Environmental Exposures and Later Life Disorders

Transcription

1 Environmental Exposures and Later Life Disorders US DOHaD Society October 17, 2016 Linda S. Birnbaum, Ph.D., D.A.B.T., A.T.S. Director National Institute of Environmental Health Sciences and National Toxicology Program

2 Rachel Carson: Patron of the Modern Environmental Movement The unintended impacts of DDT on vertebrates nearly led to the extinction of the brown pelican and the bald eagle DDT causes eggshell thinning in bald eagles DDT found to be estrogenic 1972 EPA bans DDT 1962: Silent Spring Rachel Carson

3 How do we know the environment is important in human disease? Twin studies help to separate genetic from environmental influences. Indicate that the environment plays a key role in many diseases.

4 Developmental Origin of Adult Disease: Barker Hypothesis 1989 David Barker: inverse relationship between birth weight and death from heart disease in England and Wales Dutch Hunger Winter : food supply to the Netherlands was cut off by Nazis Individuals born during this time had increased insulin-resistance as adults Fetal Origin of Adult Disease (FOAD) confirmed for: Coronary heart disease Hypertension Type II diabetes D. Barker, Trends in Endocrinology and Met. (2010)

5 The Legacy of the Barker Hypothesis: New scientific paradigm for disease New society New journal International conferences Focus on developmental nutrition and later life disease The Nine Months That Made You - BBC Documentary

6 The DES Tragedy Infertility 5-10 million people exposed Ectopic Pregnancy 3-5 x increase 40 x increase; 1:1000

7 Endocrine disruptor action is life-stage specific Developmental Effects (Organizational) Most sensitive exposure window Persistent effects Latent periods Adult Effects (Activational) Usually higher doses Effects as long as EDC present Can augment developmental effects A bad start lasts a lifetime!

8 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 occurring in an adult]; you can't go back and rewire the brain. Theo Colborn: Pioneer on EDCs ( ) -Theo Colborn, zoologist, writer

9 Exposures to Endocrine Disruptors Are Ubiquitous Agricultural Chemicals (pesticides/herbicides/fungicides), Food Additives, Packaging (plastics) Industrial Chemicals and By-Products (Air Pollutants, Solvents, PCBs) Waste Products (Dioxin, PAHs) Some bioaccumulate and/or are persistent. Pharmaceutical Products Phytochemicals Graphics by Paul Volden Personal Care Products, Flame Retardants, Coatings (BPA, Phthalates, Parabens, PFOA/PFOS)

10 We All Carry a Chemical Body Burden Of people tested by CDC: BPA in 93% PAH in 100% Phthalates in 50-97% PFCs in 91-99% PBDEs in 100% Triclosan in 80% PCBs in 100% 47 chemicals in every pregnant woman tested In breast milk (PCBs, dioxins, pesticides, mercury, flame retardants) 287 chemicals in cord blood

11 Wingspread Conference on Environmental Endocrine Disruption 1991 Turning point in the development of the field. Birth of the term Endocrine Disrupting Chemical. Wingspread Consensus Statement We are certain of the following: a large number of man-made chemicals that have been released into the environment, as well as a few natural ones, have the potential to disrupt the endocrine system of animals, including humans.

12 25 Years Later: We are Still Working to Define EDCs An endocrine disruptor is an exogenous substance or mixture that alters the function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations IPCS 2012 WHO/UNEP An endocrine disruptor is an exogenous chemical, or mixture of chemicals, that interferes with any aspect of hormone action. 2012/2015 The Endocrine Society

13 Certain Chemicals are Particularly Bad Actors Compound Use/Source Disease Links Bisphenol-A Phthalates PCBs (polychlorinated biphenyls) Plastics, thermal receipts Plastics, fragrances Electrical coolant and other uses Breast and other cancers, metabolism, puberty, neurobehavioral Low sperm count, metabolism, birth defects, asthma, neurobehavioral Cancer, developmental issues PBDEs Flame retardants Thyroid disruption, neurological issues Lead Drinking water, paint, gasoline Neurological issues, premature birth, kidney disorders Mercury Burning coal, seafood Neurological issues, diabetes Dioxin Formed in industrial processing Cancers, sperm quality, fertility, neurobehavioral DDT/DDE/DDD Pesticides Cancers, developmental toxicity

14 Disease Risk Increased by Developmental Exposures to EDCs Reproductive/ Endocrine Breast/prostate cancer (BPA) Endometriosis (Dioxin, PCBs) Infertility (Phthalates, Estrogens, Pesticides) Diabetes/metabolic syndrome (BPA, PCBs) Early puberty (Estrogens, BPA) Obesity (BPA, Tributyltin, Organochlorine pesticides) Immune/Autoimmune Susceptibility to infections (Dioxin, Perfluorinated compounds, Arsenic Autoimmune disease (Dioxin) Brain/Nervous System Alzheimer s disease (Lead) Parkinson s disease (Pesticides) ADHD/learning disabilities, IQ (PCBs, Lead, Ethanol, Organochlorine pesticides) Pulmonary/Cardiovascular Asthma (Air Pollution) Heart disease/hypertension (BPA) Stroke (PCBs)

15 EDC Poisonings in Humans Smoking during pregnancy PCB contamination of rice oil in Japan Mercury contamination in Minamata Bay PBB contamination of livestock feed Lead in gasoline and paint DES used as a drug to prevent miscarriages Arsenic contamination of drinking water

16 Windows of Susceptibility Development is sensitive time for exposure Rapid growth Active and extensive cell differentiation Increased metabolic rate Developing immune system Opportunities for initiation of lesions and promotion of altered cells Development is a highly integrated process Programming (epigenetic marks set) In utero, infants, childhood, adolescence, pregnancy, old age

17 Preconceptional Exposures to Germ Cells and Supporting Tissues Sperm Egg Alter germ cell quality, and fertility Cause DNA damage Disrupt mitochondrial integrity DNA copy number variations Alter sex-specific gene expression Interfere with meiosis Alter redox states, inflammation Alter the epigenome of germ cells Gametogenesis

18 Effects of Maternal Exposures on Offspring Obesity Maternal obesity alters oocyte maturation, embryo redox state, and offspring growth and metabolism (Simmons, 2014) Social behaviors Mom s anxiety affects offspring behavioral disorders (Saavedra-Rodríguez, 2013) Smoking Preconceptional smoking associated with increased risk of congenital heart defects (Karatza, 2009) Chemicals (POP s) Preconceptional paternal and maternal exposure to POP s associated with low birth weight (Buck Louis, 2014)

19 And Fathers Matter! Drug use Cocaine exposure to adult males influences anxiety & other behaviors of offspring (Pierce, 2014; Killinger, 2012) Similar developmental abnormalities seen in offspring of adult male use of alcohol, cannabis & tobacco Social instability Dad s stress experience affects offspring stress response and metabolism (Bale, 2012, 2014) Nutrition/ Obesity Offspring of adult males fed a Low Protein Diet show impaired liver function (Rando, 2010) Offspring to dads fed a High Fat Diet have diabetes and poor semen quality (Ng, 2014) Paternal obesity results in obese offspring (Freeman, 2011), increased rates of autism (Suren, 2013)

20 Prenatal Pesticide Exposure Lowers Child IQ 20

21 Prenatal PAH Exposure and Obesity in Childhood Study findings showed an association between prenatal exposure to PAHs and BMI scores at ages 5 and 7. (Rundle et al., Am J Epidemiol, 2012) Figure: Adjusted mean BMI z scores according to tertile of prenatal ambient air PAH exposure for children at ages 5 and 7 years

22 Immune Effects of Environmental Exposures Prenatal Exposure to PFOS and PFOA associated with increased days with fever in 1-4 Yr-old children (Dalsager et al. Env. International 2016) Prenatal exposure to Mercury and POPs leads to decreased White Blood Cell Counts in 5 Yr-old children (Grandjean et al. EHP 2016) PFC exposure linked to decreased Diptheria antibody concentrations in 7 and 13 Yr-old children (Grandjean et al. EHP 2016) Mouse model of prenatal immune activation linked to transgenerational pathological effects in brain (Weber- Stadlbauer et al. Molecular Psych. 2016) mediated by paternal lineage stable until 3 rd generation transcriptomic changes in amygdala of F 1 GPCR pathway, F 2 glutamatergic pathway, F 1 &F 2 DARPP pathway U.S. (Adapted Department from Weber-Stadlbauer of Health and Human et al. Services 2016)

23 Transgenerational Inheritance: Does it exist? What is its significance for human health? Primordial Germ Cell Developmental Window Gestating mother exposed to an endocrine disruptor (sex-determination period) F 0 F 1 F 2 germ line Male embryo (F 2 ) F 2 F 3

24 Chemicals Causing Transgenerational Changes Chemical Transgenerational Effects Mechanism BPA Behavioral changes through F4 Obesity Alteration of neuropeptide genes. DNA methylation Methoxychlor Steroid biosynthesis, ovarian effects Unclear DES Uterine and mammary gland changes Expression of Hox genes, ER signaling Vinclozolin Sperm counts DNA methylation on imprinted genes Dioxins AhR expression in prostate, liver, and sperm DNA methylation on imprinted genes TBT Obesity, hepatic steatosis Mesenchymal stem cell changes, epimutations Xin F, et al. 2015

25 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) SIACM 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

26 Good News A Good Start Lasts a Lifetime! The DOHaD paradigm offers a tremendous opportunity to prevent non-communicable disease. Reducing exposures/improving nutrition and reducing stress during development is likely to have a huge impact to reduce risk of diseases across the lifespan and generations. Longer term goals Define windows and their interaction and mechanism(s) Preconception, in utero, neonatal, pubertal Biomarkers of increased disease susceptibility Prevention Strategically reverse epigenetic programming changes Intervention You can t change your genes, but you can change your environment!

27 Working together we can improve human health across the lifespan and across the globe. Thank you! NIEHS Strategic Plan Website

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29 Lifelong Effects of Early-Life Exposures Gestation Childhood Puberty Reproductive Life Middle Life Later Life Environmental Exposures

30 Mechanisms of epigenetics

31 Examples of Developmental Origins of Health and Disease (DOHaD) Developmental Exposures Learning Differences/Behavior Asthma Increased Sensitivity to Infections Testicular Dysgenesis Syndrome Altered Puberty Infertility Obesity Breast Cancer Fibroids Premature Menopause Atherosclerosis Cardiovascular Disease Prostate Cancer Alzheimer's Parkinson's AGE

32 Effects of Eggs and Embryos from Obese Moms 1.0 Control 200 Control Obese Obese * (pmole/embryo) 0.5 * (Percent of Control) Offspring IUGR Obesity Glucose Intolerance 0 Glutathione 0 ROS CVD? (Simmons, 2014)

33 Paternal Stress and Effects on Offspring mirna from sperm of stressed animal injected into normal Zygote Stress Response of Offspring (Bale, 2014)

34 The Preconception Window Period of rapid changes Cell growth Meiotic division Hormonal changes Estrogen, progesterone, GnRH,FSH, LH, androgen Epigenetic changes Sperm Egg Can exposures during germ cell development in mom or dad effect the offspring? Gametogenesis

35 Childhood and prenatal exposures to phthalates and asthma

36 Air pollution and the growing brain Autism risk in children was also elevated in association with prenatal exposure to several airborne toxics and solvents, including lead, formaldehyde, and 1,3- butadiene. Maternal exposure to urban air pollutants, known as PAHs, can adversely affect a child s IQ. Prenatal exposure to particulate air pollution is associated with decreased IQ, attention, and memory Traffic-related air pollution during pregnancy and during first year of life is associated with autism.

37 EDC 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) Lake trout extirpation in Lake Ontario due to dioxin England (90 s) Fish found with both male and female organs

38 Decline in Human Sperm Quality Decline in sperm quality over the past 50 years (1992) Linear regression of mean sperm density reported in 61 publications BMJ, 1992, (305),

39 Decreasing Age of Puberty Age of Menarche in Europe and the US from 1790 to 1980 Euling, S. Y. et al. Pediatrics 2008;121:S167-S U.S. Governmentcommissioned Expert Panell: Earlier breast development and menarche Suggest endocrinedisrupting chemicals and body fat are important factors associated with the change African American and Mexican American girls enter puberty earlier than white girls

40 Some EA&T Endocrine Disrupting Chemicals HERBICIDES 2,4,-D 2,4,5,-T Alachlor Amitrole Atrazine Linuron Metribuzin Nitrofen Trifluralin FUNGICIDES Benomyl Ethylene thiourea Fenarimol Hexachlorobenzene Mancozeb Maneb Metiram - complex Tri-butyl-tin Vinclozolin Zineb Testosterone synthesis inhibitor Thyroid hormone disruptor INSECTICIDES Aldicarb beta-hch Carbaryl Chlordane Chlordecone DBCP Dicofol Dieldrin DDT and metabolites Endosulfan Heptachlor / H-epoxide Lindane (gamma-hch) Malathion Methomyl Methoxychlor Oxychlordane Parathion Synthetic pyrethroids Transnonachlor Toxaphene Estrogen receptor agonist Androgen receptor antagonist INDUSTRIAL CHEMICALS Bisphenol - A Polycarbonates Butylhydroxyanisole (BHA) Cadmium Chloro- & Bromo-diphenyl Dioxins Furans Lead Manganese Methyl mercury Nonylphenol Octylphenol PBDEs PCBs Pentachlorophenol Penta- to Nonylphenols Perchlorate PFOA p-tert-pentylphenol Phthalates Styrene

41 PFC 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 to years to -8.2 Diphtheria 5 years to years 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