Endocrine Disruption

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Endocrine Disruption
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• What are endocrine glands?
• Pituitary gland - regulates other glands by
  secreting a mixture of hormones.
• Thyroid - One of the largest glands in the body.
  Regulates carbohydrates, fats and proteins - in
  the body.
• Parathyroid glands - The smallest glands.
  Controls the use of calcium and phosphorus.

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• Pancreas - The pancreas produces glucagon and
  insulin to help maintain the sugar level of the
  blood through action of the liver.
• Adrenal glands - Part of each adrenal gland
  secretes a mixture of hormones, including
  aldosterone and cortisone. Another part secretes
  adrenaline.
• Reproductive system elements - Includes the
  ovaries and testes.

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Estrogen Structure and Function

• Member of the steroid family of molecules with
  fused carbon rings
• Significant role in reproduction
• Imperative in the proper functioning of mammary
  gland, cardiovascular system, and bone maintenance

Estrogens also produced in males, but the reason
remains unclear.
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Mechanism of Estrogen Action

• Estrogenic compound diffuses across membrane
• Binds to receptor in the nucleus
• Activates DNA transcription, producing mRNA
• mRNA exits nucleus and travels into the cytoplasm
• mRNA is translated into a specific protein
• Protein elicits a cellular response

LIPOPHILIC
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How are estrogen receptors synthesized?
DNA transcription
cell
mRNA translation
nucleus
tRNA
PROTEIN
protein synthesis
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Protein Structure

• primary amino acid sequence
• secondary H-bonds
• tertiary even MORE interaction
• quaternary protein party

PROTEIN RECEPTORS
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Formation of the Binding SitePROTEIN FOLDING!
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Estrogen Receptors (ERs)

• Ligand-inducible nuclear receptors
• Composed of 595 amino acid residues
• Conformational change upon binding, creating
  DNA-binding domain
• Transcription and translation induced
• Two types of ERs ERa and ERß
• Isoforms have 97 homology

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Structure of ER
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Ligand Binding Domain of ER
Estrogenic compound
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DNA Binding
The ER binds as a dimer!
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Estradiol The Natural Ligand
o,p'-DDT
4-nonylphenol (NP)
Coumestrol
Diethylstilbestrol (DES)
Kepone (chlordecone)
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ER promiscuity xenoestrogens ENDOCRINE
DISRUPTION
Structural features of common EDCs

• phenolic ring
• H-bond capability (E2-OH)
• precise steric hydrophobic centers
• general hydrophobicity
• ring structure

HOWEVER
The heavy metal cadmium is considered an EDC, as
it interacts with the LBD of the receptor.
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What is the problem?

• Our Stolen Future (Colburn)
• Pesticides may leave legacy of hormonal chaos
• Decreased sperm motility?

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Are Reported Effects Real?

• Sperm counts falling
• Testicular cancer is increasing
• More men being born with malformed penises and
  undescended testicles
• Effects caused by hormone mimics?

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Sperm Counts

• Variable
• Differ by location - New York (132) vs Minnesota
  (101) vs Calif (73)

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Breast Cancer Cases
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Alligators

• Appear to be sensitive during egg incubation to
  endocrine disrupting chemicals (EDCs)
• Effects abnormal gonadotropin secretion from
  brain altered steroid production by gonad
  altered production and transport of plasma
  steroids altered excretion of steroids in liver
  direct binding of EDCs to steroid receptors.

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Fish

• Bleached kraft mill effluent (BKME) affect fish
  in NW Florida
• Female mosquitofish and killifish exhibited
  masculinization
• Females exhibited male behavioral characteristics
  and attempted to mate with females
• synthetic androgens and plant sterols also caused
  similar effects

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Fish 2

• Causal observations by fishermen in UK found fish
  w/ male and female secondary sex characteristics
• Sumpter hypothesized that response was due to
  estrogenic components of WWTPs in UK
• Developed vitellogenin (vt) assay for use in male
  fish
• Caged carp/trout found to have induction of vt in
  rivers near WWTPs

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Why?

• Possible binding of alkylphenol ethoxylates
  (nonylphenol) to estrogenic receptors? Possible,
  but activity is weak!
• What else?

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Disrupter vs Modulator?

• An endocrine disrupter may be defined as a
  stressor that produces a permanent, adverse
  alteration of the endocrine system.
• An endocrine modulator is defined as a stressor
  that produces a temporary, non-adverse alteration
  of the endocrine system.

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Criteria for Cause and Effect Relationship

• Spatial and temporal contiguity - when you
  observe the stressor you must see an effect
• Temporal succession
• Consistent conjunction