DOHaD: Role of environmental chemical exposures

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1 DOHaD: Role of environmental chemical exposures Linda S. Birnbaum, Ph.D., D.A.B.T., A.T.S. Director, National Institute of Environmental Health Sciences and National Toxicology Program PPTox-IV Boston, MA 29 October 2014

2 We all carry a chemical body burden >287 chemicals in cord blood In breast milk (PCBs, dioxins, pesticides, mercury, PFCs, flame retardants) Of people tested by CDC: BPA in 93% Phthalates 50-97% PFCs in 91-99% PBDEs in 100% Triclosan in 80% PCBs in 100%

3 Environmental Exposures During Development asbestos formaldehyde lead brominated flame retardants atrazine phthalates vinclozolin alkylphenol compounds pyrethroids methoxychlor perflurocarbons PCBs dioxin vinyl chloride (PVC) parabens cadmium bisphenol A oxobenzene tetrachlorethylene perchlorate arsenic Triclosan/triclocarban volatile organics mercury toluene polystyrene

4 Vulnerability of Developmental Period to Environmental Chemicals DNA repair not fully functional in all cells Liver metabolism lacks the ability to detoxify chemicals Blood brain/organ barriers not fully formed Epigenetic effects change over development and lifespan Tissues and organs are forming at different rates Immune system is immature during development Epigenetic programming is plastic, responds to environment Environmental exposures during development can cause death, premature birth, low birth weight, birth defects or functional changes

5 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!

6 Developmental Programming: Epigenetics The effects of developmental exposures, environmental chemicals, persist because they alter epigenetic signaling, which lasts throughout life DNA methylation of CpG islands or shores Chromatin changes/remodeling mirna The developmental time period is the most sensitive to epigenetic alterations Early exposures alter epigenetic marks which lead to functional changes which lead to abnormal tissues which lead to disease later in life.

7 Epigenetic Impact of Xenoestrogens Xenoestrogens activate nongenomic signaling to regulate Histone Methyltransferase activity ER + DES HMT Active Me ER PI3K AKT P HMT Inactive Modulation of Histone Methylation in Chromatin Ligand Activation Non-genomic signaling Modified from Ceder et al., Nature Reviews Genetics (2009) Phosphorylation of Histone Methlytransferases

8 Human Disease Trends: Reproduction and Cancer Over recent decades there has been: significant increase in reproductive problems in some regions of the world, suggesting a strong role for unidentified environmental factors in disease etiology increase in endocrine cancers and significant decrease in human fertility rates Evidence for Endocrine Disruption Strongest, but limited, evidence for a role of developmental exposure to EDCs in breast cancer, fibroids, endometriosis, preterm birth, puberty, prostate cancer and infertility. Sufficient evidence that developmental exposures to phthalates can reduce testosterone levels leading to reduced anogenital distance in animals: limited data in humans. Top: Richiardi et al., Cancer Epidem. National Biomark. Institutes (2004); of Health Bottom: based U.S. on Department data from of Health and Human Services

9 In Utero and Childhood Arsenic Exposure and Lung Cancer (Cancer diagnosis age >25yrs) Steinmaus C et al. Cancer Epidemiol U.S. Biomarkers Department of Prev Health 2014;23: and Human Services

10 Developmental Exposures and Metabolic Disease Obesogen: chemicals that affect weight gain and metabolism Nicotine (smoking) is a developmental obesogen in humans and animal models BPA affects insulin release and cellular signaling in pancreatic β cells BPA, DEHP, PFOA, and some flame retardants (firemaster 550) lead to weight gain in animal models Pesticides/fungicides increase risk for diabetes and obesity in animal models. POPs associated with increased risk of obesity and diabetes in humans

11 WHO/UNEP SOS of EDCs 2012 Human Disease Trends: Neurodevelopment and Behavior Dramatic increase in rare neurodevelopmental disorders Sufficient data links developmental exposures to PCBs, lead, and methylmercury to neurodevelopmental effects in animals at doses similar to those of humans Sufficient data in humans links developmental PCBs exposure to lower global IQ and sexually dimorphic behaviors ADHD is linked to developmental exposures to lead, PCBs, and some.. organophosphate pesticides

12 EHP Paper of the Year-2012:Prenatal Pesticide Exposure Lowers Child IQ

13 Research Needs:: We are Underestimating the Role of Environment in Disease Risk Small subset of chemicals Examined/assays Measured/biomonitoring Single stressors Nutrition, stress, chemicals, drugs, infections Single window of sensitivity How many windows? Lifespan approach Paternally-mediated effects Transgenerational effects Single disease outcome New diseases Syndromes

14 Transgenerational Inheritance: Does it exist? What is its significance for human health? Vinclozolin Methoxychlor BPA Phthalate (DEHP) BPA plus phthalates (DEHP plus DBP) Dioxin Jet fuel 8 Permethrin plus DEET DDT TBT Cocaine Nutritional deprivation Primordial Germ Cell Developmental Window Gestating mother exposed to an endocrine disruptor (sex-determination period) F 0 F 1 F 2 F 3 F 2 germ line Male embryo (F 2 )

15 Summary There are developmental exposures to a wide variety of environmental chemicals. Human and animal data linking developmental exposures to environmental chemicals to diseases across the lifespan Epigenetics plays a major ( but perhaps not exclusive) role in the mechanism whereby developmental exposures can lead to altered sensitivity to developing diseases later in life. Some effects of developmental exposures to environmental chemicals can be transmitted across generations.

16 Together we can improve human health across the globe NIEHS Strategic Plan Website