developmentaloriginsofhealth...
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Developmental Origins of Health and Disease: A new perspec9ve on Fetal Alcohol Spectrum Disorder JOANNE WEINBERG, PHD DEPARTMENT OF CELLULAR & PHYS IOLOGICAL SC IENCES
UN IVERS ITY OF BR IT ISH COLUMBIA
7 T H NAT IONA L B I ENN I A L CONF ER ENCE ON ADO L E S C ENT S AND
A DU LT S W I TH FA SD A P R I L 6 -‐ 9 , VANCOUVER , B C
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This presenta,on may not be copied or used in any way without specific permission from Dr. Joanne Weinberg
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
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Adverse effects of prenatal alcohol exposure on long-‐term health outcomes:
Clinical evidence and data from animal models
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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)
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Vulnerability at Different Developmental Periods (From Coles, Alcohol Health & Research World 18:22-‐29, 1994)
Weinberg 2016 Of note, the brain develops throughout gesta,on and into postnatal life.
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
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Data from clinical studies to date
§ Numerous structural/func,onal abnormali,es that will impact health and well-‐being1,2,3 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 birth4
§ Decreased immune cells counts (eosinophils, neutrophils) and response to s,mula,on5
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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 Likely due to deficits in immune func,on of both infant and mother o 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 status7,8
§ Altera,ons in maternal immune func,on with alcohol consump,on6,9,10 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 kidney11 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 problems12,13 o Occur in ~ 94% of individuals with FASD o Depression (50%), ADHD/ADD (42%), anxiety/panic aDacks (38%)
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Causes of death for people with FAS14
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Why Use animal models?
§ Control of environmental variables o Dose, ,ming of exposure, other drugs, maternal nutri,on
and health, prenatal/postnatal environment
§ Control of gene,c variables o Gene,c differences in vulnerability or sensi,vity to the
same dose of alcohol o Gene,c differences in absorp,on, distribu,on,
metabolism, elimina,on of alcohol o Separate gene,c from environmental effects
§ Insight into mechanisms of ac,on can suggest strategies for interven,on (pregnant females) and treatment (exposed offspring)
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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
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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,on15-‐18
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 rate19,20
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)21-‐25
o Adverse effects on offspring kidney and blood pressure: decreased nephron numbers – implica,ons for cardiovascular health, blood pressure26-‐28
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Data from animal models § Altered mammary gland development and increased tumor suscep,bility, altered tumor phenotype29-‐33
§ Increased suscep,bility to osteoarthri,s34
§ Deficits in immune func,on and increased inflamma,on35,36 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 behavior37
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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
Developmental Origins of Health & Disease (DOHaD)
Adapted from Barker 2000
≤5.5 -6.5 -7.5 -8.5 -9.5 >9.50.0
0.5
1.0
1.5
2.0
Cardiovascular Diseasevs. Birth Weight
Birth Weight (lb)
Dea
th H
azar
d R
atio
≤5.5 -6.5 -7.5 -8.5 -9.5 >9.50
10
20
30
40
Insulin Resistance SyndromePrevalence vs. Birth Weight
Birth Weight (lb)
% w
ith In
sulin
Res
ista
nce
Syn
drom
e
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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
How can the intrauterine or early life environment Influence development?
Stress / Infec,on
Maternal Nutri,on / Health
Prenatal Development
Increased Risk for:
• Metabolic Disorders
• Cardiovascular Disease
• Immune Dysfunc,on
• Mental Health Disorders
Postnatal Development
Alcohol / Drugs
Weinberg 2016 Thank you to Parker Holman for slide anima,ons!
Many things in the environment can influence the developmental trajectory and increase the risk for later life health problems
Fetal Programming Hypothesis: Early life events can program fetal/early life neurobiological/physiological systems, altering
the developmental trajectory and increasing later life vulnerabili9es
Stress / Infec,on
Maternal Nutri,on / Health
Prenatal Development
Fetal Programming
Increased Risk for:
• Metabolic Disorders
• Cardiovascular Disease
• Immune Dysfunc,on
• Mental Health Disorders
Postnatal Development
• Behavior • Cogni,on • Learning • Memory • ADen,on
• Emo,on
Programming or reserng of key hormonal systems by early experience is one mechanism linking early life events with long-‐term health consequences
Alcohol / Drugs
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Programming effects not only physical but also behavioral, cogni,ve, emo,onal
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
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Acknowledgments
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References, cont’d 20. Nguyen et al, Physiol Rep 2:e12087. doi:10.14814/phy2.12087, 2014
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