1. Endocrine Disruption
August 1996: Statutory Authorities In August 1996, Congress passed both the Food Quality Protection Act (FQPA) [PDF, 50pp., 253KB, About PDF] and amendments to the Safe Drinking Water Act (SDWA), both containing provisions calling for the screening and testing of chemicals and pesticides for possible endocrine disrupting effects. These laws required EPA to develop a screening program that uses appropriate validated test systems and other scientifically relevant information to determine if the effect that certain substances have in humans is similar to the effect produced by a naturally occurring hormone.
The Food Quality Protection Act amends the Federal Food, Drug, and Cosmetic Act. Read more about the Federal Food, Drug, and Cosmetic Act Amendments.
1996: EDSTAC Convenes The Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), a federal advisory committee, was formed in 1996 to make recommendations on how to develop the screening and testing program called for by Congress. Representatives from industry, government, environmental and public health groups, worker safety groups, and academia comprised EDSTAC. The members of EDSTAC were tasked with developing consensus-based recommendations for a screening program that would provide EPA with the information needed to make regulatory decisions about chemicals that disrupt the endocrine system.
EDSTAC thoroughly reviewed and discussed the scientific information available about endocrine disruptors and sought the opinion of other experts and members of the public during its 2-years of deliberations. EDSTAC presented its final report to EPA in September Read more about the creation of EDSTAC and it's participants.
Click on a link below to access an overview of the endocrine system, information on endocrine disruptors, and general information about the Endocrine Disruptor Screening Program (EDSP).
 Endocrine System Overview
Endocrine Disruptors
Endocrine Disruptor Screening Program
Endocrine Disruptor Screening Program History
In August 1996, Congress passed both the Food Quality Protection Act (FQPA) and amendments to the Safe Drinking Water Act (SDWA), both containing provisions calling for the screening and testing of chemicals and pesticides for possible endocrine disrupting effects.
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2. EDCs in the Environment
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3. Endocrine Disruptor Screening Program (EDSP)
Food Quality Protection Act and Safe Drinking Water Act Amendments (1996)
Required EPA to screen pesticide chemicals for estrogenic potential
Gave EPA authority to screen certain other chemicals and to include other endocrine effects
The Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC)
Established as a federal advisory committee in 1996
Advised EPA on implementation of Congress's directive
Based on EDSTAC recommendations, EPA expanded program
Added male hormones (androgens) and the thyroid system (thyroxines)
Included effects on fish and wildlife
Congress passed the Food Quality Protection Act and the Safe Drinking Water Act (SDWA) Amendments in 1996 requiring that EPA screen pesticide chemicals for their potential to produce effects similar to those produced by the female hormones (estrogen) in humans and giving EPA the authority to screen certain other chemicals and to include other endocrine effects. Based on recommendations from an Advisory Committee, EPA has expanded the EDSP to include male hormones (androgens) and the thyroid system, and to include effects on fish and wildlife.
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4. Hormones Characteristics of a hormone What do hormones regulate?
Endogenous chemical
Elicits response in cell
What do hormones regulate?
Reproduction
Blood pressure
Glucose metabolism
Bone growth
Calcium homeostasis
Production of other hormones
More…
A hormone originally denoted a chemical made by a gland for export to another part of the body. Now a hormone is more broadly defined as any chemical, irrespective of whether it is produced by a special gland or not, for export or domestic use, that "controls and regulates the activity of certain cells or organs."
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5. Major Endocrine Organs
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6. Pituitary as the “Master Gland”
Blood
vessel
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7. Feedback Regulation of Hormones
Hypothalamus
Feedback regulation can be positive or negative depending on hormones involved
Pituitary
Peripheral
Endocrine Organ
Hormone
Target Cell
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8. Mechanisms of Endocrine Disruption
Hormone-receptor mediated
Hormone mimics (agonists)
Hormone receptor blockers (antagonists)
Altered expression of hormone or hormone receptor
Altered hormone receptor function & cell signaling
Hormone metabolism modification
Modification of hormone binding to blood transport proteins
Epigenetics
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9. Hormones Act through Receptors
Membrane receptors
Nuclear Receptors
Typical ligands are peptide hormones
Typical ligands are steroid hormones
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10. Receptor Agonists & Antagonists
membranereceptors.com
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11. Steroid Hormones Steroids hormones include: Estrogen Testosterone
Thyroxines
Progesterone
Cortisol
EDSTAC
Steroids are lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system
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12. Estrogens
17-estradiol is the most potent endogenous mammalian estrogen
Estrogenicity is often described by the affinity to bind the estrogen receptor (ER) relative to the binding affinity of 17-estradiol
However, receptor binding provides no information about receptor activation
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13. Nuclear Estrogen Receptors (ERs)
Two main types of nuclear estrogen receptors: ERα and Erβ
Tissue-specific distribution
Ligand-specific affinity
Upon binding hormone/ligand, ERs form a dimer that then can bind to gene regulatory regions of DNA
Alters gene and protein expression
RV Weatherman, Nature Chemical Biology 2, (2006)
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14. Potent Estrogen Agonists
Diethylstilbestrol (DES)
Potent synthetic estrogen administered to pregnant women between ~
Binds ERα with fold greater affinity than 17-estradiol
Women’s urine (sewage) with
17-estradiol
Synthetic estrogens from birth control pills
17B-estradiol is excreted as sulfated conjugate. Microbes in water desufate conjugate and release 17B-estradiol
May be important as more populations need to rely on recycled water.
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15. Estrogen Agonists - Pesticides
Chlordecone (Kepone)
Pesticide
1/200-1/400th affinity of 17β-estradiol for ERα
Methoxychlor
1/400th affinity of 17-estradiol for ERα
o,p’-DDT
Isomer of DDT pesticide
1/10,000th affinity of 17-estradiol for ERα
o,p-DDT binds ER 1/10,00th E2
Chlordecone binds ER 1/200th - 1/400th E2
DES binds ER fold higher affinity than ER
Bisphenol-A 1/300th
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16. Estrogen Agonists - Other Synthetic
Bisphenol A
Polycarbonate plastic manufacture
1/300th affinity of 17-estradiol for ERα
Polychlorinated biphenyls (PCBs)
Used in transformers & machinery
Some PCBs show affinity for ERα that ranges from 1/40th to 1/10,000th that of 17-estradiol
Some congeners are estrogen antagonists
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17. Androgen/Testosterone Antagonists
p,p’-DDE
Major mammalian metabolite of DDT
Relatively potent androgen receptor antagonist
Estrogen agonists
Often have weak antiandrogen activity
Chlordecone, o,p -DDT, DES
p,p’-DDE
Major mammalian metabolite of DDT
Relatively potent androgen receptor antagonist
Antiandrogenic effects seen in rats
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18. Enzyme Induction that Alters Xenobiotic Excretion
Some toxicants & drugs increase gene expression of enzymes (induction) that metabolize steroid hormones
Increases hormone excretion
Decreases circulating hormone levels
Examples:
Phase I enzyme inducers: chlordane, DDT
Pharmaceuticals: phenobarbital, some antibiotics
Can decrease efficacy of oral contraception
Can decrease efficacy of birth control pills
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19. Toxicant Inhibition of Enzymes that Alters Hormone Excretion
Sulfotransferases are important in estrogen Phase II metabolism for estrogen excretion
PCB phenol metabolites are potent inhibitors of sulfotransferases
Inhibition can increase circulating estrogen levels
End result is estrogenic effect
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20. Disruption of Hormone Distribution
PCB and PBDE phenol metabolites bind to thyroid hormone binding protein in blood
Decreases binding of thyroid hormone to blood protein
Disrupts circulating thyroid hormone levels
But… the more potent effect seems to be on sulfotransferases
Hydroxylated metabolites
Bind to transthyretin
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21. Phthalates Diethylhexyl phthalate (DEHP) Dibutyl phthalate (DBP)
Plasticizer in polyvinylcholoride (PVC)
Makes up as much as 40% weight of some PVC products
Dibutyl phthalate (DBP)
Personal care products
Pharmaceutical capsules
Benzylbutyl phthalate (BzBP)
Phthalate metabolites were found in nearly every urine sample of CDC study (NHANES)
Dibutyl phthalates (both di-n-butyl and di-isobutyl phthalates, referred to as DBP) are industrial solvents or additives used in many personal care products such as nail polish and cosmetics, and also in some printing inks, pharmaceutical coatings, and insecticides.
In animals, phthalates produced anti-androgenic effects by reducing testosterone production and, at very high levels, reducing estrogen production, effects that may be mediated by inhibiting testicular and ovarian steroidogenesis. High doses of di- 2-ethylhexyl phthalate (DEHP), dibutyl phthalate (DBP), and benzylbutyl phthalate (BzBP) during the fetal period produced lowered testosterone levels, testicular atrophy, and Sertoli cell abnormalities in the male animals and, at higher doses, ovarian abnormalities in the female animals (Jarfelt et al., 2005; Lovekamp-Swan and Davis, 2003; McKee et al., 2004; NTP-CERHR, 2000a, 2000b, 2000c, 2006). Phthalate urinary metabolite levels in men evaluated at an infertility clinic were associated with several measures of sperm function and morphology (Duty et al., 2004; Hauser et al., 2007), but similar findings were not present in young Swedish men with comparable or higher median levels of urinary metabolites (Jonsson et al., 2005). --CDC Third Report
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22. Some Phthalates Inhibit Hormone Synthesis
Inhibit testosterone synthesis in testis Inhibit estrogen synthesis in ovary Phthalate exposure in utero produces reproductive toxicity in male rat and is associated with reproductive changes in baby boys
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23. Epigenetics & Endocrine Disruption
The first transgenerational epigenetic effects were observed with endocrine disruptors Current toxicologic research continues to focus on endocrine disruptors as epigenetic modifiers
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24. Transgenerational Neuroendocrine Disruption of Reproduction
Figure 3 Context-dependent epigenetic transmission
Walker, D. M. & Gore, A. C. (2011) Transgenerational neuroendocrine disruption of reproduction
Nat. Rev. Endocrinol. doi: /nrendo
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25. Consequences of Hormone Disruption
Adult reproductive disorders
Infertility
Loss of libido
Developmental disorders
Abnormal reproductive tract development
Compromised reproductive function
Cognitive & behavioral disorders
Metabolic diseases (e.g., diabetes)
Abnormal growth of bone and muscle
Premature onset of puberty
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26. Important Concepts
Understand each of major mechanisms of endocrine disruption discussed in lecture
Consequences of hormone disruption
How these prominent examples act as endocrine disruptors:
DES
DDT and it metabolite p,p’-DDE
Phthalates
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