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9/24/2017
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Sylvia Metzger
When Trauma Shakes The Genes & Love Repairs
Prevention Conference Sylvia MetzgerColumbia, SC 2017 Nurse Family Partnership, University of Colorado, Colorado Springs
Mitigating Epigenetic Effects of Early Life Stress Through Maternal Nurturing
Objectives
Part I
• Early life stress – why does it matter?
• Developmental origins of adult mental health disease
• Epigenetics
• Biological embedding of traumatic experience
• Pre-conception parental health (mom/dad)
• Intergenerational transmission
• Prenatal Stress & Trauma
Part II
• You as a nurturer of genes across generations
• “nurturing” TOOLBOX
Early life stress
• Affects 30-40% of the Western population
• Implicated in ~ 1/2 of all childhood and 1/3 of adulthood psychiatric disorders
• Susceptibility to neuropsychiatric disorders (MDD, GAD, schizophrenia, and autism spectrum disorders)
• 1 in 10 adults depression (US)• MDD in pregnancy 8-13 % • Postpartum depression 10%
• Increased risk of chronic health conditions (DM II, CVD, respiratory, obesity)
Review in Jawahar, Murgatroyd, Harrison, & Baune. (2015) Clinical Epigenetics
Developmental originsof adult disease
Epigenetics plays the major role
Depression, anxiety, obesity, cardiovascular disease….
www.gla.ac.uk
Ed Uthman, 2000 Flickr
Fetal Programming (DOHaD)
Fetal life plays a role in understanding of non-communicable diseases that can manifest later in life.
Stress-induced programming Affects child’s neurodevelopment
(fear, substance abuse, impulsivity...)
E P I G E N E T I C Mechanisms
Fetus adapts in utero but at a cost laterNeurologic, immune, and cardiometabolic disordors
Barker (1990). British Medical JournalBarker (2004). Journal of Epidemiology & Community Health
Daskalakis et al. (2014). Psychoneuroendocrinology.
Fetal origins of Mental Health
• Maternal health – WHO global priority• Maternal antenatal well-being
• Anxiety/depression ~ more difficult/reactive infant temperament, increased reactivity to stress, cognitive deficits
• Fetal growth- predictor of later psychopathology• Low birth weight < 2.5 kg : anxiety, depression,
schizophrenia, alcohol/drug use, emotional reactivity in childhood
• Fetal neurodevelopment
O’Donnell & Meaney. (2017). American Journal of PsychiatryWerner et al. (2007). Developmental Psychobiology.
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Consequences of prenatal stress, depression, & anxiety Low birth weight Neurodevelopmental effects
• Antenatal depression/anxiety
• Increased behavioral reactivity & cortisol in response to novelty in infants
• Higher resting cortisol throughout the day among adolescents
• Reduced gray matter density in the prefrontal cortex
• Increased psychopathology later in life
Review in Monk, Spicer & Champagne. (2012). Development and Psychopathology .
Severe & prolonged prenatal stressMay increase the risk of:
IUGR
Preterm birth
Low birth weight
Prolonged stress response
Abnormal immune function
Obesity, cardiometabolic disorders
Mental health disorders Schizophrenia
ADHD Anxiety Depression Autism Temperament difficulty Impulsivity Risk-taking Aggression
Li, Olsen, Vestergaard, Obel, Baker, & Sorensen. 2010. PLoS OneBabenko, Kovalchuk, & Metz.2015
Guidice.2012
Early gestation malnutrition
↑ Obesity
Altered lipid metabolism
Cardiovascular disease
Increased stress
Cognitive function
Mid gestation malnutrition
Reduced kidney function
Obstructive airway disease
Late gestation malnutrition
Born small, stayed small
↓ Obesity Victim of Hunger Winter. Dutch Resistance Museum.
Timing of insult is critical long-lasting effects of stress via epigenetic marks
Callaghan, Graham, Li, & Richardson (2013). Frontiers in PsychiatryRosenboom, De Rooij, & Painter. 2006. Early Human Development
Hajj, Schneider, Lehnen & Haaf. 2014.
.
Affective disorders
Schizophrenia
Mental Health Disease Concordance rate between monozygotic twins
PTSD (> 25 genes identified) ~35-45%
Schizophrenia ~50% vs 17% in non-identical twins
More than our DNA
Identical twins begin to diverge epigenetically during in utero development
Ryan, Chaudie, Ancelin & Saffery. (2016). Epigenomics.
Epigenetics
• Heritable chemical modifications that change gene expression without changes in DNA sequence
• fairly stable across the lifespan, some can be reversible
• in response to our environment, lifestyle, social interactions, stressors, aging, or diseases
Epigenetic control of gene expression
“Tags” alter access to DNA and chromatin.
1. DNA methylation
2. Histone modification
3. Non-coding RNA (e.g. miRNA) expression
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1. DNA methylation • A chemical cap (CH3-) binds to or near a gene
• Gene cannot be expressed (it is turned off)
e.g. prenatal stress – methylation of placental enzyme 11 ß – HSD2 LBW infants, neurobehavioral changes
Maternal IPV ~ risk of maternal PTSD ~ disturbed child attachment : methylation of NR3C1 gene in children
childhood sexual/physical trauma : hypomethylation of NR3C1 gene
2. Histone modification- access to info• DNA hugged tightly: the info CANNOT be “read”
• Histones “loosen”, information is ACCESSED & “READ”
Histone phosphorylation
- Formation of memories during stressful events
Histone acetylation – drug therapy
- Increases access to genes via HATs (acetyltransferase)PROTEIN
- Decreases access to genes via HDACs (deacetylases) NO PROTEIN
Reul (2014). Frontiers in PsychiatryGriffiths & Hunter (2014). Neuroscience
3. miRNAs – key regulators in maternal-fetal crosstalk
Do not code, but regulate gene expression
• silence mRNA (no protein)
• alter gene expression after fertilization & during intrauterine life
• Target epigenetic regulators-key in fetal metabolic programming
• Potential biomarkers for adverse pregnancy outcomes
Floris, Kraft & Altosaar. (2016). International Journal of Molecular SciencesHollins & Cairns (2016). Progress in Neurobiology
miRNA
Stress Schizophrenia
Glucocorticoid receptor (GR)
• Cortisol binds to GRs in hippocampus
• TURNs OFF STRESS CIRCUIT!• More GR =quicker recovery from stress
• Early life stress alters DNA methylation at GR genes
http://learn.genetics.utah.edu/content/epigenetics/rats
Role of Placenta- master regulator
• Controls fetal environment
• Altered placental epigenetic signals– long-term neurodevelopmental effects
• Quickly adapts to maternal environment via epigenetic mechanisms
• Can inactivate mom’s cortisol to control how much gets to the baby but some still reaches the fetus
• Placental SEROTON – essential for fetal brain• Potential therapeutic target to lessen effects of
prenatal maternal stress?
Nuget & Bale. (2015). Frontiers in Neuroendocrinology St-Pierre, Laurent, King & Vaillancourt.(2016). Placenta
Moog et al. (2016). Biological Psychiatry
Role of HPA Hypothalamic-pituitary-adrenal axis – stress response system
Elevated maternal cortisol Overactive / dysregulated HPA in offspring
prenatal trauma childhood trauma, psychosocial stress, psychiatric disorders
Epigenetic changes in GC pathway genes: NR3C1, 11-ß- HSD2 (PLACENTA) &FKBP5
http://we-care.co.za/wp-content/uploads/2016/03/domesticviolence2-770x470.jpg
https://www.youtube.com/watch?v=BIfK0L8xDP0
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Fetal programming by maternal stress
• Mom’s Distress – HPA – cortisol - baby
• Increased maternal cortisol passes readily to fetus via placenta
• Placental enzyme (11-ß-HSD2) protects the fetus from excessive maternal cortisol
• Excessive cortisol overwhelms the system
Review in Cao-Lei et al. (2017). Neuroscience and Biobehavioral Reviews
Exposure to objective stressors (war, disasters,IPV)
• Prenatal maternal anxiety & mood disorders• ↑NR3C1 methylation in cord blood, ↑baby’s cortisol at 3 months
• DNA methylation changes in placental NR3C1
• Increased methylation in infants in moms with low prenatal but high postnatal depression, but effect reversed by MATERNAL STROKING
• Sex-specific effect? Baby girls only – greater fearfulness when prenatal stress
• Intimate partner violence during pregnancy • ↑NR3C1 methylation in offspring
Oberlander et al. (2008). EpigeneticsConrad et al. (2013) EpigeneticsMurgatryod et al. (2015). Translational PsychiatryRadtke et al. (2011). Translational Psychiatry
Prenatal Exposure to War TraumaBDNF (brain-derived neurotrophic factor)
• Keeps the nerves/brain healthy
• Plasticity/ learning
• Altered BDNF – anxiety, MDD, PTSD, hx of domestic violence, childhood maltreatment
• Key in placental/ fetal development
• War trauma
• BDNF methylation across the BDNF gene regulating the HPA axis in Intergenerational transmission
Kertes et al. (2017). Clinical Epigenetics
http://s1.ibtimes.com/sites/www.ibtimes.com/files/styles/lg/public/2015/05/14/congolese-rape-victims.jpg
Quebec Ice storm babiesProject Ice Storm 1998 Quebec : objective hardship mattered
• Altered immunity in adolescent = Lasting DNA methylation in T cells in offspring, ↑cytokines
• Altered cognitive, linguistic & motor functioning at 5 ½ yrs, autism traits at 6 ½ yr,
Cao-Lei, Veru, Elgbeili, Szyf, Laplante & King. 2016. Clinical Epigenetics
Hurricanes & tropical storms in Louisiana
• Exposure to severe storms during sensitive periods of gestation
• Increased prevalence of autism, especially if exposed near the middle or end of gestation.
Kinney, Miiller, Crowley, Huanq & Gerber. (2008). Journal of Autism and Developmental Disorders .
Maternal PTSD increased risk of PTSD in offspring
Altered stress reactivity
Immune dysfunctions
Increased cortisol in healthy female adolescent
Maternal separation from baby
induced epigenetic modifications
Baby more sensitive to stress
Maternal PTSD
Liu et al. 2016. J Anxiety DisorderMathew & Janusek. 2012.
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Chronic “toxic” stress & immunity
• INFLAMMATION : Th1 pro-inflammatory cytokines > Th2 anti-inflammatory cytokines
• Increased risk of child’s asthma & atopic disease
• Maternal HPA dysregulation – epigenetic changes (methylation of anti-inflammatory or placental enzyme genes) –placental “shield” weakened fetal HPA dysregulayion allergy
Guxens et al. (2014). Journal of Allergy and Clinical Immunology Hartwig et al. (2014). Journal of Allergy and Clinical Immunology
Suh et al. (2017). Allergy, Asthma, & Immunology research. .
Chronic social stress – low socioeconomic status
• Elevated inflammatory markers
• Altered patterns of DNA methylation, elevated amygdala function, and depression
• Can be buffered by social interventions
Cunliffe. (2016). Epigenomics.
Effects of exposure can be transmitted
Intergenerational –prenatal
The parental generation to the next one
[F0] [F1]
Transgenerational – germline
The parental [F0] across ≥ 2 generations
- No direct exposure
- At least 4 generations must be studied to exclude in utero exposure
https://www.laurakkerr.com/wp-content/uploads/2012/06/Generations-1024x768.jpg
Buss et al. (2017). Journal of the American Academy of Child & Adolescent Psychiatry
Intergenerational transmission of stressAsk not only about personal history of trauma, but about…. Parental trauma
http://buildingfamilycounseling.com/2016/12/legacy-family-trauma-part-1/
http://thescienceexplorer.com/humanity/why-do-some-children-holocaust-survivors-show-signs-trauma-epigenetics-could-be-answer
Methylation changes in glucocorticoid gene (FKBP5) found in both Holocaust survivors & their offspring
Preconception parental trauma can have intergenerational effect
Other studies: no psychopathology in offspring of Holocaust survivors –RESILIENCY
Parental trauma affects child’s biology
Yehuda & Peters. (2015). Biological PsychiatryLevav et al. (2007). The Isreal Journal of Psychiatry & Related Sciences.
Biological embedding of mom’s trauma
• Maternal history of childhood maltreatment (CM) may be transmitted to her child• Children of mothers with CM- adverse birth outcomes, neurodevelopmental & behavioral problems,
autism, obesity, poorer general health even if child does not experience direct maltreatment
• Timing: CM in her childhood worse effect on offspring
• Adverse CM-related in utero environment – more difficult infant temperament may elicit suboptimal maternal parenting behavior may affect child’s neurodevelopment outcome
• Screening for CM preconceptionally or in the early pregnancy?
Review in Buss et al. (2017). Journal of the American Academy of Child & Adolescent Psychiatry
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Preconception health
• Epigenetic signatures of stress experience~ In germ cells
• Preconception counseling is widely lacking for men
• Focus on the couple, rather than on women only
Rodgers & Bale. (2015). Biological Psychiatry
Maternal interpregnancy stress
Stress between 2 pregnancies
↑ Salivary cortisol predicted low birth weight independent of stress during the 2nd pregnancy
OPPORTUNITY before next pregnancy“Epigenetic nurturing”Screening for mental health disorders at clinics
Support groups, counseling
Guardino et al. (2016). Health Psychology
Preconception paternal stress
Altered miRNAs in sperm (mouse model)
miRNA function after fertilization
alters stress response of offspring
Day et al. (2016). Americal Journal of Stem Cells. Rodgers, Morgan,Bronson, Revello & Bale. (2013). Journal of Neuroscience
Fetal programming
Mode of delivery
Skin to skin Breastfeeding Hospital practices
Diet
antibiotics Rural vs urban homeLarge family
Journey of our Microbiome
Gut MicrobiomeGut microbiome and/or their neurometabolites & neurotransmitters
neurodevelopment
mood
behavior (stress response)
Master regulator of HPA axis (stress)
Modulates gene expression ~via epigenetics
Slattery, MacFabe & Frye. 2016. PediatricMessaoudi et al. (2011). British Journal of Nutrition
“Let food be thy medicine, and medicine be thy food. Everything in excess is opposed to nature.All disease begins in the gut.”
-Hippocrates
Psychobiotics ~ mental health • Meta-analysis (2017): probiotics may have a positive effect on symptoms of
depression, anxiety, and perceived stress in healthy human volunteers
• Prebiotics –soluble fiber digested by Lactobacilli and Bifidobacteria• promote the growth of good bacteria
• Increase BDNF levels in rats fed by Bifidobacteria
• Anxiolytic effect
Dinan & Cryan. (2016). Genome MedicineMcKean, Nauq, Nikbakht, Amiet & Colson. (2017). Journal of Alternative and Complementary Medicine
Savignac et.al. (2013). Neurochemistry International
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The Microbiota- Gut-brain- axis
• Microbiome programs HPA stress axis early in life
• Early life stress impacts neurodevelopment • Bacterial diversity/composition change abruptly in
response to stress
• HPA axis is sensitive to gut microbial disruption• Maternal separation in early life – predisposes to IBS
via alterations of microbiome
Borre et al. (2014). Trends in Molecular MedicineO’Mahony, Hyland, Dinan & Cryan. (2011). Psychopharmacology
Bidirectional communication GI & CNS
Early life stress & microbiome
Maternal diet, prenatal care, and stress matter!
Prenatal stress depletes vaginal Lactobacillus
Maternal separation - Lactobacillus depletion –increased distress and susceptibility to infections 3 days post-separation
Bifidobacterium infantis – HPA stress activation rescue
• Attenuates stress response
Jašerević, Rodgers & Bale. (2015). Neurobiology of StressBailey & Coe,1999. Developmental psychobiology
Gareau et al.(2007). Gut .
Prenatal stress alters Baby’s microbiota
Infants of mothers with high cumulative stress – changes in microbiota
↑ Proteobacteria (Escherichia)
Escherichia dominate in infants tx with Abx, preterm with NEC, colicky infants
Enterobacteria dominate in infants with allergy/eczema
↓ Lactic acid bacteria (Lactobacillus) & Bifidobacteria
Bifidobacteria = healthy infant microbiota
Predisposion to GI symptoms and allergic reactions
Zijlmans, Korpela, Riksen-Walraven, de Vos & Weerth. (2015). Psychoeuroendocrinology
Potential therapeutic strategy?
• Bifidobacterium and Lactobacillus supplementation – beneficial effect on anxiety/depression?
• Fecal microbiota transplantation : MS, PD, autism, ADHD, chronic fatigue syndrome, IBD, metabolic syndrome, obesity
NIH Human Microbiome Project (2017) http://hmpdacc.orgVaginal Microbiome Consortium. (2016) Vmc.vcu.edu/momspi
Evrensel, & Ceylan. (2016). Clinical Psychopharmacology and Neuroscience
Preconception counseling
LIFESTYLE, DIET & STRESS REDUCTION
Maternal diet may increase vulnerability to mental disorders
Maternal pre-pregnancy obesity
~ child’s inattention & emotional difficulties
~affective disorder (depression) later in life
Paternal pre-conception obesity
~ newborns showed hypomethylation, even if mom not obese! Reprogrammed gametes!
Obesity – chronic inflammation- depression (microbiota?)
Rodriguez. (2010). Journal of Child Psychology and PsychiatryRobinson et al. (2013). Jjournal of Developmental Origins of Health and Disease
Soubry et al. (2013). BMC Medicine
Screening & interventions for perinatal depression
Infants of depressed mothers
Secure attachment less likely
↑ Avoidant & Disorganized attachment
Martins & Gaffan. (2000). Journal fo Child Psychology and Psychiatry
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Skin to skin contact – keeps Oxytocin happy
• Severe early life stress – lower oxytocin in adulthood
• OXYTOCIN releases throughout breastfeeding
• Maternal fatigue ↓
• Temporary anxiolytic-like calming effect on postpartum maternal mood disturbance
Toepfer et al. (2017). Neuroscience and Behavioral ReviewsNiwayama et al. (2017). Breastfeeding Medicine
Human milk & Breastfeedingtoxic stress buffers
SOCIOECONOMIC Poverty permanently activates stress
response
Cumulative burden of suboptimal or neglectful caregiving
Formula cost saving
NFP – ↓disparities in BF
Hallowell, et al. & the Expert Panel on Breastfeeding of the AAN (2017). Nursing Outlook
Bode et al. (2014). Advances in Nutrition: An International Review Journal
BIOLOGICALNeuroprotection
↓Inflammation
antioxidant
Stem cells
BEHAVIORALSkin to skin
↓stress response
BREASTMILK as Epigenetic Modulator
Human milk component
Prevention of Gene expression
Lactoferrin NEC, disorders of immune system
NK-kB (reduced)
Prostaglandin J ObesityNAFLD
PPAR gama(increased)
Undigestableoligosaccharides
Gut dysbiosis(infectious disease, immune system disorders, obesity)
Acts on expression of different genes (e.g NF-kB)
Verduci et al. (2014 ) Nutrients.
Different microbiota – BM vs Formula
Exclusively breastfedFirst 2 wks - simple but stable microbiotaMore Bifidobacteria (ss.infantis) & Bacteroides
Formula fedMore diverse but less stableLess beneficial bacteria – Bifido, LactoMore Proteobacteri0a (e.coli), Firmicutes
Jost, Lacroix, Braegger, & Chassard. 2015. Nutrition Reviews.Guaraldi & Salvatori. 2012. Frontiers in cellular and infection microbiology.
Probiotics
• Activia• Altered gene expression of
carbohydrate metabolism
• Continuous consumptions may be needed
McNulty et al. (2011). Science Translational MedicineIslam. (2016). Medicine
Maternal diet
• Dietary compounds – methyl donors
• Regulators of nuclear DNA methylation
• SAMe – main CH3 donor, produced in the body from methionineCicer arietinum Triticum sativum Phaseolus mungo Mucuna pruriens Allium cepa
Kanherkar et al. (2017). Evidence-Based Complementary and Alternative Medicine
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Maternal diet
• Reduced histone acetylation
interferes with signaling pathway towards inflammation
• Neuroprotective potential • May mitigate alcohol-induced deficits
• ↓ neuroinflammationRat study
Kanherkar et al. (2017). Evidence-Based Complementary and Alternative MedicineTiwari, & Chopra. (2012). Psychopharmacology
Mindfulness – neurobiological modifier
Mitigate the negative effects of stress & trauma related to ACE
↓ sx of depression, PTSD and anxiety after 8 wk MBSR program
Beneficial effect continued for 2.5 yrs
8 hr meditation session
• Rapidly altered global histone modifications
• Reduced expression of
- pro-inflammatory genes
- histone deacetylase
Ortiz & Sibinga. 2017. ChildrenMcEwen. (2016). Annals of the New York Academy of Sciences
Kaliman et al. (2015). Psychoneuroendocrinology.
Yoga
Excellent for mood/anxiety disorders
• Better daily dietary choices after yoga
• Higher antioxidant defense
• Positive effects on immunity
Stress reduction• Interferon ↑• Proinflammatory NF-kB ↓
Rapid changes in gene expression of PMNCs
• Within 2 hrs of starting the practice
Kanherkar et al. (2017). Evidence-Based Complementary and Alternative MedicineQu et al. (2013). PloS ONE.
Sleep • Prenatal sleep deprivation can affect baby’s brain development
• delays and impairs the development of sleep-wake cycles in offspring
McEwen. (2016). Annals of the New York Academy of SciencesAswathy, Kumar, & Gulia (2017). Jjournal of Sleep Research
.
Healing power of Love –bonding/attachment
The Oxford Parent Infant Project
Individual work with parent-baby
Video interaction guidance
Help with parenting skills
Watch, Wait and Wonder technique
- Baby leads
(http://www.oxpip.org.uk/ )
.
Tucker. (2015) Journal of Family Health
Home visiting Prevents/buffer “toxic stress”
• Improve parental capacity
• Promote nurturing to turn off the stress response
• Advocate to decrease maternal/childhood adversities & link to resources (poverty, IPV, substance abuse, food scarcity etc).
• Prevent intergenerational transfer of toxic stress & disparities
Garner. (2013). Pediatrics.
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NFP - “epigenetic nurturing”
Healthy Foundations Study – biological embedding of vulnerability
• Early positive intervention NFP – lasting positive epigenetic effects
• 27 yrs old children of NFP mothers• DNA methylation at 1015 sites across 593 genes, some enriching
neurodevelopment
Society of Biological Psychiatry (2015). SOBP Abstracts The Lasting Influence of Early Intervention on the Methylome (K. J O’Donnell et al, 2015)
With permission, Emily
Thank you!
Sylvia Metzger, MPH, MSN, FNP-C, CNL, IBCLC, ANLC, LCCE
Nurse-Family Partnership, University of Colorado Colorado [email protected]