachel Carson 1972 EPA
bans DDT, FDA warnings on DES in pregnant
women 1977 EPA bans PCBs 1979-95 Meetings
publications on estrogens in the
environment 1995 EPA endocrine disruptor
workshop NAS/NRC panel meets 1996 Our
Stolen Future, Colborn, Dumanoski Myers,
published FQPA passed Safe Drinking
Water Act amended 1998 International
Conference on Endocrine Disruptors, Kyoto 1999
NRC report, Hormonally Active Agents in the
Environment
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What are endocrine systems for?

• Endocrine Functions
• Maintain Internal Homeostasis
• Support Cell Growth
• Coordinate Development
• Coordinate Reproduction
• Facilitate Responses to External Stimuli

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What are the elements of an endocrine system?

• Sender Sending Cell
• Signal Hormone
• Nondestructive Medium Serum Hormone Binders
• Selective Receiver Receptor Protein
• Transducer Transducer Proteins 2º Messengers
• Amplifier Transducer/Effector Enzymes
• Effector Effector Proteins
• Response Cellular Response (2º hormones)

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What kinds of hormone are there?

• Known Hormonal Classes
• Proteins peptides
• Lipids (steroids, eicosanoids)
• Amino acid derived
  (thyronines, neurotransmitters)
• Gases (NO, CO)

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What is a hormone receptor?
Hormone Receptors are cellular proteins that bind
with high affinity to hormones are altered in
shape function by binding they exist in
limited numbers. Binding to hormone is
noncovalent reversible. Hormone binding will
alter binding to other cellular proteins may
activate any receptor protein enzyme actions.
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What are the main types of receptors?
Membrane Receptors Imbedded in target cell
membrane integral proteins/ glycoproteins
penetrate through membrane For protein
charged hormones (peptides or neurotransmitters)
3 major groups Serpentine 7 transmembrane
domains, Growth factor/cytokine 1 transmembrane
domain, Ion channels Nuclear Receptors Nuclear
proteins that act in pairs bind to specific
Hormone Recognition Elements (HREs) sequences
on the DNA in the promoter regions of target
genes For small, hydrophobic molecules
(steroids, thyroid hormones)
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Known Classes of Endocrine Disruptors
Estrogens DES, o,p-DDT, DEHP, bisphenol
A Anti-estrogens hexachloro-4-biphenylol,
luteolin Anti-androgens p,p-DDE,
vinclozolin Progestogens norethindrone,
norgestrel Adrenal toxins o,p-DDD, glycyrrhizic
acid Thyrotoxic agents PCBs, goitrin Aryl
hydrocarbons often anti-estrogens TCDD, PAH
Pancreatic toxins azoxyglycosides,
streptozotocin Metals cadmium, nickel,
aluminum Retinoids vitamin A analogs
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Endocrine Disruptors Include
Pesticides (herbicides, insecticides,
) Plasticizers Natural plant metabolites Pharmac
euticals (contraceptives, drugs,) Detergents Chem
icals from cooking burning Antibiotics Metals
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Results of Disruptions
Inability to maintain homeostasis Altered growth
development Altered responses to external
stimuli Altered behavior Suppressed
gametogenesis Elevated gestational
losses Embryonic malformation Induced neoplasia
or carcinogenesis
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Agonist, Antagonist, Mixed Activity
Hormones receptors co-evolve. It is common to
have several hormone receptors demonstrate
varying affinity for the same hormone. It is
also common for one hormone to have some affinity
for several different receptor types.
Promiscuity often occurs with opioids steroids.
Progestins can bind glucocorticoid receptors.
Clomiphene binds estrogen receptors
demonstrates mixed anti-estrogenic estrogenic
actions. Cyproterone acetate is a progestin
anti-androgen. TCDD is an anti-estrogen
thyroid agonist.
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Basis for Endocrine Pathology of Direct
Disruptors Interference with Hormone Synthesis
Action
Synthetic enzyme inhibitor Agonist or antagonist
binding to receptor Alteration of normal
dose-response relationships
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Biologically available (free) hormone levels vary
due to
Changes in synthesis Changes in secretion Changes
in degradation Changes in binding
proteins Age Gender Developmental
stage Reproductive status Stage of temporal rhythm
so, alterations at any process or stage changes
free hormone levels.
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Mechanisms for Indirect Endocrine Disruption
Involve Modification of
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Mechanisms for Indirect Endocrine Disruption
Involve Modification of
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Mechanisms for Indirect Endocrine Disruption
Involve Modification of
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Detoxification Pathways
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Human Sperm Suppression
From the Study of Scottish Male Reproductive
Health www.link.med.ed.ac.uk/ HEW/repro/default.ht
m
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Disruption of Sex Determination
Stages sensitive to hormonally active agents
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Are Endocrine Disruptors Causal?
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Diethylstilbestrol
SAX TOXICITY EVALUATION THR Poison by
intraperitoneal and subcutaneous routes.
Moderately toxic by ingestion and other routes. A
human carcinogen and teratogen by many routes. It
causes skin, liver and lung tumors in exposed
humans as well as uterine and other reproductive
system tumors in the female offspring of exposed
women. An experimental carcinogen, neoplastigen,
tumorigen and teratogen by various routes. A
transplacental carcinogen. Glandular system
effects by skin contact. Human reproductive
effects by ingestion. Implicated in male
impotence and enlargement of male breasts. Other
experimental reproductive effects. Mutagenic
data.
Bis (2-ethylhexyl) phthalate
New Jersey Department of Health and Senior
Services Cancer Hazard Bis (2-Ethylhexyl)
Phthalate may be a CARCINOGEN in humans. It has
been shown to cause liver cancer in
animals Reproductive Hazard Bis (2-Ethylhexyl)
Phthalate may be a TERATOGEN in humans since it
has been shown to be a teratogen in animals.
Bis (2-Ethylhexyl) Phthalate may damage the
testes...
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Impacts on Cancer Rates
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Conclusions
Endocrine disruptors or hormonally active agents
have been with us for millennia as elements of
plants and cooking. The new abundance of
synthetic compounds has unleashed a wave of new
challenges to our physiology, including the
endocrine system. The impacts are as pleiotropic
as endocrine actions are. Not surprisingly they
involve altered reproductive success, growth, and
cancer risks because of endocrine controls or
inputs in these processes. Due care will help
minimize impacts, but some increased risks are
here permanently.