Endocrine%20disrupters

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Endocrine disrupters
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Endocrine disruption

• Endocrine disrupters (ED) or endocrine disrupting
  chemicals (EDC) are exogenous chemical agents
  that interfere with the pathways of natural
  hormones (estrogens, androgens)

• Synthesis
• Secretion
• Transport
• Binding
• Action
• Metabolism
• Elimination

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Pituitary-gonad axis
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How do hormones act?

• Cross membrane into cytoplasm and nucleus
• Cross membrane and bind receptor in cytoplasm --gt
  carried to nucleus
• Bind to receptor on cell surface --gt carried into
  the cytoplasm
• Bind receptor on cell surface and activate second
  messages cascade (hydrophilic hormones peptides
  eg. insulin)

• Inside nucleus, they affect gene expression of
  hormone-dependent genes by binding to special
  sites on regulatory regions of DNA
  (estrogen-responsive elements ERE)

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Basic facts about hormones

• Timely synthesis and action
• Negative feedback control of production
• Small amounts usually needed for action
• Small perturbations of concentration have effects
• Developmental implications
• Include reproductive, thyroid and immune system
  effects

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Endocrine disrupters

• Mimic or Block natural hormone action
• Can be synthetic (most) or naturally occurring
  (phytoestrogens, animal hormones)
• May or may not have structural similarity with
  endogenous hormone
• Alter gene expression not structure (not
  mutagens)
• Are lipophilic and cross membranes

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Mode of action of EDs

• Mimics - bind and activate receptors just as the
  natural hormone
• Antagonists - bind but do not activate receptors
• Inhibitors of synthesis of natural hormone
• Inhibitors of degradation/removal of natural
  hormone (HO-PCBs)
• Interfere with transport from production site to
  action site

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Xenoestrogens

• Phytoestrogens
• Lignans
• Isoflavons
• Synthetic
• DES (diethylstilbesterol)
• PCBs
• Dioxins
• DDT/DDE
• Alkylphenols
• Phthalate esters
• Bisphenol-A

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Implications of ED toxicity

• Developmental - estrogen/androgen ratio disturbed
  (placental barrier crossing)
• Two sets of partially developed sex organs
  (imposex) (TBT aromatase suppression)
• Improperly developed sex organs (DDT)
• Sterility (DES)
• Male sperm counts and quality (fertilizing
  ability) structural abnormalities
• Female structural abnormalities of reproductive
  organs
• Cancer - in utero exposure
• Female CCA (DES), breast (and endometriosis)
• Male prostate, testicular
• Hypothyroidism - PCBs?

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Sex hormones are products of cholesterol basic
structure
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Synthesis of the various adrenal steroid hormones
from cholesterol
3b-DH is 3b-dehydrogenase, P450c11 is
11b-hydroxylase, P450c17 is 17a-hydroxylase,
P450c21 is 21b-hydroxylase.
From http//web.indstate.edu/thcme/mwking/steroid
-hormones.html
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Synthesis of major female hormones in the ovary
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Synthesis of the male sex hormones in Leydig
cells of the testis.
P450SSC, 3b-DH, and P450c17 are the same enzymes
as those needed for adrenal steroid hormone
synthesis. 17,20-desmolase is the same as
17,20-lyase of adrenal hormone synthesis.