Endocrine Disrupting CompoundsAny exogenous agent that causes adverse health effects in an intact organism, or its progeny, consequent to changes in endocrine function.
Specifically.Any exogenous chemical that interferes with the production, release, transport, binding, action, or elimination of natural hormones responsible for the maintenance of homeostasis and regulation of developmental processes.
Chemicals: Wide Variety - PesticidesHerbicidesFungicidesPlasticizersSurfactantsOrganometalsHalogenated PAHsPhytoestrogensAt Least 4 Modes of ActionServing as steroid receptor ligands.Modifying steroid hormone-metabolizing enzymes.Perturbing hypothalamic pituitary release of trophic hormones.Miscellaneous or unknown.Interactions with the functions of estrogens, androgens, and thyroid hormones have been the most highly studied.
Prototypical Exoestrogens: Note the Diverse Chemical Structures
Nuclear Receptor Super FamilySteroid ReceptorsAndrogen R.Progesterone R.Glucocorticoid R.Mineralocorticoid R.
Thyroid ReceptorsThyroid Hormone R.Retinoic Acid R.RXRVitamin D R.
Mechanisms of Endocrine Disruption Binding and activating the estrogen receptor (thereby acting as an estrogen)Binding but not activating the estrogen receptor (thereby acting as an anti-estrogen
Mechanisms (Continued)Binding other receptors (e.g., androgen receptors in males)activating the receptor thereby acting like an androgennot activating the receptor thereby acting like an anti-androgenModifying the metabolism of natural hormones
Mechanisms (Continued)Modifying the number of hormone receptors in a cell (reduce or increase the number)Modify the production of natural hormonesInteractions with steroid binding proteins
Individual MechanismsBinding and activating the estrogen receptor (thereby acting as an estrogen) Exogenous estrogens can bind to the estrogen receptor but the affinity with which these exogenous estrogens bind to the receptor is usually only a fraction of the binding affinity of 17 B-estradiol.
Xenobiotics may affect transcription and signal transduction.Can act through both i) receptor-mediated and non-receptor-mediated mechanisms.e.g., genistein is a weak est receptor agonist, but can also modulate the activity of tyr kinases and DNA topoisomerases.
Estrogen Receptor (Continued)Compounds may act as either estrogens or anti-estrogens depending on the cellular environment.Certain hydroxylated PCBs are able to bind the estrogen receptor and activiate gene transcription at high concentrations. However, these PCB metabolites are weak agonists at appropriate concentrations, and they may have the potential to interfere by competing with endogenous estrogens for binding sites.
Estrogen Receptor (contd)We have additive effects: several chemicals binding and activating the estrogen receptor their combined effects will be additive.e.g., butylbenzyl phthalate and di-n-butyl phthalate can add their effects to any natural estrogen present.Synergism, however, has not yet been demonstrated.
Estrogen Receptor (Continued)Hydroxylated PCBs: altered temperature dependent sex determination in turtles.It has been suggested that PCBs and other combinations of weak environmental estrogens such as the insecticides dieldrin and toxaphene, have synergistic activities that are mediated by the estrogen receptor.160 to 1600 x more potent than either of the individual chemicals aloneother studies just suggest additive interactions / Still a controversy on this subject.
Estrogen Receptor (contd)PCBs: learning and locomotor deficits in juvenile rodents and monkeys.e.g., Arochlor 1254 hypothyroidism and testes weight and sperm production in rats Stunted growthCognitive deficitsDelayed eye openingHyperactivityAuditory deficits
Individual MechanismsBinding but not activating the estrogen receptor (thereby acting as an anti-estrogen = ______________?E.g., Est receptor: tamoxifen is an anti-breast cancer drug, but is an agonist in preservation of bone mineral density.E.g., Androgen receptor antagonists (some insecticides) cause demasculinizing traits.
Individual MechanismsE.g., Glucocorticoid receptor: antagonists adversely affect growth and development.Mixed agonists/antagonists. Binding and activation or lack of activation depends on the:Affinity for the receptorReceptor number[xenoagonist][endogenous hormone]
The effects are predicted to be summed.
Individual MechanismsBinding other receptors (e.g., androgen receptors in males) DDT: has been reported to induce reproductive abnormalities, particularly in wildlife species such as the American alligator, birds, and laboratory rodents. The breakdown product of DDT, DDE, is able to act as an anti-androgen by blocking the testosterone receptor and producing effects that are phenotypically similar to those caused by estrogens.
Other Receptors (Continued)Retinoid X receptor forms heterodimers with either the thyroid hormone receptor or with the peroxisome proliferator activated receptor and these heterodimers can bind to the estrogen response elements on DNA.While these heterodimers are capable of binding to the estrogen response elements on DNA they are not capable of increasing gene expression.
Other Receptors (Continued)Instead, binding of the heterodimers to the estrogen response elements results in decreased transcription due to competition with the estrogen receptor for the estrogen response elements.
The heterodimers may act as a specific inhibitor of estrogen receptor mediated gene transcription and ER-mediated signal transduction.
Other Receptors (contd)All of this suggests that there is receptor cross-reactivity of the appropriate response elements.Exogenous compounds have great broad receptor specificity across the nuclear receptor superfamily.
Individual MechanismsModifying the metabolism of natural hormones Endocrine disrupters may affect homeostasis through alterations in steroid synthesis or metabolism. Therefore, any substance that modifies either the enzymes involved in steroid biosynthesis and/or metabolism of steroids could be classified as an endocrine disrupter.A number of compounds acting through the Ah receptor have demonstrated anti-estrogenic activities. TCDD is one of these compounds.
Individual Mechanisms:Modifying the metabolism of natural hormones Some chemicals, e.g., lindane and atrazine, can affect the metabolic pathway of estradiol producing more estrogenic metabolites.
Individual Mechanisms:Modifying the metabolism of natural hormones Effects of EDCs on Hormone Synthesis and Metabolism:A cpd may adversely affect the levels of critical endogenous hormones by inducing or inhibiting biosynthetic or metabolic enzyme activity.e.g., phytoestrogens can interact with 17--DH, which regulates levels of 17--estradiol or estrone.
Individual Mechanisms:Modifying the metabolism of natural hormones phytoestrogens can modulate overall estrogen levels in addition to acting as a ligand for the estrogen receptor.E.g., perchlorate competitively inhibits thyroid I uptake disrupts thyroid hormone synthesis.
Timing of ExposureSensitivity of an individual to gonadal steroids depends on where (s)he is temporally in life.Thus, a chemical may have little-to-no impact on a young/older adult, but may have profound development-disrupting effects if exposure occurs in utero or during puberty.
Timing of Exposure (contd)E.g., PCBs and dioxin affect development more during gestational than during lactational exposure.Generally, sensitivity to EDCs is greater during fetal and perinatal exposure than during adulthood.However, sometimes, fetal serum-binding proteins may protect the fetus from harmful EDCs (lower sensitivity).e.g., -fetoprotein binding 17--estradiol protects the fetal male rat from maternal estrogens.
Timing of Exposure (contd)IMPORTANT: Estrogen levels are NOT feedback regulated in a typical homeostatic mechanism (- feedback).RATHER, there is a feed-forward mechanism (+ feedback) [estradiol] throughout most of pregnancy in rodents and humans.
Timing of Exposure (contd)Thus, an exogenous dose of any estrogen agonist will be additive to the endogenous level, be cause there is NO (-) feedback to endogenous hormone production in a compensatory way.
Timing of Exposure (contd)Also, in rodents and humans, the specific estradiol binding proteins, -fetoprotein, test/estradiol binding protein also steadily during pregnancy to protect the fetus from the high levels of circulating estrogens;C.f., rodent littermates influenced by neighbors gender.
Timing of Exposure (contd)Xenoestrogens that fail to bind to these proteins have increased bioavailability and therefore, increased receptor-binding ability. But, E.g., DES has ~100-fold lower affinity for est receptor than does E2.E.g., Fungal estrogen, zearalenone, is ~0.66% as potent as E2 for the uterotrophic responses in humans; 5% in rats.
Individual Mechanisms:Modifying the metabolism of natural hormones Other chemicals activate enzymes, which accelerate the metabolism of hormones, thereby disrupting their natural state.E.g., the testes contain specific enzymes to metabolize estrogens to a metabolite, which can no longer bind the estrogen receptor.
Individual Mechanisms:Modifying the metabolism of natural hormones However, these enzymes are compromised by a xenoestrogen, metabolism , exposure of the testes to estrogen problems during fetal development.
Metabolism (Continued)A number of genes have been shown to be in
Click here to load reader