The document discusses endocrine disruptors and the endocrine system. It defines the endocrine system and how it regulates important physiological functions through hormones. Endocrine disruptors are exogenous chemicals that can interfere with hormone production, binding, or response and disrupt homeostasis. Several known classes of endocrine disruptors are identified, including some that are estrogenic, anti-estrogenic, anti-androgenic, and disrupt thyroid or insulin regulation. Specific endocrine disruptors discussed include DDT, BPA, atrazine, PCBs, DES, and streptozotocin, along with their hormonal effects and impacts.

1. Endocrine Disruptors
NST11

2. What is the Endocrine System?
d. Endocrine system regulates many important aspects of
mammalian physiology, including development, growth, metabolism,
mood, behaviors, and many other tissue functions.
c. Potent chemicals, they exert profound effects on the target at
very low concentrations (pM ~ nM). Must be regulated within very
narrow limits.
b. Hormones are a class of synthetic substances produced
by glands that are transported by the circulatory system to target
distant organs to regulate physiology and behavior.
a. Endocrine system is a system of glands that secrete or release
signaling molecules, called hormones, that affect the physiology of
particular organs.

3. Endocrine System

4. Endocrine vs. exocrine
Gland Secretion
Method of
transport
Where secretion
functions
Exocrine Juice, often containing
enzymes
Duct Organ near gland
Endocrine Hormone Bloodstream Organ near and
distant

5. Classification of Hormones (structure based)
2. Amine hormones
3. Steroid hormones
- Derived from cholesterol
- Lipid soluble
e.g. sex hormones, glucocorticoids
1. Peptide hormones
- Formed chains of amino acids
- Longer chains are called protein hormones
- Most of our body’s hormones are peptide hormones
- Water soluble
e.g. insulin, glucagon
- Derived from the modifications of amino acids
- Water soluble except for thyroid hormones
e.g. Catecholamines, thyroid hormones

6. Catecholamines (example of amine hormone)
(Noradrenaline)
(Adrenaline)

7. Thyroid hormones (example of amine hormone)

8. Fat soluble hormones
(intracellular)
Water soluble hormones
(cell surface)
Act through
membrane receptors
Act through nuclear receptors,
which are transcription factors
(proteins that can directly
affect gene expression)
Hormonal signaling

9. a. Dissolve in water (hydrophilic)
b. Are formed from amino acids - which are themselves the
structural units of proteins and are soluble in water.
c. Cannot pass through the target cell membranes (which include
fatty components).
d. Affect cells by binding to cell surface receptors of the target cell.
(The shape of the receptor molecule in the cell membrane must
match the shape of the "signaling molecule”).
e. Insulin, glucagon, catecholamines (dopamine, epinephrine, and
norepinephrine), growth hormone, and etc…
f. Uses 2nd messanger (e.g.cAMP, cGMP) and signaling cascade
to mediate the effect.
Water soluble hormone:

10. Signaling pathway of catecholamines
G-protein coupled receptors
(GPCRs)
Mediates ’flight-or fight’ response

11. Insulin
a. A peptide hormone produced by pancreatic beta cells.
b. Water soluble, peptide hormones
c. Regulates the metabolism of carbohydrate, fat, and protein
the absorption (anabolic), especially glucose from the blood to
fat, liver, and skeletal muscle.
d. Secreted when the blood glucose levels are high.
e. Antagonized by glucagon (catabolic) that is secreted by
pancreatic alpha cells. Glucagon works in the opposite
manner: increased secretion when blood glucose is low.
Glucagon increases glucose levels by stimulating
glycogenolysis and gluconeogenesis.

12. Insulin (beta cell) Glucagon (alpha cell)

13. Insulin and glucagon maintains glucose homeostasis
a. Hormone levels are under stringent control.
b. Homeostasis: “the tendency of an organism or cell to regulate its
internal environment and maintain equilibrium, usually by a system of
feedback controls, so as to stabilize health and functioning”
c. Glucose homeostasis range: 70 to 110 mg/dL to supply your
brain and nervous system with adequate fuel.

14. Glucacon
Glucose
Insulin

15. a. Dissolve in fat rather than in water.
b. Are usually formed
from cholesterol (cholesterol molecules being important
components of cell membranes)
c. Fat-soluble hormones can pass through cell membranes
d. Affect cells by binding to receptors inside the target cell.
e. Glucocorticoids (e.g. cortisol), thyroid hormone, estrogen,
aldosterone, testosterone…
Fat soluble hormone:

16. Steroid Hormone signaling:
e.g. Glucocorticoid
Glucocorticoid Receptor (GR)
- a nuclear transcription factor

17. Negative feedback mechanism of hormonal control
- Regulatory mechanism between the hypothalamus and pituitary
is that they regulate their own secretion/synthesis through negative
feedback inhibition.
- to keep hormone levels within a
particular appropriate physiological
range.

19. TSH: Thyroid stimulating Hormone
TRH: Thyrotropin releasing Hormone
Hypothalamic–pituitary–thyroid axis (HPT axis)
: example of negative feedback

20. Endocrine disruptors

21. - 80,000 ~ 100,000 chemicals are used in the US.
- High volume of chemicals (HVC): 1 million pounds
a year, 2,539 chemicals listed as HVC in 2010.
- The most heavily used HPV chemicals in commerce
were largely untested.
- Only 7% of the HPV chemicals had a “complete”
set of screening level toxicity data.
Chemical exposure in our daily lives

22. Endocrine Disruptors Include;
Pesticides (herbicides, insecticides, …)
Plasticizers
Natural plant metabolites
Pharmaceuticals (contraceptives, drugs,…)
Detergents
Chemicals from cooking & burning
Antibiotics
Metals
Cosmetics
Many Endocrine disruptors can potentially affect fetus, as many of
them can cross placental barrier

23. Endocrine disruptors are exogenous chemicals that
either mimic or block hormone actions
These can happen through;
1) Altering hormone levels
2) Binding to receptors (agonism)
3) Blocking normal hormone
binding to receptors (antagonism)
4) Altering hormonal responses
and many other steps in hormonal
actions

24. Differences between toxicants and endocrine disruptors
Linear dose/response curve
High dose predicts low dose effect
Threshold
Think pharmacology
Non-monotonic
May be more active at lower doses
No threshold
Think endocrinology
Traditional Toxicants Endocrine disruptors
Dose
Respone
“Low-dose effects”; responses that may occur at doses well below those
levels previously tested and determined to be safe.
Y=a+bX Y= ???

25. Results of Disruptions
Inability to maintain homeostasis
Altered growth & development
Altered responses to external stimuli
Altered behavior
Suppressed gametogenesis (i.e. spermatogenesis,
oogenesis)
Elevated gestational losses
Embryonic malformation
Induced neoplasia or carcinogenesis

26. Organochlorine Insecticides:
Dichlorodiphenyltrichloroethane (DDT)

27. Organochlorine Insecticides:
Dichlorodiphenyltrichloroethane (DDT)
- 1873: Synthesis by Paul Muller (German graduate student)
- 1939: Insecticidal activity discovered and used in WW II to combat malaria
typhus, and other insect-borne human diseases--deemed the “miracle”
pesticide for its persistence, selectivity, and broad range of control.
- Late 1940s: DDT came into wide agricultural and commercial use
- 1948: Nobel Prize in physiology and medicine to Paul Muller for control of
insect transmitted diseases
- 1959: 80 million pounds were applied
- 1971: Usage declined to 13 million because of insect resistance and growing
environmental and health concerns.
- 1972: DDT was banned in the US (export allowed) because of its harmful
environmental impact and potential harm to human health
- From 1940s-1970s ~675,000 tons were applied in the US

28. DDT Environmental Impact
Clear Lake (California) --DDD (chemical variant of DDT) was
used as insecticide to control gnats at 14 ppb in 1950s
-1000 pairs of grebes failed to reproduce
-inhibited shelling of eggs—200 dead birds
-visceral fat in birds—1600 ppm
Nearly led to the decimation of the American Bald Eagle

29. DDT Ban
1962 Rachel Carson’s “Silent Spring” is credited for
the DDT Ban in 1972 and inspired to the creation of
Environmental Protection Agency (EPA).
• Claimed detrimental effects of DDT on the
environment—especially birds
• Carson accused the chemical industry of spreading
disinformation and public officials of accepting industry
claims uncritically.
• Implicated DDT in bioconcentration and
biomagnification in food chains
• Caused a lot of backlash from scientists
• Raised political and public awareness to DDT; potential
carcinogenicity of DDT led to EPA ban in 1972

30. Later studies show DDT as endocrine disruptors
* IC50: half maximal inhibitory concentration
(The lower IC50, the higher affinity to receptor)
Exposing to DDT causes reproductive abnormality

31. Diethylstilbestrol (DES)
- Synthetic non-steroid estrogen (1938). Binding affinity to estrogen
receptor α (ERα) is at least 3-5 fold stronger than physiological estradiol.
estradiol DES

32. Diethylstilbestrol (DES)
- Synthetic non-steroid estrogen (1938). Binding affinity to estrogen
receptor α is at least 3-5 fold stronger than physiological estradiol.
- Estrogens are female sex steroid hormones. They are responsible for
female reproductive organ development. Beneficial function estrogen at
physiological levels include;
- Increase bone formation and decrease bone resorption
- Decrease low-density lipoprotein (LDL) cholesterol
- Anti-inflammatory
- Generally decrease visceral fat but increase subcutaneous fat
- In normal women, estrogen levels are up and down during menstrual cycle
- From about 1940 to 1971, DES was prescribed to pregnant women (~ 3
million in the US) in the mistaken belief it would reduce the risk of pregnancy
complications and losses (miscarriage).
- But later studies show that actually DES increases the risk of miscarriage.

33. - In 1971, DES was shown to cause a rare vaginal tumor in females who
had been exposed to DES in utero. FDA advised against using it in
pregnant women.
- 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.
- DES mainly activates estrogen receptor-α (ERα) and promotes
abnormal proliferation of reproductive duct cells.
- Used in hormonal replacement therapy until late 1980s.

34. Atrazine
- Used on corn for grassy and broadleafed weeds; one of the most highly
used herbicides for corn and grain.
- Strong inhibitors of photosynthesis—selectivity depends on ability of
tolerant crops to metabolize the parents compound whereas susceptible
plants do not.
- Male frogs can turn into females after exposure to atrazine
at low ecologically relevant doses.
- Atrazine induces an enzyme aromatase that converts testosterone
(androgen) to estrogen. Aromatase inhibitors are used to treat breast
cancer.

36. Tyrone B. Hayes et al. PNAS
2002;99:5476-5480
Abnormal gonads in a male Xenopusfrog, the
result of exposure to the herbicide atrazine.

37. Polychlorinated biphenyls (PCB)
- PCBs are a class of synthetic, persistent, lipophilic, halogenated
aromatic compounds that were widely used in industrial and consumer
products for decades before their production was banned in the late
1970s. PCBs were used in cutting oils, lubricants, and as electrical
Insulators (resistant to extreme temperature and pressure).

38. Polychlorinated biphenyls (PCB) and thyroid
hormones are structurally similar

39. Polychlorinated biphenyls (PCB)
- PCBs remain ubiquitous environmental contaminants. They are
biologically concentrated and stored in human fat tissue. The
general population is exposed primarily through ingestion of
contaminated foods (they are easily accumulated in food chains).
- PCBs have been shown to affect estrogen (both estrogenic and
anti-estrogenic) and androgen (anti-androgenic) systems.
- PCBs disrupt thyroid hormone functions at multiple levels.

40. TSH: Thyroid stimulating Hormone
TRH: Thyrotropin releasing Hormone
Thyroid hormones are essential for
life and are important for the regulation
of metabolism, development and
growth.
- Increase metabolic rate
- Reduce plasma cholesterol
- Increase heart beat, cardiac output
- Increase protein and carbohydrate
catabolism
Hypothalamic–pituitary–thyroid axis (HPT axis)

41. Streptozotocin (STZ)
- Originally identified in the late 1950s as an antibiotic. But in the mid-
1960s streptozotocin was found to be selectively toxic to the pancreatic
beta cells (impairs insulin secretion> type I diabetic).
- Pancreatic islets contain alpha cells (secrete glucagon), beta cells (secrete
Insulin).

42. - STZ causes DNA damage and killed the cells. It is specific to beta
cells because it can only enter the cells through glucose
transporter 2, which is only expressed in beta cells.
- Destroying beta cells results in no insulin in the body: diabetes
- Type 1 diabetes: insulin-dependent; auto-immune, as our own
immune system attack and destroy beta cells, 5% of diabetes.
- Type 2 diabetes: insulin-independent; body still secretes insulin,
but insulin cannot exert its function to reduce blood glucose
levels (Insulin resistance). 95% of diabetes.
- High blood glucose causes many complications: cardiovascular,
kidney failure, foot ulcers, eye damage…..
- STZ causes type 1 diabetes-like symptom.

43. - A synthetic chemical used in bottles, eyeglass lenses, toys, CD/DVDs,
cell phones, cans, electronics……..
- Has been found to exert estrogen-like effects.
- May act as an antagonist for thyroid hormone receptor and
androgen receptor.
- Also can make you fat through thyroid dysfunction and through
activating PPARγ (obesogen).
- Studies in laboratories show BPA could have effects on development,
reproduction and behaviors….
- But industry insists that low does of BPA is not harmful.
- National Institute of Environmental Health (NIEHS) and EPA gather 38
experts in endocrine disruption and BPA to evaluate 700 studies: 2007
Bisphenol A (BPA)

44. Known Classes of Endocrine Disruptors
Estrogens DES, DDT, DEHP, bisphenol A
Anti-estrogens hexachloro-4-biphenylol, luteolin
Anti-androgens DDE, vinclozolin, bisphenol A(?)
Progestogens norethindrone, norgestrel
Adrenal toxins DDD, glycyrrhizic acid
Thyrotoxic agents PCBs, goitrin
Aryl hydrocarbons[often anti-estrogens] TCDD, PAH
Pancreatic toxins azoxyglycosides, streptozotocin (destroy
insulin-secreting cells)