an introduction to the endocrine system through a study of endocrine disruptors
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An Introduction to the Endocrine System through a Study of Endocrine Disruptors. Nervous and Endocrine Systems. Act together to coordinate functions of all body systems Nervous system Nerve impulses/ Neurotransmitters Faster responses, briefer effects, acts on specific target - PowerPoint PPT PresentationTRANSCRIPT
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An Introduction to the Endocrine System through a Study of
Endocrine Disruptors
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Act together to coordinate functions of all body systems
Nervous system◦ Nerve impulses/ Neurotransmitters◦ Faster responses, briefer effects, acts on specific
target Endocrine system
◦ Hormone – mediator molecule released in one part of the body but regulates activity of cells in other parts
◦ Slower responses, effects last longer, broader influence
Nervous and Endocrine Systems
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2 kinds of glands◦ Exocrine – ducted◦ Endocrine – ductless
Secrete products into interstitial fluid, diffuse into blood Endocrine glands include
◦ Pituitary, thyroid, parathyroid, adrenal and pineal glands
◦ Hypothalamus, thymus, pancreas, ovaries, testes, kidneys, stomach, liver, small intestine, skin, heart, adipose tissue, and placenta not exclusively endocrine glands
Endocrine Glands
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Hormones affect only specific target tissues with specific receptors
Receptors constantly synthesized and broken down
Hormone Activity
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◦Lipid-soluble – use transport proteins Steroid Thyroid Nitric oxide (NO)
◦Water-soluble – circulate in “free” form Amine Peptide/ protein Eicosanoid
Chemical classes of hormones
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Response depends on both hormone and target cell
Lipid-soluble hormones bind to receptors inside target cells
Water-soluble hormones bind to receptors on the plasma membrane◦ Activates second messenger system◦ Amplification of original small signal
Responsiveness of target cell depends on◦ Hormone’s concentration◦ Abundance of target cell receptors◦ Influence exerted by other hormones
Permissive, synergistic and antagonistic effects
Mechanisms of Hormone Action
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Regulated by◦ Signals from nervous
system◦ Chemical changes in
the blood◦ Other hormones
Most hormonal regulation by negative feedback◦ Few examples of
positive feedback
Control of Hormone Secretion
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Natural or synthetic compounds that alter the hormonal and homeostatic systems that enable an organism to communicate with and respond to its environment.
Exposure to EDCs can be environmental or developmental.
What are endocrine-disrupting substances (EDCs)?
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Age at exposure Latency from
exposure Mixture of
chemicals
Dose/response Long-term latent
effects
Key issues to understanding the consequences of exposure
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All endocrine systems are susceptible
The endocrine disruptors have shared properties.
There are similarities in the receptors and enzymes involved in the synthesis, release, and degradation of hormones.
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Effects may be inherited
Can be transmitted to future generations through epigenetic modifications or continued exposure of offspring to the compounds.
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What does the evidence show?
There is strong evidence of adverse reproductive outcomes:
•Infertility•Cancers•Malformations
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What does the evidence show?
There is growing evidence for effects on other endocrine systems:
•Thyroid•Neuroendocrine•Obesity and metabolism•Insulin and glucose homeostasis
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Where are EDCs?EnvironmentFoodConsumer products
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What do EDCs do?EDCs interfere with hormone biosynthesis, metabolism, or action.
Such interference results in a deviation from normal homeostatic control or reproduction.
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The Scientific Statement of the Endocrine Society
(2009)Presents evidence that EDCs have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology
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EDCs represent a public health concern
Based on •results from animal models•human clinical observations•epidemiological studies
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Mechanisms of EDC action are diverse
Some pathways include:
•Estrogenic•Antiandrogenic•Thyroid•Neurotransmitter receptors
and systems
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EDCs represent a broad class of
molecules•Organochlorinated pesticides
and industrial chemicals•Plastics and plasticizers•Fuels•Others present in the environment or inwidespread use
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Endocrine Disruptors industrial solvents/lubricants: Polychlorinated biphenols (PCBs) Polybrominated biphenols (PBBs) DioxinsPlastics: bisphenol A (BPA)Plasticizers: phthalatesPesticides: methoxychlor, chloropyrifos, DDTFungicides: vinclozolinPharmaceuticals: DES
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Endocrine DisruptorsNatural chemicals in food and feed:Phytoestrogens – genistein and coumestrol
- widely consumed and in infant formula (soy-
based)
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PCBs and Dioxin
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Dioxin and PCBs
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Bisphenol A (BPA)
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National Toxicology Program review (2009)
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Chloropyrifos and methoxychlor
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Phytoestrogens
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DES – synthetic estrogen (teratogen) human use and animal feed additive (increase size)
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Steroids
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What do you notice about the structure of EDCs as compared to steroids?
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What do you notice about the structure of EDCs as compared to steroids?
It is the phenolic structure:
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They are thought to mimic natural steroid hormone and enable EDCs to interact with steroid hormone receptors as analogs or antagonists.
Several classes of EDCs act as antiandrogens and as thyroid hormone receptor agonists or antagonists.
Androgenic EDCs have been identified.
Mode of action?
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EDCs enter the food chain and can bioaccumulate (due to low water solubility and high lipid solubility.
Contaminated drinking water Breathing contaminated air and contacting
contaminated soil Occupational exposure to pesticides and
industrial chemicals
How can we be exposed?
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Challenges to discerning EDC involvement in a particular disorder◦ Each person’s unique exposure to a variety of
known and unknown EDCs◦ Individual differences in metabolism, body
composition, and genetic traits◦ Human disorders usually result from long term
chronic exposure to low levels of mixtures of EDCs◦ Latency between exposure to EDCs and
occurrence of clinical disorder makes causal connection difficult (may be years or decades)
Clinical Challenges to Diagnosis
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EDCs act by more than one mechanism. An EDC may have mixed steroidal
properties: it may be both estrogenic and antiandrogenic.
An EDC may be metabolized into different subproducts with different properties.
Balance between estrogenic and androgenic properties of EDCs may be significant because reproduction in both sexes involves an interplay of androgens and estrogens.
Mechanisms of Endocrine Disruption
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Many organs are targeted by sex steroids and vulnerable to endocrine disruption.◦ Hypothalamic-pituitary-gonadal system◦ Breast◦ Uterus◦ Cervix◦ Vagina◦ Brain◦ Bone, muscle and skinIn addition, reproductive dysfunction can result
from thyroid disruption
Mechanisms of Endocrine Disruption
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Interference with development and function of the female reproductive tract can predispose women to:
Infertility Ectopic gestation Poor pregnancy outcomes Endometriosis Uterine fibroids Altered anatomy and functionality
Clinical Impacts on Female reproduction
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Hypothesized that the significant increase of breast cancer in the industrialized world in the last 50 years may be due to exposure to hormonally active chemicals.
Similar increase in incidence of testicular cancer, male genital tract abnormalities, and decrease in sperm quantity/quality suggest a link to the introduction of these chemicals into the environment.
EDCs linked to cancer?
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Interface between Nervous and Endocrine systems
Controls diverse functions, such as reproduction, stress, growth, lactation, metabolism and energy balance, osmoregulation, other homeostatic regulators
Mediates ability of organism to respond to environment through rapid (neuronal) and more sustained (endocrine) responses
Neuroendocrine System
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Neuroendocrine cells in brain have both neuronal and endocrine properties
As a result, EDCs can have neurobiological and neurotoxic effects along with endocrine effects
Several levels of organization: the brain (hypothalamus), the pituitary gland, and a target organ
The reproductive Hypothalamus-Pituitary-Gonad (HPG) connection is the best studied in the area of endocrine disruption
Neuroendocrine System
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Gonadotropin-releasing hormone (GnRH) (also called Luteinizing hormone) is produced in the hypothalamus and drives reproduction throughout the life cycle. It is the primary stimulus to the pituitary and the gonads.
Endocrine disruption of reproductive neuroendocrine systems
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GnRH release stimulates gonadotropin release from anterior pituitary
Gonadotropin release activates steroidogenesis and gametogenesis in the ovary and testes
Steroid hormones produced by the gonad act on target tissues that release estrogen, progestin and/or androgen receptors (AR)
Many EDCs interfere with steroid hormone actions
What GnRH does in the Body
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But GnRH neurons do not have steroid receptors This means that other cells in the brain that do have
steroid receptors and that regulate GnRH cells through afferent neural inputs are targets for EDCs
Neuronal cells with steroid receptors include those that make neurotransmitters (such as serotonin and dopamine) and can regulate GnRH neurons
EDCs have been shown to cause neurotoxicity to these neurons
This is evidence of convergence of effects of EDCs on the link between neural and endocrine systems
Sex steroids control GnRH neurons