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Challenges of Endocrine Disrupting Chemicals

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Challenges of Endocrine Disrupting Chemicals Challenges of Endocrine Disrupting Chemicals Linda S. Birnbaum, PhD, DABT, ATS Scientist Emeritus and Former Director (Retired) National Institute of Environmental Health Sciences and National Toxicology Program EURION 5 February, 2020 – Paris, France Rachel Carson: Matron of the Modern Environmental Movement The unintended impacts 1947 DDT causes eggshell of DDT on vertebrates thinning in bald eagles nearly led to the extinction 1953 DDT found to be of the brown pelican and estrogenic the bald eagle. 1972 EPA bans DDT 1962: Silent Spring Rachel Carson The DES Tragedy Infertility *Palmer, 2001 Ectopic Pregnancy 3-5 x increase 5-10 million people exposed 40 x increase; 1:1000 Endocrine System • Chemical signals controlling many biological responses • Reproduction • Development • Neurological • Cardiovascular • Metabolism/Maintenance • Cancer • 3 major components -glands, hormones, target and immune systems Major Hormones Types • Four structural groups, with members of each group having many properties in common: • Peptides and proteins • Luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, growth hormone, many many others • In females, FSH stimulates the growth/maturation of ovarian follicles, and LH triggers ovulation • In males, FSH enhances production of androgen binding protein by sertoli cells of the testes; critical for spermatogenesis. LH stimulates leydig cell production of testosterone • Amino acid derivatives • Thyroid hormones, catecholamines Major Hormones Types • Steroids • Derived from cholesterol • Differ only in the ring structure and side chains attached to it • Androgens, estrogens, progestogens, others • Enzymes that produce steroid hormones are located in mitochondria and smooth ER • Steroids are lipid soluble and thus are freely permeable to membranes so are not stored in cells • Since not water soluble, have to be carried in the blood complexed to specific binding globulins • Sex steroid binding globulin carries testosterone and estradiol Endocrine Disrupting Chemicals: A Global Health Problem Hormones EDCs Nuclear • “An exogenous substance or mixture Receptors that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub) populations.” • The United Nations Environment Programme (UNEP) and the World Health Organization (WHO), “State of the Science of Endocrine Disrupting Chemicals” • EDCs are becoming a "global threat" that needs to be addressed Endocrine disruptor action is life-stage specific Adult Effects (Activational) • Usually higher doses • Effects as long as EDC present • Can augment developmental effects Developmental Effects (Organizational) • Most sensitive exposure window • Persistent effects • Latent periods A bad start…lasts a lifetime! Low Doses of Hormones Can Induce Permanent Alterations in Development “From the day of conception until an individual is born or hatched, the development of each stage of life is fully under the control of hormones. Changes that happen during development are far less reversible [than those Theo Colborn: Pioneer occurring in an adult]; you on EDCs (1927-2014) can't go back and rewire the brain.” -Theo Colborn, zoologist, writer Exposure and associated effects in wildlife • Lake Apopka Florida (90’s) Alligators afflicted with disabled genitalia and fewer eggs • Great Lakes (70’s -90’s) Herring gull chicks dying in eggs, mink stop reproducing • Great Lakes (40’s -80’s) L. Gillette Lake trout extirpation in Lake Ontario due to dioxin • England (90’s) Fish found with both male and female organs Reports Supporting Importance of EDCs in Human Health • Endocrine Society Statements on EDCs (2009, 2012, 2015) • WHO/UNEP State of the Science of EDCs (2012) • SAICM Nairobi (2012), Mexico City (2013), Geneva (2015) • Royal College of Obstetricians and Gynecologists (2013) • American Society for Reproductive Medicine/American Congress of Obstetricians and Gynecologists (2013) • FIGO Opinion: Reproductive Health Impacts of Exposure to Toxic Environmental Chemicals (2015) • Royal College of Obstetricians and Gynecologists • Endocrine Society • American Society of Reproductive Medicine • European Society of Human Reproduction and Embryology • Society of Obstetricians and Gynecologists of Canada Exposures to Endocrine Disruptors Are Ubiquitous Agricultural Chemicals (pesticides/herbicides/fungicides), Food Additives, Packaging (plastics) Industrial Chemicals and By-Products (Air Pollutants, solvents, PCBs) Some Waste Products bioaccumulate (Dioxin, PAHs) and/or are persistent Pharmaceutical Products Phytochemicals Personal Care Products, Flame Retardants, Coatings (BPA, phthalates, parabens, PFOA/PFOS) Graphics by Paul Volden Disease Risk Increased by Developmental EDC Exposures Reproductive/ Endocrine Brain/Nervous System • Breast/prostate cancer (BPA) • Alzheimer’s disease (Lead) • Endometriosis (Dioxin, PCBs) • Infertility (Phthalates, Estrogens, • Parkinson’s disease (Pesticides) Pesticides) • ADHD/learning disabilities , IQ (PCBs, • Diabetes/metabolic syndrome (BPA, PCBs) Lead, Ethanol, Organochlorine • Early puberty (Estrogens, BPA) pesticides) • Obesity (BPA, Tributyltin, Organochlorine pesticides) Immune/Autoimmune Pulmonary/Cardiovascular • Asthma (Air Pollution) • Susceptibility to infections (Dioxin, Perfluorinated compounds, Arsenic • Heart disease/hypertension (BPA) • Autoimmune disease (Dioxin) • Stroke (PCBs) Street et al. 2018; Barouki et al. 2018; WHO 2012 Examples of EDC exposures in Humans Smoking during PCB contamination pregnancy of rice oil in Japan Mercury contamination in Minamata Bay PBB contamination of livestock feed Lead in gasoline and paint DES used as a Arsenic contamination drug to prevent of drinking water miscarriages EDC Exposure and Immune Response Effect on antibody concentrations at ages 5 years (pre-booster) and 7 years was associated with PFC exposures reflected by the serum concentration at 18 months after multiple imputation to allow for missing observations among the 587 members of a Faroese birth cohort. Antibody Measure Change (%) 95% CI Tetanus 5 years -11.9 -30.0 to 10.9 7 years -23.8 -33.1 to -8.2 Diphtheria 5 years -16.0 -34.9 to 8.3 7 years -27.6 -45.8 to -3.3 Results are from regression model adjusted for age and sex; 7 yr. olds were adjusted for booster status Very similar results were seen in children who were exposed to PCBs Grandjean et al., 2012 and 2010 Decline in Human Sperm Quality • Meta-analysis shows significant decline in sperm counts (1973-2011), driven by a 50–60% decline among men unselected by fertility from North America, Europe, Australia and New Zealand. Mean total sperm count by fertility and geographic Mean sperm concentration by year groups *sample collection in 244 estimates collected in 1973–2011 Levine et al. 2017 FETAL ORIGIN OF ADULT DISEASE: TESTICULAR CANCER Decreasing Age of Female Puberty 2008 – U.S. Government- Age of Menarche in Europe and commissioned Expert Panell: the US from 1790 to 1980 • Earlier breast development and menarche • “Suggest … endocrine-disrupting chemicals …and body fat are important factors associated” with the change • African American and Mexican American girls enter puberty earlier than white girls Euling, S. Y. et al. Pediatrics 2008;121:S167-S171 Endometriosis Increasing • Affects ~176M women worldwide with impacts on quality of life • Environmental exposures may increase risk: soy formula feeding, BPA, dioxin • Often co-occurs with fibroids (nonmalignant uterine tumors) • May be linked to ovarian and uterine cancers • EDC exposure linked to pathogenesis of endometriosis Trends in Reproductive Health in USA Sharpe and Irvine,2004 Prenatal Exposure to EDCs and Cancer Animals Humans • DES – uterine carcinoma in mice • DES • Genistein – uterine • Vaginal adenocarcinomas in young adenocarcinoma in women • Tamoxifen – breast cancer in rats • Natural Estrogens • PBBs – liver tumors in rats and • Increase in breast cancer mice • DDT/DDE • TCDD – breast cancer following • Breast cancer DMBA in rats Classical Pathway for Estrogens (and other nuclear receptors) Activity Direct Gene Induction Membrane Receptors (protein hormones) Membrane Nucleus Modes of EDC Action • Receptor binding • ER, AR, AhR, GR, GABA • Agonists and Antagonists • Enzyme Inhibition • Steroidogenesis, thyroid peroxidase • Enzyme induction • CYP450s, thyroxine conjugation • Signal transduction pathways • Phosphatases/kinases, transcription factors • “The mechanisms by which hormones and EDCs exert specific actions are dependent on specific actions at the cellular and tissue levels as well as on circadian rhythms, seasonal changes, life stage and sex” Key characteristics of endocrine-disrupting chemicals KCs of EDCs La Merrill, M.A., et al. (2020) Nat Rev Endocrinol 16, 45–57 Key Questions • What Natural Hormones? • Estrogens, Androgens, Thyroid (“EAT”) • Others – Steroids (Glucocorticoids, Vit. D, Non-Steroids (Prolactin, Insulin), Non- Classical (Vit. A) • What Responses? • Cancer, Reproductive, Developmental, Neurological, Cardiovascular, Immunological, Bone, Others… • What Exposures? • Timing (Critical Windows, Latency [DOHaD], Ongoing vs. Past History), Mixtures (additive at Environmental Levels?), Measurement (analytical issues, targeted vs. untargeted) • What Doses? • “Low Dose” (Definition)? Non-monotonic Dose Response (multiple mechanisms)? Key Concepts • Cross-talk • Context is everything • Combinatorial Complexity • Population Risk • Distribution of susceptibility • Distribution of Response •
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