A Bad Start Lasts a Lifetime: Need for Green Chemistry

Transcription

1 A Bad Start Lasts a Lifetime: Need for Green Chemistry Jerrold J. Heindel, PhD Scientific Program Administrator Division of Extramural Research and Training National Institute of Environmental Health Sciences

2 Gene-Environment and Disease All complex diseases have genetic and environmental component. Epidemics of chronic diseases like diabetes, childhood asthma, ADHD, obesity, premature puberty, infertility over the last 40 years. Genetics has not changed over that time. Must be due to environmental, dietary and behavioral changes. We will never understand the etiology of diseases without an understanding of the role of environment (environmental chemicals, nutrition, stress, infections, drugs).

3 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 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 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 METALS Testosterone synthesis inhibitor Thyroid hormone disruptor Estrogen receptor agonist Androgen receptor antagonist

4 Characteristics of Endocrine Disrupting Chemicals Low dose effects High dose effects are different from low dose effects Non-monotonic dose responses Wide Need range to predict of effects persistence of a chemical BEFORE widespread Endocrine signaling introduction govern all into tissues/organs and distribution in the environment Nuclear and membrane receptors, neurotransmitters, metabolism Persistent If ubiquitous, and may latent achieve effects persistence due to continuous exposure Developmental exposure most sensitive window Transgenerational effects (vinclozolin, dioxin, BPA, phthalates) Many of the chemicals we hear about are persistent, e.g., Ubiquitous PCBs, dioxin, exposure PBDEs, PFCs Consumer products OR ubiquitous, e.g., BPA, phthalates Pharmaceuticals Industrial products

5 Sensitivity Varies Across the lifespan People vary in their susceptibility to the toxic effects of chemical exposures Most Sensitive lifestages Development Childhood, Puberty Adult Aged In Addition Those with pre-existing conditions or genetic-based vulnerabilities People who are more highly exposed.

6 Developmental Basis of Disease I Development (in utero and first few years of life) is a sensitive time for exposure to environmental chemicals. Tissues/organs forming, Lack of DNA repair, Poor liver metabolism, Developing immune system, Lack of blood/brain barrier, metabolic rate Programming (epigenetic marks set) Teratology Studies Teratology Studies: Birth defects, Low birth weight, premature birth or functional changes

7 Developmental Basis of Disease II Functional changes: changes at gene and cell level.looks normal but at molecular level altered gene expression (altered proteins), altered protein activity and/or altered number of cells that persist after stress is gone. and lead in increased sensitivity to disease later in life. Functional changes are not detected in typical teratology studies. Need developmental exposures and lifetime examination for multiple disease outcomes. Need omics endpoints.

8 Developmental Basis of Disease: A New Paradigm Developmental exposure (in utero and neonatal) to environmentally relevant doses of environmental chemicals can lead to increased susceptibility to disease. Susceptibility to disease persists long after the exposure is gone even decades later. The toxicant-induced responses are most likely the result of altered gene expression or altered protein regulation (functional change). This functional change or aberrant developmental programming, permanently alters gland, organ or system potential leading to disease. Difficult to detect and characterize in human studies latency. Need animal models a new testing paradigm. HARM IS DISPROPORTIONATE TO DOSE

9 A Bad Start Lasts a Lifetime Blastocyst Embryo Fetus Infant Child Adolescent Long Term Health Consequences Proper development orchestrated by hormones Periconception Prenatal Postnatal Childhood Environmental Stressors: Environmental chemicals Nutrition, infections, stress, drugs T.Woodruff and L.Giudice UCSF

10 Persistent and Latent Effects How can it be that developmental stressors can cause effects that persist long after the exposure? A Paradigm Shift Epigenetics... chemical modifications of DNA and chromatin which are heritable and affect genome function (transcription, replication, recombination, but don t affect DNA backbone..

11 Epigenetic/Developmental Basis of Disease! Normal Tissue Cell CH 3 CH 3 CH 3 Ac Normal Differentiating Cell (Development) Altered Proteins EDCs and/or Protein Ac Concentrations CH 3 Altered Gene Expression (persists due to epigenetic marks) Disease/Dysfunction

12 Developmental Diseases Reproductive/Endocrine Breast/prostate cancer Endometriosis Infertility Diabetes/metabolic syndrome Early Puberty Obesity Immune/Autoimmune Pulmonocardiovascular Asthma Heart disease/hypertension Stroke Brain/Nervous System Alzheimer's disease Parkinson s disease ADHD/learning disabilities Susceptibility to infections Autoimmune Disease

13 Reproductive/Endocrine Breast/prostate cancer (BPA) Endometriosis (Dioxin, PCBs)) Infertility ( Phthalates, Estrogens, Pesticides) Diabetes/metabolic syndrome (BPA) Early Puberty (Estrogens, BPA) Obesity (BPA, Tributyl Tin, Organochlorine Pesticides) Immune/Autoimmune Susceptibility to infections (Dioxin) Developmental Diseases Autoimmune Disease (Dioxin) Pulmonocardiovascular Asthma (Air Pollution) Heart disease/hypertension (BPA) Stroke (PCBs) Brain/Nervous System Alzheimer's disease (Lead) Parkinson s disease (Pesticides) ADHD/learning disabilities (PCBs, Lead, Ethanol, Organochlorine Pesticides, Flame Retardants)

14 Developmental Exposure to DES and Weight Gain Proof of Principle Control DES Month 4 Month Exposure of CD 1 mice to DES for 5 days at birth results in increased weight gain star>ng at puberty in female mice. No change in food intake or exercise. Newbold et al.

15 Normalized Weight Change (%) Prenatal TBT and Weight Gain in Mice Males Control TBT Normalized Weight Change (%) Females Control TBT Time (months) Prenatal TBT exposure causes permanent physiological changes resulbng in predisposibon to weight gain

16 Competitive Binding of TBT 3000 his 6 hrxrα 7000 his 6 hpparγ Specific Bound cpm K d = 7.5 nm K d = 12.5 nm K d = 20 nm K d = 300 nm LG268 TBT Concentra>on nm Troglitazone TBT Concentra>on nm TBT binds to and acbvates RXR and PPARγ with high affinity

17 TBT Induces Human Mesenchymal Stem Cells to Form Adipocytes hmscs + MDII + TBT Conversion of hmsc to adipocytes is one potenbal mechanism of TBT acbon

18 PFOA Phthalates Tributyl Tin Genistein Estradiol DES Fructose? NicoBne Bisphenol A PCBs? Lead Organophosphate pesbcides (Parathion, Diazinon, Chlorpyrifos) PBDEs? Monosodium glutamate Obesogens Just the Tip of the Iceberg?

19 Developmental Basis of Prostate Cancer: Two Hit Model (Gail Prins, Shuk Mei Ho) EB/ BPA *T+E Day Day 1, 3, 5 Treatment (1 st Hit) Oil High-dose EB: 2500 µg/kg BW (sc injection) Low-dose EB: 0.1 µg/kg BW Environmental relevant dose Bisphenol A: 10 µg/kg BW Sample groups: Day 10 Day 90 Day 200 Day 200 w/t+e2 Day 90 Treatment (*2 nd Hit) 1 st Hit effect: -Neonatal estrogen effect 2 nd Hit effect: -Adult hormonal effect

20 Dorsal Prostate PIN Scores after Second Hit in Adulthood Relative PIN Scores * ** * * ** Oil High EB Oil High Low BPA EB EB Oil High Low BPA EB EB Adult T+E Low EB BPA

21 Transgenerational or Gametic Epigenetic Inheritance Vinclozolin, Methoxychlor, Phthalates, Dioxin, Bisphenol A

22 Transgenerational or Gametic Epigenetic Inheritance Vinclozolin (Fungicide) 3rd Generation Control Methoxychlor (Pesticide) 3rd Generation Vinclozolin 20% Infertile 90% Reduced Sperm (Skinner)

23 A Bad Start Lasts a lifetime Poor nutrition Prepregnancy Pregnancy Infancy/childhood Stress Environmental/Social,Drugs Pregnancy Infancy/childhood Infections Because of the data supporting the developmental basis of disease. We know what to do and when to do it to PREVENT DISEASE! Prevention is always better than treatment! Pregnancy Childhood Exposures to environmental chemicals Prepregnancy Pregnancy Infancy/childhood

24 Risk Paradigm Role of Green Chemistry ENVIRONMENT TIME INDIVIDUAL SUSCEPTIBILITY HUMAN HEALTH & DISEASE Sources Exposure Internal Dose Early Biological Effect Altered Structure/ Function Adverse Effect

25 Bemidji Statement We have the sacred right and obligation to ensure that our decision-making is guided by consideration of the welfare and well being of the seventh generation to come. Guardiansofthefuture.org A Bad Start really does last a lifetime Indeed it may last several lifetimes! A Good start also lasts a lifetime!