Endocrine Disruption http://www.epa.gov/scipoly/oscpendo/pubs/edspoverview/index.htm http://www.epa.gov/scipoly/oscpendo/index.htm 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 1998. 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. ENVIRON 310 2017

EDCs in the Environment www.public.iastate.edu ENVIRON 310 2017

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. ENVIRON 310 2017

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." ENVIRON 310 2017

Major Endocrine Organs http://biology.clc.uc.edu/courses/bio105/endocrin.htm ENVIRON 310 2017

Pituitary as the “Master Gland” Blood vessel http://www.anselm.edu/homepage/jpitocch/genbio/endocrinenot.html ENVIRON 310 2017

Feedback Regulation of Hormones Hypothalamus Feedback regulation can be positive or negative depending on hormones involved Pituitary Peripheral Endocrine Organ Hormone Target Cell ENVIRON 310 2017

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 ENVIRON 310 2017

Hormones Act through Receptors Membrane receptors Nuclear Receptors Typical ligands are peptide hormones Typical ligands are steroid hormones http://www.rci.rutgers.edu/~uzwiak/GBSummer12/GB102Summer12Lect/Endocrine_System.html ENVIRON 310 2017

Receptor Agonists & Antagonists membranereceptors.com ENVIRON 310 2017

Steroid Hormones Steroids hormones include: Estrogen Testosterone Thyroxines Progesterone Cortisol EDSTAC Steroids are lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system ENVIRON 310 2017

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 ENVIRON 310 2017

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, 175 - 176 (2006) ENVIRON 310 2017

Potent Estrogen Agonists Diethylstilbestrol (DES) Potent synthetic estrogen administered to pregnant women between ~1950-70 Binds ERα with 20-40 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. ENVIRON 310 2017

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 20-40-fold higher affinity than ER Bisphenol-A 1/300th ENVIRON 310 2017

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 ENVIRON 310 2017

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 ENVIRON 310 2017

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 ENVIRON 310 2017

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 ENVIRON 310 2017

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 ENVIRON 310 2017

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 ENVIRON 310 2017

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 ENVIRON 310 2017

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 ENVIRON 310 2017

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:10.1038/nrendo.2010.215 ENVIRON 310 2017

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 ENVIRON 310 2017

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 ENVIRON 310 2017