An Introduction to the Endocrine System through a Study of Endocrine Disruptors 1
An Introduction to the Endocrine System through a Study of Endocrine Disruptors
An Introduction to the Endocrine System through a Study of Endocrine Disruptors1Act together to coordinate functions of all body systemsNervous systemNerve impulses/ NeurotransmittersFaster responses, briefer effects, acts on specific targetEndocrine systemHormone mediator molecule released in one part of the body but regulates activity of cells in other partsSlower responses, effects last longer, broader influence
Nervous and Endocrine Systems22 kinds of glandsExocrine ductedEndocrine ductless Secrete products into interstitial fluid, diffuse into bloodEndocrine glands includePituitary, thyroid, parathyroid, adrenal and pineal glandsHypothalamus, thymus, pancreas, ovaries, testes, kidneys, stomach, liver, small intestine, skin, heart, adipose tissue, and placenta not exclusively endocrine glandsEndocrine Glands3
4Hormones affect only specific target tissues with specific receptorsReceptors constantly synthesized and broken downHormone Activity5Lipid-soluble use transport proteinsSteroidThyroidNitric oxide (NO)Water-soluble circulate in free formAminePeptide/ proteinEicosanoid Chemical classes of hormones6Response depends on both hormone and target cellLipid-soluble hormones bind to receptors inside target cellsWater-soluble hormones bind to receptors on the plasma membraneActivates second messenger systemAmplification of original small signalResponsiveness of target cell depends onHormones concentrationAbundance of target cell receptorsInfluence exerted by other hormonesPermissive, synergistic and antagonistic effectsMechanisms of Hormone Action7Regulated bySignals from nervous systemChemical changes in the bloodOther hormonesMost hormonal regulation by negative feedbackFew examples of positive feedbackControl of Hormone Secretion
8Natural 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)?9Age at exposureLatency from exposureMixture of chemicalsDose/responseLong-term latent effectsKey issues to understanding the consequences of exposure10All endocrine systems are susceptibleThe endocrine disruptors have shared properties.
There are similarities in the receptors and enzymes involved in the synthesis, release, and degradation of hormones.11Effects may be inheritedCan be transmitted to future generations through epigenetic modifications or continued exposure of offspring to the compounds.
12What does the evidence show?There is strong evidence of adverse reproductive outcomes:
13What does the evidence show?There is growing evidence for effects on other endocrine systems:
ThyroidNeuroendocrineObesity and metabolismInsulin and glucose homeostasis
14Where are EDCs?EnvironmentFoodConsumer products15What do EDCs do?EDCs interfere with hormone biosynthesis, metabolism, or action.
Such interference results in a deviation from normal homeostatic control or reproduction.
16The 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 endocrinology17EDCs represent a public health concernBased on results from animal modelshuman clinical observationsepidemiological studies18Mechanisms of EDC action are diverseSome pathways include:
EstrogenicAntiandrogenicThyroidNeurotransmitter receptors and systems19EDCs represent a broad class of moleculesOrganochlorinated pesticides and industrial chemicalsPlastics and plasticizersFuelsOthers present in the environment or inwidespread use
20Endocrine Disruptors industrial solvents/lubricants: Polychlorinated biphenols (PCBs) Polybrominated biphenols (PBBs) DioxinsPlastics: bisphenol A (BPA)Plasticizers: phthalatesPesticides: methoxychlor, chloropyrifos, DDTFungicides: vinclozolinPharmaceuticals: DES
21Endocrine DisruptorsNatural chemicals in food and feed:Phytoestrogens genistein and coumestrol- widely consumed and in infant formula (soy- based)
PCBs and Dioxin23
Dioxin and PCBs24
Bisphenol A (BPA)25
National Toxicology Program review (2009)26
27Chloropyrifos and methoxychlor
29DES synthetic estrogen (teratogen) human use and animal feed additive (increase size)
Steroids30What do you notice about the structure of EDCs as compared to steroids?
31What do you notice about the structure of EDCs as compared to steroids?It is the phenolic structure:
32They 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?33EDCs enter the food chain and can bioaccumulate (due to low water solubility and high lipid solubility.Contaminated drinking waterBreathing contaminated air and contacting contaminated soilOccupational exposure to pesticides and industrial chemicalsHow can we be exposed?34Challenges to discerning EDC involvement in a particular disorderEach persons unique exposure to a variety of known and unknown EDCsIndividual differences in metabolism, body composition, and genetic traitsHuman disorders usually result from long term chronic exposure to low levels of mixtures of EDCsLatency between exposure to EDCs and occurrence of clinical disorder makes causal connection difficult (may be years or decades)35Clinical Challenges to DiagnosisEDCs 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.36Mechanisms of Endocrine DisruptionMany organs are targeted by sex steroids and vulnerable to endocrine disruption.Hypothalamic-pituitary-gonadal systemBreastUterusCervixVaginaBrainBone, muscle and skinIn addition, reproductive dysfunction can result from thyroid disruption37Mechanisms of Endocrine DisruptionInterference with development and function of the female reproductive tract can predispose women to:InfertilityEctopic gestationPoor pregnancy outcomesEndometriosisUterine fibroidsAltered anatomy and functionality
38Clinical Impacts on Female reproductionHypothesized 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. 39EDCs linked to cancer?Interface between Nervous and Endocrine systemsControls diverse functions, such as reproduction, stress, growth, lactation, metabolism and energy balance, osmoregulation, other homeostatic regulatorsMediates ability of organism to respond to environment through rapid (neuronal) and more sustained (endocrine) responsesNeuroendocrine System40Neuroendocrine cells in brain have both neuronal and endocrine propertiesAs a result, EDCs can have neurobiological and neurotoxic effects along with endocrine effectsSeveral levels of organization: the brain (hypothalamus), the pituitary gland, and a target organThe reproductive Hypothalamus-Pituitary-Gonad (HPG) connection is the best studied in the area of endocrine disruption41Neuroendocrine SystemGonadotropin-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.42Endocrine disruption of reproductive neuroendocrine systemsGnRH release stimulates gonadotropin release from anterior pituitaryGonadotropin release activates steroidogenesis and gametogenesis in the ovary and testesSteroid hormones produced by the gonad act on target tissues that release estrogen, progestin and/or androgen receptors (AR)Many EDCs interfere with steroid hormone actions43What GnRH does in the BodyBut GnRH neurons do not have steroid receptorsThis means that other cells in the brain that do have steroid receptors and that regulate GnRH cells through afferent neural inputs are targets for EDCsNeuronal cells with steroid receptors include those that make neurotransmitters (such as serotonin and dopamine) and can regulate GnRH neuronsEDCs 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 systems44Sex steroids control GnRH neurons