October 11

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October 11 Endocrine Disruptors - exogenous
substances or mixtures that alter function of the
endocrine system and consequently cause adverse
health effects in an intact organism, or its
progeny (European Commission,1996).
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• Sampling of Early Human Reports
• aviation crop-dusters handling DDT reported to
  have reduced sperm counts (1949)
• DES, a drug used to prevent miscarriage was
  reported to cause adverse effects in offspring
  (1971)
• industrial workers at plants producing
  chlordecone (kepone a chlorinated hydrocarbon
  pesticide) were reported to have lost their
  libido, become impotent and to have low sperm
  counts (70s)
• experiments in laboratory animals demonstrated
  the estrogenic activity of those pesticides
  (1982).
• man-made compounds used in the manufacture of
  plastics reported to be estrogenic (1991) -
  nonylphenol and bisphenol-A.
• more recent reports about phthalate plasticizers
• Reports on PCBs and thyroid disruption

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• The endocrine, reproductive, and behavioral
  effects of these chemicals are believed due to
  their ability to
• Mimic the effect of endogenous hormones
• Antagonize the effect of endogenous hormones
• Disrupt the synthesis and metabolism of
  endogenous hormones
• Disrupt hormonal synthesis
• Disrupt hormonal transport
• Disrupt the synthesis of hormone receptors.
• Most notably estrogens androgens thyroid

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• Role of Estrogens Females
• Sexual maturation
• Menstrual cyclicity
• Bone development and continued growth and
  maintenance
• Metabolism of fats
• Regulate certain aspects of blood clotting
  (relevant to arteriosclerosis)
• Believed relevant to many aspects of feminine
  behavior and abilities

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• Role of Estrogens Males
• Normal bone development
• Certain aspects of male reproductive development
• Spermatogenesis
• Other physiological effects perhaps relevant to
  prostate cancer

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• Role of Androgens Males
• many aspects of male reproductive development
• Male sexual maturation
• Spermatogenesis
• Sex drive
• Many aspects of behavior and abilities
• Role of androgens Females
• Female sex drive

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• Role of Thyroid Hormones
• Regulate metabolism
• During early development, control certain aspects
  of brain development relevant to intelligence,
  sensory function, and motor functioning

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Pituitary is master controller of the rest of the
bodys endocrine system. Hypothalamus - area of
brain that controls the pituitary. Certain
neurons in the hypothalamus respond to neural and
hormonal signals by secreting hormones (releasing
hormones and inhibiting hormones).
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Hormones from the Hypothalamus Releasing
hormones influence the pituitary to release
hormones that act on other glands in body (tropic
hormones). Inhibiting hormones influence the
pituitary to inhibit release of certain hormones.
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Feedback system Levels of hormones in blood are
detected by cells in hypothalamus. Result is to
release releasing or inhibiting hormones to
pituitary This keeps hormonal levels at proper
balance like a thermostat
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• Role of Hypothalamus - Anterior Pituitary
• Hormones from hypothalamus travel in special
  blood system (portal system) to Anterior
  Pituitary
• Bind with receptors in Anterior Pituitary gland
• Release of AP hormones is increased or decreased
  (examples reproductive hormones thyroid
  hormones stress hormones)
• AP hormones then travel in blood and find
  receptors on major organs (gonads, thyroid,
  adrenals, etc) - tropic actions

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TRH from hypothalamus
TSH from anterior pituitary
Thyroid hormones go into blood
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Hormones from the Hypothalamus -----gt Bind
receptors in AP -----gt In response, AP
releases hormones -----gt Hormones
travel in blood to receptors on target
organs---gt Target organs respond in ways that
effect release of


hormones-----gt Hormones travel
to brain where the hypothalamus

reads levels -----gt Then,
Hypothalamus secretes releasing or inhibiting
factors -----gt
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Developmental role of hormones Organizational
effects - permanent effects on tissue
differentiation of body and brain Activational
effects - effects that occur later in life
mostly beginning at puberty
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Hormones act by 1. Promoting the proliferation,
growth and differentiation of cells In early
development, this applies to brain tissue as well
as the reproductive tissues. At puberty,
hormones trigger physical changes. (Development
al roles) 2. Modulating the rate of cell
function This may promote metabolic activity
and/or may promote hormone release (Homeostatic
and rhythmic/cyclical controls)
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• How can hormonal disruption influence sexual
  development?
• Development of Reproductive Systems
• Chromosomal sex is determined at fertilization
• XX - defines female
• XY - defines male
• Phenotype is determined by gene-environment
  interactions
• Phenotype depends on hormones present at
  specific points in time at specific amounts

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Reproductive systems are made up of 3 categories
of sex organs I. Gonads - testes or
ovaries II. Internal sex organs Female -
uterus, fallopian tubes, vagina Male -
epididymis, vas deferens, seminal vesicles,
prostate III. External sex organs Female -
labia, clitoris, outer vagina Male - penis,
scrotum
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• I. Development of Gonads (testes or ovaries)
• A. Males and females have identical immature
  gonads during first month of gestation
• B. During 2nd month, differentiation of immature
  gonads is controlled by presence/absence of
  hormones.
• MALES
• a gene on the Y chromosome causes production of
  testis-determining factor (tdf) - early 2nd month
• testis-determining factor initiates the dev. of
  the immature gonad to become testes (male)
• in absence of gene and/or tdf, immature gonads
  become ovaries
• in presence, gonads become testes

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II. Development of Internal Sex Organs A. 1st and
part of 2nd month - embryo has bisexual internal
organs In same person (male or female), the
precursors for both male and female internal
organs are present. Tissues that can become
female internal organs - Mullerian system
Tissues that can become male internal organs -
Wolffian system B. Whether male or female
internal parts development depends on the
hormonal environment ! At end of 2nd month,
hormonal release begins and continues into 3rd
month.
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C. 3rd month (fetal period) MALE - To develop
male internal organs, testes (male gonads) must
produce hormones and receptors must respond! 1.
Anti-mullerian hormone - tells the Mullerian
(potentially female) system not to
develop Mullerian tissues have receptors for
anti-Mullerian hormone - when bound, tissues do
not develop into female internal sex organs 2.
Androgens - tell the Wolffian system to develop
into internal male sex organs Wolffian tissues
have receptors for androgens when bound by
androgens, male internal organs develop
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C. 3rd month (fetal period) - continued FEMALE
To develop female internal organs, hormones must
be absent. In absence of hormones, Mullerian
system develops into female internal sex organs.
Wolffian tissues disappear. No hormonal
stimulation is required (default
setting). Mullerian system develops into
fallopian tubes, uterus, internal vagina
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• III. Development of External Sex Organs
• A. In first 2 months of gestation, males and
  females have the same external appearance.
• B. During the 3rd month, male or female external
  sex organs develop.
• 1. MALES
• testes (gonads) produce dihydrotestosterone
• this triggers development of external sex organs
  - the penis and scrotum

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• III. Development of External Sex Organs
• 2. FEMALES
• in absence of hormones, female external parts
  develop - the labia, clitoris and outer vagina

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• Reproductive System Development The Brain
• (as understood from research in animal models)
• Perinatal Period
• perinatal - around the time of birth
• first few days postnatal in the rat occur
  prenatally and postnatally in human
• androgens organize the development of the
  hypothalamus along the male pattern (control of
  future steady hormone release)
• absence of androgens, hypothalamus develops for
  future control of cyclical pattern of hormone
  release

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• Sexual dimorphism in human brain
• preoptic area of hypothalamus is larger in males
  than females
• connections between hemispheres are usually
  larger in females
• differences in cortical maturation rate - males
  slower to develop assymmetry
• subtle differences in hippocampus
• subtle differences in thalamus

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What if hormones are not allowed to act on
receptors and trigger development? What if
environmental hormonally-active agents are
present? Gonads? Internal sex organs? External
genitalia? Brain and behavior? These are major
concerns related to the effects of endocrine
disruptors.