Developmental Origins of Health and Disease: A new perspec9ve on Fetal Alcohol Spectrum Disorder

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1 This presenta,on may not be copied or used in any way without specific permission from Dr. Joanne Weinberg Developmental Origins of Health and Disease: A new perspec9ve on Fetal Alcohol Spectrum Disorder JOANNE WEINBERG, PHD DEPARTMENT OF CELLULAR & PHYSIOLOGICAL SCIENCES UNIVERSITY OF BRITISH COLUMBIA 7 TH NATIONAL BIENNIAL CONFERENCE ON ADOLESCENTS AND ADULTS WITH FASD APRIL 6-9, VANCOUVER, BC

2 Learning Objec9ves Describe the adverse health outcomes in individuals with FASD Explain how prenatal alcohol exposure could act on the fetus to increase vulnerability to later life diseases/disorders Explain what types of interven,ons might be possible to adenuate some of the adverse health outcomes observed in FASD

3 Adverse effects of prenatal alcohol exposure on long- term health outcomes: Clinical evidence and data from animal models

4 Dose- Response Curve for Teratogens As dose increases, more fetuses at risk, effects more severe (From Jacobson & Jacobson, Alcohol Health & Research World 18:30-36, 1994)

5 Vulnerability at Diﬀerent Developmental Periods (From Coles, Alcohol Health & Research World 18:22-29, 1994) Of note, the brain develops throughout gesta,on and into postnatal life.

6 A Developmental Origins of Health and Disease (DOHaD) Framework NIAAA Program Announcement: Fetal adapta,ons in response to adverse intrauterine condi,ons may increase the risk for diseases or disorders across the lifespan At this,me, the impact of prenatal alcohol exposure on the development of adult- onset disease and health condi,ons is largely unknown Understanding how exposure of the embryo and fetus to alcohol may alter health and chronic disease later in life represents a significant public health concern and warrants inves,ga,on The DOHaD framework is rela,vely new to the FASD field. But it provides an extremely important approach for understanding later life outcomes and for developing appropriate interven,ons

7 Data from clinical studies to date Numerous structural/func,onal abnormali,es that will impact health and well- being 1,2,3 o Cardiac anomalies o Urinary and kidney anomalies o Neural tube defects o CleU lip with or without cleu palate o Gastrointes,nal and genital abnormali,es o Dental anomalies o Limb and joint abnormali,es, scoliosis o Eye abnormali,es - ptosis, strabismus, epicanthal folds, microphthalmia, myopia Increased risk of preterm birth 4 Decreased immune cells counts (eosinophils, neutrophils) and response to s,mula,on 5

8 Data from clinical studies to date Higher incidence of minor infec,ons (recurrent ear and respiratory) and major/life- threatening infec,ons (early- onset sepsis in very low birth weight alcohol- exposed newborns) 5,6 o o Likely due to deficits in immune func,on of both infant and mother Level of alcohol intake important factor in predic,ng neonatal infec,on risk Increased incidence of certain types of cancer (neuroblastoma, leukemia) - possibly related to compromised immune status 7,8 Altera,ons in maternal immune func,on with alcohol consump,on 6,9,10 programming effects on developing fetus: o Altered cytokine levels in maternal circula,on (Chambers et al and the CIFASD, preliminary data) - implica,ons for offspring brain, physiological, cogni,ve, behavioral, immune development Func,onal abnormali,es of the kidney 11 o Impairment in renal acidifica,on and potassium excre,on, defect in urinary concentra,ng ability, even in the absence of any structural abnormali,es. Mental Health problems 12,13 o Occur in ~ 94% of individuals with FASD o Depression (50%), ADHD/ADD (42%), anxiety/panic adacks (38%)

9 Causes of death for people with FAS 14

10 Why Use animal models? o o o o Control of environmental variables Dose,,ming of exposure, other drugs, maternal nutri,on and health, prenatal/postnatal environment Control of gene,c variables Gene,c differences in vulnerability or sensi,vity to the same dose of alcohol Gene,c differences in absorp,on, distribu,on, metabolism, elimina,on of alcohol Separate gene,c from environmental effects Insight into mechanisms of ac,on can suggest strategies for interven,on (pregnant females) and treatment (exposed offspring)

11 Cellular and molecular mechanisms of alcohol s teratogenic effects The varying paderns observed in children with FASD suggest mul,ple mechanisms, likely ac,vated at different stages of development or at different dose thresholds of exposure Mul,level analyses needed as we collect data on adverse health outcomes in rela,on to FASD. o Can we get enough informa,on on dose,,ming, level of exposure o Can we get good informa,on on prenatal/early life environments? o Can we begin to separate effects of alcohol from effects of adverse early life environments? Understanding mechanisms can allow for targeted interven,ons and have policy implica,ons o Need to consider both direct (neuronal cell damage/death, inhibi,on of protein/dna synthesis) and indirect (nutri,on, placenta dysmorphology, vascular, oxida,ve stress/free radicals, growth factors, hormones, cell signaling, cell adhesion, epigene,cs [changes in gene expression]) effects

12 Data from animal models Many organ systems show adverse effect of prenatal alcohol exposure on structure and func,on o Pancreas abnormali,es: structural changes, adiposity, glucose intolerance, pre- diabe,c insulin insensi,vity, insulin func,on o Heart problems changes indica,ve of leu ventricular hypertrophy following chronic low dose alcohol during gesta,on; adverse effects on heart muscle; smaller volume of heart cells; impaired neural control of heart rate 19,20 o Changes in fetal and postnatal lung: impaired and delayed growth and development, decreased surfactant, cellular changes sugges,ve of pulmonary fibrosis, changes in immune cells in lung (disrup,on of alveolar macrophage ac,vity - deficits in clearing infec,ous agent) o Adverse effects on offspring kidney and blood pressure: decreased nephron numbers implica,ons for cardiovascular health, blood pressure 26-28

13 Data from animal models Altered mammary gland development and increased tumor suscep,bility, altered tumor phenotype Increased suscep,bility to osteoarthri,s 34 Deficits in immune func,on and increased inflamma,on 35,36 o Deficits in immune cell responses to s,mula,on (mitogens and alcohol) o Altered immune func,on in the neonatal period a pro- inflammatory bias o Increased severity and dura,on of immune ac,vity or inflamma,on in response to challenge in adulthood increased severity and dura,on of arthri,s, increased inflamma,on following bacterial challenge Increased vulnerability to depressive- and anxiety- like behavior 37

14 Insights from Animal models Animal models mirror many of the health problems, diseases and disorders seen in children with FASD If these health problems, diseases, disorders can be reproduced in an animal model under controlled condi,ons - dose,,ming of exposure, other drugs, maternal nutri,on and health, prenatal/postnatal environment, gene,cs Then are these secondary disabili1es as they have been called previously? Or are they primary problems, or at least have a primary component, and based largely on the effects of alcohol? No doubt that problems may be exacerbated by adverse prenatal/early life environments, but they are not necessarily due to environmental causes In the real world, many children with FASD also experience early life stress and adversity, and stress/adversity may some,mes con,nue into childhood or adolescence. Early life stress/adversity can result in some of the same long- term deficts/ problems/health issues as FASD. In those situa,ons it may be difficult if not impossible to separate the effects of FASD from those of early life adversity Animal models can help us sort out these issues

15 Developmental Origins of Health & Disease (DOHaD) Rela,onships between early environment and adult outcomes first published by David Barker and colleagues, who showed correla,ons between low birth weight and adverse health outcomes (eg., cardiovascular disease, insulin resistance/diabetes) as birth weight decreased, incidence of disease/disorders increased Cardiovascular Disease vs. Birth Weight Insulin Resistance Syndrome Prevalence vs. Birth Weight Death Hazard Ratio % with Insulin Resistance Syndrome >9.5 Birth Weight (lb) >9.5 Birth Weight (lb) Adapted from Barker 2000

16 How can the intrauterine or early life environment Influence development? Maternal Nutri,on / Health Alcohol / Drugs Stress / Infec,on Many things in the environment can influence the developmental trajectory and increase the risk for later life health problems Increased Risk for: Metabolic Disorders Cardiovascular Disease Immune Dysfunc,on Mental Health Disorders Prenatal Development Postnatal Development Thank you to Parker Holman for slide anima,ons!

Fetal Programming Hypothesis: Early life events can program

developmental trajectory and increasing later life vulnerabili9es

Programming Programming effects not only physical but also

Disorders Cogni,on Cardiovascular Disease Learning Immune Memory

Development Postnatal Development Programming or reserng of key

17 Fetal Programming Hypothesis: Early life events can program fetal/early life neurobiological/physiological systems, altering the developmental trajectory and increasing later life vulnerabili9es Maternal Nutri,on / Health Alcohol / Drugs Stress / Infec,on Fetal Programming Programming effects not only physical but also behavioral, cogni,ve, emo,onal Increased Risk for: Metabolic Behavior Disorders Cogni,on Cardiovascular Disease Learning Immune Memory Dysfunc,on ADen,on Mental Emo,on Health Disorders Prenatal Development Postnatal Development Programming or reserng of key hormonal systems by early experience is one mechanism linking early life events with long- term health consequences

18 Implica9ons for interven9on Can we reverse or rescue the programmed phenotype? Evidence suggests that we should be able to intervene to change at least some outcomes Direct mechanisms of alcohol damage - neuronal cell damage/death, inhibi,on of protein/dna synthesis may not be reversible But if indirect mechanisms are involved in alcohol s adverse effects nutri,on, placenta structure, vascular development, oxida,ve stress/free radicals, growth factors, hormones, cell signaling, cell adhesion, epigene,cs we might be able to adenuate these effects o Nutri,on o Drugs that target cell signaling pathways, altered cell adhesion molecules, epigene,c altera,ons, hormonal changes, inflamma,on, free radicals/ oxida,ve stress o Some treatments could act independently, some may be adjunc,ve treatments to boost the efficacy of current medica,on o Behavioral interven,ons also very important - may adenuate adverse effects and improve outcome

19 Acknowledgments

20 References 1. Qazio- Masakawa et al, Pediatrics; 63: , Hofer & Burd, Birth Defects Res A Clin Mol Teratol 85: , Boggan et al, Alcohol Clin Exp Res 13: , O Leary et al,. Br. J. Obstet Gynaecol 116: , Johnson et al., Pediatr Res 15, , Gauthier et al, Alcohol 33: , GoDesfeld & Abel, Life Sci 48:1-8, La,no- Martel et al, Cancer Epidemiol Biomarkers Prev 19: , Chambers et al, Alcohol Clin Exp Res, abstract in press 10. Crews et al, Alcohol Clin Exp Res 30: , Asadi, J Renal Inj Prev 3:83-86, Streissguth 13. O Connor & Paley, Devel Disabili,es Research Rev 15: , Thanh & Johnson, J Popul Ther Clin Pharmacol 23:e53- e59, Gardebjer et al, FASEB J 29: , Probyn et al, PLoS ONE 8:e doi: /journal.pone , Dobson et al, Nutr Diabetes 2:e57; doi: /nutd , Dobson et al, Alcohol48: , Parkington et al, Clinical experimental Pharmacol Physiol 37:e91- e98, 2010

21 References, cont d 20. Nguyen et al, Physiol Rep 2:e doi: /phy , Probyn et al, J DOHaD 4: , Giliber, et al, Paediatr Respir Rev 14:17-21, Sozo et al, Am J Physiol Lung Cell Mol Physiol 296:L510-8, Inselman et al, Pediatr Res 19:12-4, Gauthier et al, Am J Physiol Lung Cell Mol Physiol. 299:L8- L16, Gray et al, J Am Soc Nephrol 21:1902, Gray et al, Clin Exp Pharmacol Physiol 39: , Gray et al, Am J Physiol Regul Integr Comp Physiol 295:R568- R574, Cohick et al, Adv Exp Med Biol 815: , Polanco et al, Alcohol Clin Exp Res 34: , Polanco et al, Horm Cancer 2: , Probyn et al, Am J Physiol Regul Integr Comp Physiol 304:R791- R798, Hilakivi- Clarke et al, Br J Cancer 90: , Ni et al, Toxicol LeD 238: , Zhang et al, Brain Behav Immun 26: , Lussier et al., Alcohol Clin Exp Res 39: , Hellemans et al, Neurosci Biobehav Rev 34: , 2010

Nutritional Supplementation and Fetal Alcohol Spectrum Disorder

Nutritional Supplementation and Fetal Alcohol Spectrum Disorder 1,2 Anna Patten, PhD; 1,2 Brian Christie, PhD; 3 Courtney Green, PhD and 3 Jocelynn Cook, PhD MBA. 1 Division of Medical Sciences, University