Transcript Document 579293

Environmental Endocrine
Disruptors
Part I: Toxicity
Hypothalamus
Thyroid
gland
Adrenal
glands
Testicles
(men)
Pineal gland
Pituitary gland
Parathyroid
gland
Michael H. Dong
MPH, DrPA, PhD
Pancreas
Ovaries
(women)
Readings
05/30/2004, Elk Grove, California, USA
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 body’s
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.
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.
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.
Endocrine System (II)
 The glands that make up the (human’s)
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 body’s 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.
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.
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 woman’s
menstrual cycle, including ovulation.
 Growth hormone and antidiuretic hormone
are also crucial hormones secreted by the
anterior and posterior pituitary, respectively.
(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 catecholamine hormones play an important role in
metabolism, the immune system, and stress.
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.
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.
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 hormone’s normal function.
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 intruder’s 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.
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.
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.
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, oxychlordane, tributyltin, and trifluraline.
Literature Evidence (I)
 Many in vitro assays are currently used in
U.S. EPA’s 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.
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 female’s and
penises 25% smaller than the normal males’.
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 children’s play
behavior.
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 disruptor’s 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
disruptor’s availability for exposure.