This document discusses teratogens and endocrine disruptors. It defines teratogens as agents that can permanently alter development, giving examples like thalidomide and rubella virus. Endocrine disruptors are chemicals that interfere with hormone signaling and include many pesticides, plastics, and pharmaceuticals. These chemicals are linked to developmental abnormalities, reproductive issues, cancer risks, and other health impacts due to their effects on hormone receptors and hormone levels during development. While natural hormones have always been present, the abundance of synthetic endocrine disruptors is posing new challenges to human health and physiology.

1. 

TERATOGENS
ENDOCRINE DISRUPTORS

2. In addition to genetic mutations that can affect
development, numerous environmental factors
can disrupt development
Abnormalities caused by exogenous
agents are called ‘disruptions’
Agents responsible for these disruptions are
called ‘teratogens’.

3. 
Rachel Carlson-1962-DDT- Destroying birds
egg

Lenz-1962- Thalidomide- a sedative drug used
to manage pregnancy- limb and ear
abnormalities in fetus

Rubella infection– 20,000 fetuses- blind deaf or
mentally retarded.

4. Human development is usually divided into two periods:
1) embryonic, 2) fetal

5. A teratogen is an agent
that can produce a
permanent alteration of
structure or function in
an organism exposed
during embyronic or fetal
life.

6. Many agents can
produce a teratogenic
effect under some
circumstances.

7. 
Nature of the agent
Dose
Route
Frequency of exposure
Duration of exposure

8. 
Gestational timing
Concurrent exposures
Concurrent illness
Genetic susceptibility
– Mother
– Fetus

9. Cell growth or proliferation
Cell death
Cell migration
Cell and tissue interactions
Disruptions

10. Principal mechanisms
– Gene mutation
– Chromosomal abnormalies
Before or after conception
Males and females both
affected

11. Birth Defects Caused
By Teratogenic
Exposures Are
Preventable.

13. Endocrine Disruptors

14. 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.

15. 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

16. 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

17. 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.

18. 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 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)

19. 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

20. Endocrine Disruptors Include
Pesticides (herbicides, insecticides, …)
Plasticizers
Natural plant metabolites
Pharmaceuticals (contraceptives, drugs,…)
Detergents
Chemicals from cooking & burning
Antibiotics
Metals

21. Results of Disruptions
Inability to maintain homeostasis
Altered growth & development
Altered responses to external stimuli
Altered behavior
Suppressed gametogenesis
Elevated gestational losses
Induced neoplasiEmbryonic
malformation
a or carcinogenesis

22. 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.

23. 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

24. 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.

25. Hormone Transport or Secretion Kinetics
Enterohepatic Metabolism
Feedback loops, Neural controls
users.rcn.com/jkimball.ma.ultranet/Biolog
www.fst.rdg.ac.uk/courses/
yPages/H/hypothalamic_feedback.gif
fs916/lect5/l5b.gif
www.nurse-prescriber.co.uk/

26. Modified from D.J. Liska, The
Detoxification Enzyme Systems,
www.thorne.com/altmedrev/
fulltext/detox3-3.html.

27. Human Sperm
Suppression
From the Study of
Scottish Male
Reproductive Health
www.link.med.ed.ac.uk/
HEW/repro/default.htm

28. Disruption of Sex Determination
Stages
sensitive to
hormonally
active
agents

29. 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...

30. 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).

31. 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.