Michael H. Dong

1
Environmental Endocrine Disruptors Part I
Toxicity
Pineal gland
Hypothalamus
Michael H. Dong MPH, DrPA, PhD
Pituitary gland
Thyroid
Parathyroid
gland
gland
Adrenal
Pancreas
glands
Ovaries
Testicles
(women)
(men)
Readings
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05/30/2004, Elk Grove, California, USA
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Course Objectives

• Be familiar with the terms used, especially
  those pertaining to environmental endocrine
  disruption.
• Undertake a brief review of the human endocrine
  system, which regulates our bodys day-to-day
  function and development.
• Understand the basic modes of endocrine
  disruption.
• Appreciate the potential, yet at times even
  dreadful, effects of endocrine disruption.

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Endocrine Disruption

• Endocrine disruption can be defined as one or
  more biochemical actions disrupting the endocrine
  system, or as the resultant effects.
• Its impact on health is not a new concept, as
  evident from the epidemic linking a rare form of
  vaginal cancer to the maternal use of the
  estrogen DES (diethylstilbestrol).
• A good number of laboratory assays also have
  shown successfully that some pesticides and
  industrial chemicals can induce similar hormonal
  disruption.

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Endocrine System (I)

• Cells, organs, and functions in the human or
  animal body are regulated practically every day
  by the endocrine system.
• Structurally, the endocrine system is a
  collection of ductless glands that secrete
  chemical messages known as hormones.
• Main function of the endocrine network is to
  maintain homeostasis of and long-term control in
  the body by means of chemical signals. It works
  in parallel with the nervous system to control
  many body functions.

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Endocrine System (II)

• The glands that make up the (humans) endocrine
  system are hypothalamus, pituitary, thyroid,
  parathyroid, adrenals, pineal body, pancreas,
  ovaries, and testicles.
• The primary function of these glands is to
  synthesize and secrete hormones.
• Acting as bodys messengers, hormones transfer
  information and instructions from one set of
  cells to another the shape of each hormone
  molecule is specific and can bind to certain
  cellular receptors only.

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Types of Hormones

• Hormones are typically grouped into three
  classes steroids, amines, and peptides.
• Nearly all the steroid hormones are lipids
  synthesized from cholesterol they are
  responsible for the development of many male and
  female sex characteristics.
• Amine hormones are (all) derived from the amino
  acid tyrosine secreted by the thyroid.
• Most hormones are peptides, thus each with only
  a short chain of amino acids they are
  synthesized largely as proteins first.

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Hypothalamus, Pituitary

• The hypothalamus is located below the thalamus,
  in the lower center part of the brain beneath
  this gland is the pituitary, which has the size
  of a pea. Together, these two glands control
  many other endocrine functions.
• Hormones from the two glands are crucial to
  pregnancy, birth, lactation, and a womans
  menstrual cycle, including ovulation.
• Growth hormone and antidiuretic hormone are also
  crucial hormones secreted by the anterior and
  posterior pituitary, respectively.

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(Para)Thyroid, Adrenals

• Thyroid is located in the front and middle of
  the lower neck thyroxine and T3 are two
  important hormones from this gland.
• Located within each of the thyroid lobes are a
  pair of tiny oval-shaped glands called
  parathyroid hormones from this gland are the
  most important regulator of serum calcium.
• The two adrenals are each situated atop of each
  kidney their corticosteroid and catechol-amine
  hormones play an important role in metabolism,
  the immune system, and stress.

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Pineal, Pancreas

• The pineal body is located near the center of
  the brain, having the shape of a tiny clone its
  hormone melatonin has significant effects on
  reproduction and daily physiologic cycles, most
  notably the circadian rhythms.
• Pancreas has both exocrine and endocrine
  functions its bulk is a ducted gland secreting
  digestive enzymes into the small intestine. Its
  endocrine function is by means of its many small
  clusters of endocrine cells, from which the
  hormones glucagons and insulin play an important
  role in regulating blood sugar level.

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Ovaries, Testicles

• The female ovaries and the male testicles,
  responsible for many sex characteristics, are
  referred to as the gonad glands or sex organs.
• Female ovaries synthesize the hormones estrogen
  and progesterone in varying amounts depending on
  where in her cycle a woman is.
• Testicular production of the sex hormone
  testosterone (a principle androgen) begins during
  fetal development, continues for a short time
  after birth, nearly ceases during childhood, and
  then resumes at puberty.

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Modes of Disruption (I)

• There are two basic avenues of endocrine
  disruption, each of which involves primarily two
  modes of biochemical reactions. One avenue is on
  the function or the structure of the glands or
  the target cells, directly or not.
• The other avenue is on the metabolism and the
  function of hormones that the endocrine glands
  secrete or that the target cells bind to.
• In all cases, the disruption can lead to either
  an excessive activation or an excessive
  inhibition of a hormones normal function.

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Modes of Disruption (II)

• The endocrine glands as a target organ can be
  impaired or affected directly or indirectly
  through certain toxicologic disruptions.
• For example, their hormone secretion can be
  impaired by an intruders ability to inhibit the
  biosynthesis or the secretion process.
• Other examples include the secondary endocrine
  toxicity of DES on the ovary and of testosterone
  secretion, and the primary toxicity of nicotine
  on the adrenal, nitrogen on the ovary, and
  estrogens on the pituitary.

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Modes of Disruption (III)

• Many foreign substances can mimic certain
  hormones and hence can bind to those target
  cellular sites receptive of natural hormones.
• Some others can modulate the metabolic pathway
  of certain (sex) hormones still some others can
  speed up the metabolism.
• In short, the modes of endocrine disruption
  include agonistic and antagonistic receptor
  binding, and those actions that affect the
  biosynthesis, storage, release, transport, and
  clearance of hormones.

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Pesticides as EEDs (I)

• Many pesticides have been identified as
  environmental endocrine disruptors (EEDs).
• More pesticides appear to have an adverse effect
  on the thyroid hormones than on others.
• Some pesticides that are prominent thyroid
  hormone disruptors are acetochlor, alachlor,
  ethylene thiourea, fipronil, heptachlor, maneb,
  methomyl, and zineb.
• Mercury, pentachlorophenol, and PCBs are some
  of the thyroid hormone disruptors that are not or
  no longer used as pesticides.

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Pesticides as EEDs (II)

• Pesticides identified as environmental endocrine
  disruptors (EEDs) with estrogenic effects
  include DDT, dieldrin, endosulfan, fenvalerate,
  kepone, lindane, methoxychlor, permethrin,
  triadimefon, and triadimenol.
• Pesticide EEDs considered as androgenic or
  antiandrogenic are atrazine, p,p-DDE, lindane,
  procymidone, vinclozolin, etc.
• Those affecting the reproductive system are
  fewer, including ketoconazole, oxy-chlordane,
  tributyltin, and trifluraline.

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Literature Evidence (I)

• Many in vitro assays are currently used in U.S.
  EPAs mandated Endocrine Disruptor Screening
  Program these assays are used as the first
  tiered test to identify and confirm the potential
  of hundreds (or perhaps thousands) of chemicals
  as endocrine disruptors.
• There are also sufficient in vivo studies
  showing that many chemicals are capable of
  inducing endocrine disruption, even at very low
  doses comparable to background levels in people
  living in many places.

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Literature Evidence (II)

• Field observations in wildlife over the years
  reveal a worrying trend of endocrine disruption
  affecting their population growth.
• From 1970s to 1980s, a great number of herring
  gulls and other fish-eating birds were noted to
  have deformities caused by exposure to dioxin
  released into the Great Lakes.
• More astounding is the observation in the 1980s
  that male alligators in Lake Apopka had
  testosterone levels as low as a females and
  penises 25 smaller than the normal males.

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Literature Evidence (III)

• Although epidemiologic evidence is harder to
  come by, intriguing observations from
  epidemiology studies continue to emerge.
• For example, two epidemiology studies had linked
  atrazine to ovarian tumors in Italian women this
  antiandrogenic herbicide is known to be capable
  of affecting steroid metabolism and ovarian
  functions.
• A more recent study showed that perinatal
  exposure to PCBs is linked to childrens play
  behavior.

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Impacts of Toxicity Data

• Evidence shown thus far represents only a small
  fraction of the vast amount of toxicity data on
  endocrine disruption yet it appears to have
  carried the collective weight of evidence for
  biologic plausibility and consistency.
• A disruptors toxicity is critical, but the
  lesser of the two components of a health risk.
• The other component tends to offer more
  preventive measures and hence appears to play a
  greater role, in that it counts on the
  disruptors availability for exposure.