Download Endocrine Toxicology

Introduction to Toxicology
EV 460/660 & BI 460/660
Fall 2014
Toxic Effects on the Endocrine System
Introductory Comments
A.
integration of bodily function – neural and endocrine systems – neuroendocrinology
B.
historical perspective – underdeveloped area of toxicology, past emphasis on carcinogenesis
C.
current concern over environmental endocrine disruptors has greatly heightened research in area
-- bulk of evidence for toxicant-induced endocrine disruption comes from wildlife toxicology
-- evidence in vertebrate wildlife is most extensive in non-mammalian species
-- primary targets in all species seem to be sex steroids and thyroid hormones
-- problem of relative weak comparative endocrinology basic science database
-- as always, tremendous difficulties in inter-species extrapolations to humans
-- some suggestive data from human populations; but firm cause-effect data not evident
-- by virtue of potential importance has become a research priority
-- efforts underway to develop rapid, cost-effective screening methods, ultimate success is problematic
(as in other areas)
Brief Review of Endocrine System
A.
emphasis placed upon endocrines with well documented toxic-induced alterations and on potential
targets for endocrine disruption by environmental chemicals (as currently evidenced by wildlife toxicology
literature)
B.
Current focus is on sex steroids and thyroxine
– these do share a common mechanism of action -- e.g., binding to intracellular/cytosolic receptors,
translocation to the nucleus, and stimulation of transcription
-- however, there is no apriori reason to believe that endocrine alteration by environmental chemicals is
limited to these groups of hormones
C.
negative feedback loops in hormonal regulation, multiple targets/mechanisms for toxic effects
D.
hypothalamic-pituitary axis
-- anterior vs. posterior pituitary
-- hypothalamic releasing factors/hormones
-- hormones of the anterior pituitary and target tissues for these hormones
E.
gonads – ovaries and testes, hormones of ovaries and testes
F.
thyroid-- hormones of thyroid
Environmental Endocrine Disruptors and the Thyroid Gland
A.
Thyroid function – required to regulate metabolic rate of essentially all cell types, essential for normal
growth and development, particularly normal development of the nervous system (cretinism); adequate
dietary intake of iodine required for normal function; older literature focused on goiter and thyroid tumors;
newer literature focuses on mechanisms of action and more subtle impairments of thyroid function,
newest literature deals with environmental endocrine disruptors
B.
Endocrine disrupting environmental toxicants – potential impacts on thyroid
1.
environmental toxicants causing hepatic enzyme induction and increased metabolism/excretion
-- increase glucuronidation and sulfation of T 4 and T3 and biliary excretion
-- chlorinated hydrocarbons (ex. DDT, chlordane, TCDD) and polyhalogenated biphenyls (PCBs)
2.
environmental toxicants interfering with hormone synthesis
-- herbicides – potential mechanisms including inhibition of thyroid peroxidase [oxidizes inorganic
iodide (I-) to molecular iodine (I2) required for hormone synthesis], inhibition of T4
synthesis, inhibition of serum levels of iodine, and atrophy of thyroxine synthesizing cells
-- fungicides (ex. Nabam, Zineb, Zuram) – inhibit iodine uptake by thyroid
Environmental Endocrine Disruptors and Reproductive Endocrinology
A.
Adverse effects of environmental chemicals on reproductive endocrinology and reproductive function are
now well documented in wildlife species – including numerous macroinvertebrate species and all
vertebrate phyla
-- observed effects include decreased fertility, demasculinization and defeminization (morphological
aberrations), alterations in levels of sex steroid hormones, alterations of expression of sex- linked genes,
alterations in sex determination and sex ratios
B.
Lack of agreement on terms
-- endocrine disruptors or disrupters seems to be most common and to have caught the fancy of public
and government agencies
-- some of the proliferation of terms may be related to “name it leads to fame” phenomenon
-- some alternative terms that have been proposed – ecohormones, xenohormones, and xenoestrogens
-- latter term (xenoestrogens) has two origins
--- many of the endocrine altering environmental chemicals have estrogenic effects
--- phytoestrogens -- plant secondary compounds with estrogenic effects known for some time
C.
Multitude of potential mechanisms for endocrine alteration by environmental chemicals, including
alterations in production, release, transport, metabolism, action, and/or elimination of endogenous
hormones
D.
Current focus is on interactions of environmental chemicals with hormone receptors
-- chemical may act as a receptor agonist – hormone mimic
-- chemical may act as a receptor antagonist – hormone blocker
E.
Numerous environmental toxicants have been found to interact with the estrogen receptor, most act as
estrogen mimics – these include numerous organochlorine insecticides (DDT and metabolites DDD, DDE,
chlordecone, toxaphene, dieldrin, endosulfan, etc.), PCBs, TCDDs, some herbicides, fungicides, and
nematocides
F.
Relatively few compounds have been found to have anti-estrogenic effect or to directly interact with the
testosterone receptor
G.
Anti-estrogenic and anti-androgenic effects of estrogen mimics are due to feedback inhibition of
gonadotropin secretion by the anterior pituitary
-- estrogen mimic reduces secretion of gonadotropins which reduces the secretion of estradiol and other
estrogens or testosterone and other androgens
-- anti-estrogenic action can lead to defeminization through suppression of estrogen levels and normal
physiological effects of estrogens
-- anti-androgenic action can lead to demasculization through suppression of androgen levels and normal
physiological effects of androgens
H.
Critical periods of developmental exposure to normal levels of sex steroids
-- appropriate levels of sex steroids during critical periods of development determines morphological
development of sex-typical reproductive structures, development of gametogenic structures, sex steroid
secretory structures, and differentiation of the nervous system into “female brain” or “male brain”
I.
Development of in vitro assays for screening potential endocrine altering chemicals – an example
-- E-screen test utilizes cell line derived from human breast tissue; cell proliferation is dependent upon
estrogen or estrogen-like stimulation; has been proposed to screen for estrogen mimic chemicals or
mixtures
J.
Human health implications
-- at this time there is no conclusive evidence of endocrine alteration in the general population of humans
by environmental endocrine disruptors; there are some suggestive data, but major epidemiological
studies are inconclusive
-- existing epidemiological studies have been criticized for multiple methodological flaws and results have
often been contradictory
-- potential areas of concern
males – declining sperm counts and increasing male infertility
females – rising rates of breast cancer, rising rates of endometriosis, declining age of girls at
menarche