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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.

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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

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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/ )

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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 Springssmetzger@uccs.edu