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Endocrinology Biology 595EN
October 2003
Endocrine Disruptors
Kenneth L. Campbell
Professor of Biology
University of Massachusetts at Boston
This presentation is made possible
by a grant entitled
“Shortcourses in Endocrinology at
Minority Undergraduate Institutions”
from the
National Institute of General Medical
Sciences (NIGMS)
to
The Minority Affairs Committee of the
Endocrine Society
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.
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.
Timeline for Endocrine Disruptors
1874
1881
1930-77
1938
1942-72
1941-54
1959
1962
1972
1977
1979-95
1995
1996
1998
1999
DDT synthesized
PCB synthesized
Widespread PCB use in transformers & as cutting oils
DES synthesized
Widespread DDT application in malaria control & agriculture
FDA & USDA: DES approved for use in humans & animals
DES produces cancer in experimental animals
Publication of Silent Spring by Rachel Carson
EPA bans DDT, FDA warnings on DES in pregnant women
EPA bans PCBs
Meetings & publications on estrogens in the environment
EPA endocrine disruptor workshop; NAS/NRC panel meets
Our Stolen Future, Colborn, Dumanoski & Myers, published;
FQPA passed & Safe Drinking Water Act amended
International Conference on Endocrine Disruptors, Kyoto
NRC report, Hormonally Active Agents in the Environment
What are endocrine systems for?
Endocrine Functions
• Maintain Internal Homeostasis
•
•
•
•
Support Cell Growth
Coordinate Development
Coordinate Reproduction
Facilitate Responses to External Stimuli
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)
What kinds of hormone are there?
Known Hormonal Classes
• Proteins & peptides
chemcases.com/olestra/
images/insulin.jpg
• Lipids (steroids, eicosanoids)
• Amino acid derived
(thyronines, neurotransmitters)
chem.pdx.edu/~wamserc/
ChemWorkshops/ gifs/W25_1.gif
• Gases (NO, CO)
website.lineone.net/~dave.cushman/
epinephrine.gif
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.
Membrane Receptors
Imbedded in target cell membrane; integral proteins/
glycoproteins; penetrate through membrane
For protein & charged hormones (peptides or
neurotransmitters)
What are the main types of receptors?
3 major groups: Serpentine = 7 transmembrane
domains, Growth factor/cytokine = 1 transmembrane
domain, Ion channels
Nuclear Receptors
Nuclear proteins that usually 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)
Cross your eyes, relax, & see if you can see how 2
molecules of steroid receptor, green & yellow,
interact with a specific sequence, SRE, in DNA.
Receptors for steroids, T3, retinoids, vitamin D, &
aryl hydrocarbons all work this way.
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
Endocrine Disruptors Include
Pesticides (herbicides, insecticides, …)
Plasticizers
Natural plant metabolites
Pharmaceuticals (contraceptives, drugs,…)
Detergents
Chemicals from cooking & burning
Antibiotics
Metals
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
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.
Relative Affinities for Receptors of the Insulin Family to Family Members
Receptor
Relative Affinities
Insulin
Insulin >Proinsulin (10%) >IGF II >IGF I
>>Relaxin(~0)
IGF I
IGF I > IGF II >Insulin ~ Proinsulin
IGF II
IGF II = IGF I >>Insulin ~ Proinsulin
Relaxin
Relaxin >NGF >Proinsulin > IGF >>Insulin (~0)
NGF
NGF (only)
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.
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
www.pharmacist.com/images/
estrogen_molecule.gif
17β-Estradiol
www.ac-nantes.fr/peda/
disc/scphy/dochtml/3ieme/ch
ouroug/images/molecule.gif
Diethylstilbesterol
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.
Mechanisms for Indirect Endocrine
Disruption Involve Modification of:
Hormone
Transport
or Neural
Secretion
Kinetics
Enterohepatic
Metabolism
Feedback
loops,
controls
users.rcn.com/jkimball.ma.ultranet/Biolog
yPages/H/hypothalamic_feedback.gif
www.nurse-prescriber.co.uk/
www.fst.rdg.ac.uk/courses/
education/visual_lib/pp18.jpg
fs916/lect5/l5b.gif
Detoxification Pathways
Modified from D.J. Liska, The
Detoxification Enzyme Systems,
www.thorne.com/altmedrev/
fulltext/detox3-3.html.
Human Sperm
Suppression
From the Study of
Scottish Male
Reproductive Health
www.link.med.ed.ac.uk/
HEW/repro/default.htm
Disruption of Sex Determination
Stages
sensitive to
hormonally
active
agents
Penoscrotal type hypospadias
www.vghtpe.gov.tw/~peds/
lecture/pedsintr/73.jpg
Are Endocrine
Disruptors Causal?
www.ourstolenfuture.org/Images/graphs/
hypospadias.jpg
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...
Impacts
on Cancer
Rates
www.link.med.ed.ac.uk/
HEW/repro/default.htm
Breast Cancer Risks. Reference group
(R) vs quartiles of dieldrin exposure
(adapted from Høyer et al. 1998 in Our
Stolen Future Website: www.ourstolen
future.org/ Images/graphs/breast%20
cancer%20dieldrin%20risk.jpg). Vertical
bars = 95% confidence interval. Dose
response is significant (p = 0.01).
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.