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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