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Don’t Drink the Water Don’t Breathe the Air

Don’t Drink the Water Don’t Breathe the Air. Environmental Estrogens, Endocrine Disruptors, and Human Reproduction. Kirtly Parker Jones MD. Learning Objectives Each Participant should: 1. Understand the potential mechanisms by which endocrine disruptors may effect an organism

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Don’t Drink the Water Don’t Breathe the Air

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  1. Don’t Drink the WaterDon’t Breathe the Air Environmental Estrogens, Endocrine Disruptors, and Human Reproduction Kirtly Parker Jones MD

  2. Learning Objectives Each Participant should: 1. Understand the potential mechanisms by which endocrine disruptors may effect an organism 2. Identify chemicals which are suggested to be potential endocrine disruptors 3. Evaluate the evidence suggesting that environmental estrogens or endocrine disruptors play a role in human disease

  3. Endocrine Disruptors • For over 50 years, there have been reports concerning chemicals in the environment with hormone-like effects on wildlife • Silent Spring

  4. DefinitionsEndocrine Disruptors • Environmental compounds that interfere with the normal function of endogenous hormones - may stimulate or block the actions of hormones, or can interfere with their metabolism.

  5. Endocrine Disruptors • They have been recognized to include a diverse range of chemicals including pesticides, plasticizers, flame retardants, industrial byproducts, pharmaceuticals, and plant-derived compounds

  6. DefinitionsEpigenetic • DNA modifications that do not involve changes in the sequence of DNA. Epigenetic changes can affect gene expression (phenotype) and can be transmitted from one generation to the next Vallombrosa Consensus Statement

  7. DefinitionDES • Synthetic estrogen given as a feed additive to livestock and prescribed for pregnant women 1947-1971 to prevent miscarriages (experiments started in 1942) – interferes with normal development of the reproductive tract and fertility of sons and daughters Vallombrosa Consensus Statement

  8. DefinitionsBisphenol A • Building block of polycarbonate plastics used in food containers, water bottles, baby bottles, CD cases, eye glass lenses, lining of food cans and as dental sealants. Binds with nuclear and extracellular estrogen receptors Vallombrosa Consensus Statement

  9. DefinitionDioxins • A class of highly persistent chemicals, some of which are highly toxic, that result from industrial combustion/incineration, burning of household trash, chlorine bleaching of pulp/paper and some kinds of chemical manufacturing – also contained in cigarette smoke Vallombrosa Consensus Statement

  10. DefinitionsAlkylphenol Ethoxylates • APEs are high-volume chemicals that have been used for more than 40 years as detergents, emulsifiers,. Some uses include ingredients in spermicides, cosmetics, and detergents and as inert ingredients in pesticides. Some are endocrine disruptors, particularly as contaminants in aquatic environments. Vallombrosa Consensus Statement

  11. DefinitionsPerfluorinated Compounds • PFCs are persistent, bioaccumulative chemicals found in a wide array of products including stain resistant coating for carpets and clothing, non stick cookware (Teflon) and insecticides. Widespread contamination of human tissues has been documented with highest levels in the US Vallombrosa Consensus Statement

  12. DefinitionsPhthalates • Chemicals added to personal care products to enhance penetration and hold scent/color and as plasticizers in rigid plastics to increase flexibility. Found in vinyl flooring, plastic shower curtains, cosmetics and fragrances, shampoos and lotions, toys, pharmaceutical and herbal pill coatings, and in hospital equipment including IV bags and tubing

  13. DefinitionsPolybrominated diphenyl ethers • PBDEs are persistent, bioaccumulative chemicals added to electronics, upholstery foam, textiles and other materials to make them flame resistant. Chemical structure is similar to PCBs and have been rapidly accumulating in wildlife and human tissues Vallombrosa Consensus Statement

  14. DefinitionsPolychlorinated Biphenyls • PCBs are persistent, bioaccumulative compounds banned in the US in the late 1970s, although widespread contamination still exists. PCBs were used in hundreds of commercial and industrial applications including lubricants, plasticizers, insulators, caulking, and paint Vallombrosa Consensus Statement

  15. Endocrine Disruptors • Studies in 1960s and 1970s characterized the estrogenicity of DDT, kepone, and PCBs • In 1990s - new plasticizers (phthlates, bisphenol) and new pesticides • Phytoestrogens and mycoestrogens • Human estrogen contaminants

  16. Endocrine Disruptors and Human Fertility • Declining sperm counts? • Declining male/female birth ratios? • Increasing hypospadias? • Increasing testicular cancer? • Increasing breast cancer? • Increasing premature thelarche? • Decreasing Fertility?

  17. Endocrine Disruptors • Late exposure may effect mature adults • Early exposure may have effect on fetus or embryo with adult consequences • Epigenetic effects may effect DNA for several generations

  18. Endocrine DisruptorsThe Challenge • Identify xenoestrogens among synthetic chemicals and natural estrogens in the environment • Develop a methodology to assess interactions among mixtures of xenoestrogens and naturally occuring estrogens • Discover markers of exposure

  19. Endocrine DisruptorsMechanism of Action • Mimic the effect of endogenous hormones • Antagonize endogenous hormones • Disrupt synthesis and metabolism of endogenous hormones or their receptors • Change structure of DNA which may effect transcription • None of the above

  20. Endocrine Disruptors:The Wake Up Call • In 1949 crop dusters spraying DDT were found to have reduced sperm counts • Workers at a kepone (insecticide) plant had low sperm counts and decreased libido • The demasculinization of alligators exposed to DDE Sonnenschein and Soto, J Steroid Biochem Mol Biol, 1998

  21. Endocrine Disruptors:Amphibian Model • Amphibians may be very sensitive to environmental estrogen disruptors • Exposed to chemical effluents in water environment • Frog hepatocytes competively bind estrogens and estrogenic activity can be assessed in industrial chemicals Lutz, Sci Total Environm.1999

  22. Xenoestrogens • Frog hepatocyte model can rank affinity for chemicals that bind to estrogen receptor • E2>tetrachlorobiphenyl>diethylphthlate> bisphenol A 5 industrial effluents tested: 3 showed>50% estradiol in this assay

  23. Confounding Factors • Natural estrogen production varies with age, gender, and reproductive cycles. Women produce more estrogen than men, estrogen is high in fetal life, low in childhood, high in reproductive ages, low in menopause. Environmental estrogens may have differing effects depending on gender and time of life and genetics

  24. Confounding Factors • Natural hormones are more potent than any known environmental estrogens (phytoestrogens or mycoestrogens) or industrial xenoestrogens • Industrial pollutants (DDT and PCBs) accumulate in fat over time and have extremely long half-lives (10 years or more) and accumulate up food chain

  25. Confounding Factors • Combinations of certain synthetic compounds may have a synergistic effect – two compounds may be more potent than either by itself • Environmental estrogens may antagonize others effects • Environmental estrogens bind differently to different estrogen receptors

  26. Dietary Estrogen Equivalents Organochlorine Compounds – pesticides Safe SH, Environ Health Persp, 2000

  27. Wildlife Studies • PCBs and DDT found extensively in the Great Lakes thought to have decreased fertility in fish and birds • PCBs and DDT were restricted and then banned in the 1970s – still are abundant though in decreased concentrations • After ban of DDT, dramatic increase in gulls, cormorants, terns and eagles

  28. Wildlife StudiesBritish Fish and Men • Alkyphenol ethoxylate surfactants (AEs) – industrial detergents and degradation products of polystyrene are found in high concentrations in industrial effluents and sediments in lakes and rivers in Europe • Found to be “estrogenic” – induced vitellogenin (an egg protein) in male fish

  29. Wildlife StudiesBritish Fish and Men • Nonyphenol (an AE – emulsifier, solvent) thought to be linked to declines in Atlantic salmon • Nonyphenols are estrogenic in the lab • Widespread estrogenized fish populations in British rivers and estuaries initially linked to nonyphenols and related compounds…..

  30. Wildlife Studies British Fish and Men • Identification of estrogens in sewage treatment effluents that received mainly domestic human wastes showed that the major estrogenic compounds were estradiol, estrone, and minor components of ethinyl estradiol (the estrogen in the “pill”) in sufficient quantities to estrogenize fish Routledge et al. Environmental Science and Technology 1998

  31. Endocrine DisruptorsSperm Counts • Meta analysis BMJ 1992 – “genuine decline in semen quality over the past 50 years.” • Subsequent studies show great regional and temporal variability in populations, but no clear declines in the industrial world (sperm donor from NYC highest, LA lowest)

  32. Endocrine Disruptors Correlation between levels of PCBs and phthlates and semen quality – highest levels associated with lowest semen quality

  33. Endocrine DisruptorsHypospadias • Hypospadias and cryptorchidism observed in rodents exposed in utero to estrogenic and antiandrogenic compounds • Significantly increased incidence of crytporchidism observed in male offspring of female (but not male) gardeners – no chemical exposure specifically documented Weidner et al. Environ Health Persp, 1998

  34. Endocrine DisruptorsHypospadias • Hypospdias increased in more affluent areas of the world up to 1985, then has declined in most areas of the world • No specific environmental estrogen exposure identified

  35. Endocrine DisruptorsTesticular Cancer • Increasing in most countries • DDE associated as it is antiandrogen? • Testicular cancer higher in Denmark (14/10000) than Finland (3/10000) but DDE in mothers the same • DDE concentrations falling as testicular cancers are rising

  36. Endocrine DisruptorsSex Ratios • Accidental exposure to dioxin in Italy let to decrease in sex ratio – this area has also been noted for increased exposure to other plastic byproducts and insecticides

  37. Dioxin Exposure and Sex Ratios Dioxin in ppt Mocarelli et al, Lancet, 2000

  38. Dioxin Exposure and Sex Ratio

  39. Dioxin Exposure and Sex Ratio • Mechanism of action of dioxin exposure and sex ratio is not clear • Males exposed at puberty had children with the lowest sex ratios • Similar findings noted in rats exposed to dioxin

  40. Endocrine DisruptorsPhthlates • Used to soften plastics – medical supplies, cosmetics, plastic wraps, beverage containers • Cause spontaneous abortion in rats, prolong estrous phase and delay ovulation • Act as an estrogen to the rat endometrium • Adverse actions in women not clearly known

  41. Endocrine DisruptorsPhthlates • Puerto Rico has this highest incidence of premature thelarche ever reported • Increase has been noted over the past 2 decades • Defined as the growth of breast tissue prior to 8 years without other manifestations of puberty Colon, I. Environmental Health Perspectives, 2000

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