Disclosures None Adverse Childhood Experience Household - PDF document

Learning Disabilities and Mental Health: What’s Environment Got to do Mark Miller MD, MPH Director, Pediatric Environmental Health Specialty Unit University of California San Francisco* Public Health Medical Officer Office of Environmental Health Hazard Assessment, CA EPA Director, CA EPA Program for Children’s Environmental Health (Comments do not represent state of California) UCSF Developmental Disabilities March 2014 * Funded by US EPA and Agency for Toxic Substances Disease Registry through AOEC Disclosures None

Adverse Childhood Experience • Household dysfunction, M c m c o abuse and neglect in e o o o n childhood a ‐ r n s Associated with n b d • Adult heart, lung and i i liver disease as well as d t other chronic i conditions (such as cancer, diabetes, mental health) Anda ‐ Eur Arch Psychiatry Clin Neurosci (2006) 256 : 174–186

Neuropsychiatric Symptoms of Chemical Exposures Symptom Carbon TCE Lead Mercury disulfide Depression X X X X Anxiety X X X X Mania X X X X Violence X X X X Concentration X X X X Dementia hallucinations X X X Memory loss X X X X paranoia X X X Mood lability X X X X Adapted from Brown Psychiatric Clinics of NA 2007 Traits/Abilities vs. Clinical Syndromes Trait/Ability Clinical Syndrome  Attention ability  Impulsivity  ADHD  Executive function  Learning disabilities  Memory  Asperger ’ s syndrome  Social adjustment  Autism  Reading / verbal skill

Traits/Abilities vs. Clinical Syndromes Trait/Ability Clinical Syndrome Quantitative, dimensional Qualitative, categorical Objective tests Clinical judgment Animal models (subjective) Apply to “ normal ” No animal models populations Different from “ normal ” Definable criteria Variable diagnostic criteria Useful research tools Provide management strategies Greenland Snow and Ice Lead 160 15 140 Pb 120 (pg/gm) ice core 100 80 mean toddler 60 blood 2 40 lead 20 0 -5766 -2000 1773 1805 1841 1890 1915 1949 1959 1974 1988 1992 1999 Derived from Candelone Et Al. 1995 J of Geophysical Research Vol.100 No. D8 and CDC, NHANES 2 and 3

The Significance of Small Effects: The Population Perspective Effects of A Small Shift in IQ Distribution mean 100 6.0 million 6.0 million ”Intellectual Disability" "gifted" 40 60 80 100 120 140 160 I.Q . 70 130 In Harm’s Way Greater Boston PSR 5 Point Decrease in Mean IQ mean 95 57% INCREASE 9.4 million 2.4 million ”Intellectual Disability" "gifted" 40 60 80 100 120 140 160 In Harm’s Way I.Q. Greater Boston PSR 70 130 Based on B Weiss

F ig. 1. B ox plots of the estimated 4th-grade reading E O Gscores from quantile regression models (N=57,678). Miranda et al 2009 Miranda et al 2009

LEAD Cognitive and Behavior Traits Lead at low levels: Interact with protein kinase C • Stimulate transmitter release ADHD • Disconnected from stimuli Impulsivity, distractability Hyperactivity, conduct Executive function, social Mimics Calcium skills • Blocks Ca channels critical LD to signal transmission Reading, math Word/pattern recognition • Result synapses that survive Other pruning are more random Anti ‐ social, aggressivity, fine motor • Altered architecture may not be something you see Illustration from wikipedia open source CDC finds BPA in 92% of Americans children>adults • BPA acts as a weak estrogen • Animals – Prenatal exposures lead to changes in behavior including hyperactivity, aggression, impaired learning • Human – Prenatal Exposure associated Over 50% of canned goods on US market shelves with increased externalizing are lined with BPA resin. It is not possible to behavior* identify the BPA lining via visual inspection. – Girls > boys : Photo: creative comons Wikipedia *Braun JM et al., 2009

Synaptic plasticity Dendritic spine 1000s per dendrite • Input from neurons LadyofHats Neuro ‐ chemical foundation of learning, memory, motivation • Rapidly changing in response to environment Estradiol rapidly increases CA1 pyramidal cell dendritic spine synaptic density • deficiencies related to neuro ‐ degenerative disorders and age ‐ related cognitive deficits? • Sexually dimorphic Diagrams Wikipedia public domain BPA – environmental estrogen prenatal exposure adult effect • Prenatal BPA “completely abolishes” estrogen ‐ activated hippocampal spine synapse formation at levels less than EPA ref dose (in female primates) – Similarly, in males interferes with testosterone synaptic response (rats) • Associated with increased anxiety, disorders of mood and cognition (rodents) Rubin, Endocrinology 06

Interventions Matter • 20 people/five families • Changed from canned/packaged food to none • Change in BPA and MEHP levels Rudel et al., 2011 Environmental Health Perspectives 17 Chlorpyrifos Impacts Neurodevelopment • Detected in >64% of maternal and newborn blood samples • Follow up at 3 yrs. for 189 children • Highly exposed – Delays in psychomotor and mental developmental indexes (Bayley) • PDI delays 5 times as great (MDI 2.4 times) • Symptoms ADHD and PDD significantly more likely (child behavior checklist) • Declines in working memory and full scale IQ at age 7 Rauh et al. Pediatrics 20 06 Rauh et al., EHP 2011

Chlorpyrifos has Measurable Impact on Brain Structure (non ‐ occupational) Brain anomalies in children exposed prenatally to a common organophosphate pesticide, Rauh et al., PNAS 2012 Regional enlargements of the cerebral surface (primarily underlying white matter) • Posterior middle temporal, inferior postcentral gyri bilaterally – Attention and receptive language • Superior frontal gyrus, superior temporal gyrus, cuneus, and precuneus – Social cognition • Gyrus rectus (related orbitofrontal regions) – Reward, emotion, and inhibitory control • L superior frontal gyrus (dorsal and mesial surfaces) – Executive function

Genetics = Gene + Expression Epigenetics Wikipedia commons Mother high licker groomer pup Increased Serotonin Demethylation tone of GR exon 1 Deacetylation of histones around GR less methylation GAD1 Increased NGF1 ‐ A activity exploratory, less fearful hippocampus Permanent and stress reactive more increase in GR expression in cognitively intact in old hippocampus age. Adult High hippocampal GR levels Champagne and Meany, Behavioral Neuroscience 2007 High licker groomer behavior Champagne et al., Journal Neuroscience 2008 Zhang et al, Journal Neuroscience Sept. 2010

Phenotypes maintained in next generation without manipulation of housing, etc. 3 rd generation Postnatal Offspring Maternal environment LG type LG type (standard housing) isolated low LG low LG Licker groomer Standard or Standard or LG LG enriched Low LG enriched LG LG Champagne and Meany, Behavioral Neuroscience 2007 Champagne et al., Journal Neuroscience 2008 Zhang et al, Journal Neuroscience Sept. 2010 Impacts on HPA System Non ‐ licker groomer Licker groomer Glucocorticoid Receptor GR Hippocampus Hippocampus Hypothalamus Hypothalamus CRF Pituitary Pituitary ACTH Adrenals Adrenals Glucocorticoids Glucocorticoids

Bullied Monozygotic Twins: More frequent, severe experience = lower cortisol secretion Oullert ‐ Morin J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(6 Bullied Monozygotic Twins Have Blunted Cortisol Response to Stress Psychosocial stress test Oullert ‐ Morin J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(6):

Higher Perceived Social Standing Of Parents Predicts Amygdala Reactivity to Angry Faces Potential Embedding of Parental Social Standing, Gianaros et al. SCAN 2008 Prenatal Stress – Effects in Adult Female Offspring • Exposures – Relationship hardship (eg. Divorce) – Death/severe illness of someone close – Severe financial, car accident, refugee • Impacts – Altered HPA axis response (Trier Social Stress and ACTH stimulation) – Bias to Th2, IL ‐ 4, IFN –gamma, IL6, IL10 production Entringer et al Dev Psychobiol 2008 Entringer et al Hormones and Behavior, 2009

Allostasis – active process for adaptation (brain – body) Limbic Plasticity effected by • Parental resources • Education Allostasis • Exposures/nurturance Neuroendocrine Allostatic Immune load Autonomic biomediators Adaptation Costs: metabolic, cardiovascular, immune, behavioral dysregulation Adapted from McEwen and Gianaros, 2010 Neurobiological Underpinnings of Resilience and Vulnerability Positive Positive Tolerable Tolerable Toxic Stress Toxic Stress Stress Stress Stress Stress Chaos, abuse, Chaos, abuse, Exhilarating Exhilarating Adverse life events Adverse life events neglect neglect challenge/outcome challenge/outcome Poor emotional and Poor emotional and social support social support Mastery/control Mastery/control BUT BUT Negative effect on Negative effect on brain architecture brain architecture Good social and Good social and Good self esteem Good self esteem emotional support emotional support Early life adversity Early life adversity Karatsoreos and McEwen, Resilience and Vulnerability: A neurobiological perspective F1000 Prime Reports 2013 http://f1000.com/prime/reports/b/5/13