Developmental Toxicology of EDCs: Learning & Memory - PDF

LECTURE-3 Developmental Toxicology of EDCs: Effects on Learning and Memory and Neurocognitive Disorders Sakhila K. Banu, PhD., Professor Endocrine Toxicology VIBS 422/622: ENDOCRINE TOXICOLOGY  Neurocognitive disorders Parkinsons...

LECTURE-3 Developmental Toxicology of EDCs: Effects on Learning and Memory and Neurocognitive Disorders Sakhila K. Banu, PhD., Professor Endocrine Toxicology VIBS 422/622: ENDOCRINE TOXICOLOGY  Neurocognitive disorders Parkinsons Alzheimers Rachel Carson’s Silent Spring Arsenic in rice PESTICIDES  Timeline for Endocrine Disruptors 1874 DDT synthesized 1881 PCB synthesized 1930-77 Widespread PCB use in transformers 1938 DES synthesized 1942-72 Widespread DDT application in malaria control & agriculture 1941-54 FDA & USDA: approved DES use in humans & animals 1959 DES produces cancer in experimental animals 1962 Publication of Silent Spring by Rachel Carson 1972 EPA bans DDT, FDA warnings on DES in pregnant women 1977 EPA bans PCBs 1979-95 Meetings & publications on estrogens in the environment 1995 EPA endocrine disruptor workshop; NAS/NRC panel meets 1996 Our Stolen Future, Colborn, Dumanoski & Myers, published; FQPA passed & Safe Drinking Water Act amended 1998 International Conference on Endocrine Disruptors, Kyoto 1999 NRC report, Hormonally Active Agents in the Environment  Stages of Prenatal and Postnatal Organ Development Early Prenatal Mid Late Prenatal Postnatal Central nervous system (3wks - 20 years) Ear (4-20 wks) Kidneys (4-40 wks) Heart (3-8) Limbs (4-8) Immune system (8-40 wks; competence & memory birth-10yrs) Skeleton (1-12 wks) Lungs (3-40 wks; alveoli birth-10yrs) Reproductive system (7-40wks; maturation in puberty) Week 1-16 Week 17-40 Birth – 25 years Sensitive windows of development: Each tissue has several windows of development. Certain window(s) are more sensitive or susceptible window for the effects of EDCs. Notice that some tissues continue developing after birth and into infancy and childhood, providing a longer window for exposures to EDCs. Source: Altshuler, K; Berg, M et al. Critical Periods in Development, OCHP Paper Series on Children's Health and the Environment, February 2003. 7 weeks 12 weeks  Children’s Health and Toxic Chemicals: What We Know  Children are surrounded by a large and number of EDCs.  Many of the chemicals to which children are at risk of exposure have not been tested for their possible developmental toxicity.  Children are heavily exposed and more vulnerable to many EDCs than adults.  EDCs are detectable in most American children's bodies, even in newborn infants.  Decreased ability to detoxify many EDCs  Heightened biological vulnerability – eg., thalidomide, DES, fetal alcohol syndrome  More years of future life Justify why/how children are vulnerable to EDCs more than the adults? The Central Question in Pediatric Environmental Health: What is the Evidence that Toxic Chemicals in the Environment Cause Disease in Children? Why Are Children Especially Vulnerable to Toxic Chemicals?  Thalidomide – 1960s drug developed as tranquilizer or sleeping medicine  In 1961, Dr. McBride, Australian obstetrician began to associate this “so-called” harmless compound with severe birth defects in the babies he delivered.  In July of 1962, FDA inspector Frances Kelsey, stopped the drug’s approval within the United States despite pressure from the pharmaceutical company and FDA supervisors.  Dr. Kelsey felt the application for thalidomide contained incomplete and insufficient data on its safety and effectiveness. Frances Oldham Kelsey, Who Saved U.S. Babies From Thalidomide, Dies at 101 (08-07-2015).  The Hero of the FDA Frances O. Kelsey born on Vancouver Island, British Columbia, in 1914. She earned a master's degree from McGill University in Montreal at age 20 Complete both an M.D. and Ph.D. in pharmacology at the University of Chicago. https://history.howstuffworks.com/historic al-figures/frances-kelsey-thalidomide.htm Describe how Frances Kelsey saved American children from the thalidomide-induced birth defects? Most chemicals to which children are exposed have not been adequately tested for toxicity  350,000 + chemicals in commerce  ~5,000 are high production volume (HPV) chemicals - produced in quantities of 1 million pounds or more per year  No basic toxicity information is available on half of HPV chemicals  No information on developmental toxicity is available for 80% of HPV chemicals Define HPV chemicals.  What are Neural Pathways?  Neural Pathways are nerve fibers that carry information between different parts of the central nervous system (CNS).  Our brains have ten million such pathways and we can create new pathways in our brains.  Learning is the process for building these new pathways. Complex Pathways of Emotion and Motivation  Human Brain The Brain’s Vital Statistics Adult weight: about 3 pounds Number of neurons: 100,000,000,000 (100 billion)  Inside the Human Brain  The brain has billions of neurons, each with Neurons an axon and many dendrites.  To stay healthy, neurons must communicate with each other, carry out metabolism, and repair themselves. While learning: Neurons produce Neurotransmitters.  Learning requires neurons to make new links with other neurons 1 Dendrites (fibers) grow out of the neurons when you practice new skills (Fig.1) When two dendrites grow close together, a contact point is formed. A small gap at the contact point is called the synapse (Fig.2). Messages are sent from one neuron to another as electrical signals travel across the 2 synapse. When you practice something, the dendrites grow thicker with a fatty coating of myelin (Fig.3) The thicker the dendrites, the faster the signals travel. 3 With enough practice, the dendrites build a double connection (Fig.4) Faster, stronger, double connections last a very long time. You remember what you have learnt. 4 Thyroid hormone is critical for neuronal differentiation, migration, myelination, synaptogenesis and dendritic branching. What are the critical functions of thyroid hormone?  Dendritic segments of medium –sized pyramidal neurons. Left: Example of apical segment from a normal 7-year-old child. Right: Example of apical segment from a 12-year-old Prenatal development of the human brain profoundly retarded child. showing a series of embryonic and fetal (After Purpura, 1974.) stages. (Adapted from Cowan, 1979.)  Schematic representations of the pattern of neural migration along the radial glial cells (after Rakic, 1981). Migrating neurons leave the ventricular and sub- ventricular zones and travel to more superficial layers. En route they pass through the deeper neurons, which are already in place. * Thyroid hormone is critical for neuronal differentiation, migration, myelination, synaptogenesis and dendritic branching. Functions of TH in brain development. Postnatal development of human cerebral cortex around Broca’s area as taken from camera lucida drawings of Golgi-Cox preparations (from Conel, 1939–1967)  EDCs and Learning Disorders.  EDCs accumulating in the environment worldwide adversely affect or alter thyroid hormone (TH) levels.  Changes in TH can compromise brain development from conception on, resulting in learning disorders.  Studies conducted in the Great Lakes Basin provide a strong evidence that some EDCs (PCBs) act as thyroid hormone disruptors (THD).  PCBs exert their toxicity via alterations of TH function during development.  PCBs and dioxins are structurally related to TH; PCBs exert their neurotoxicity via interference with TH metabolism.  TH has profound effects on neurologic function in people of all ages.  Hypothyroidism during development caused by genetic factors or EDCs produces irreversible neurologic damage ranging from behavioral problems, impaired learning, and memory loss and gross mental retardation. Mention any four EDCs that can disrupt thyroid hormone and impair brain development. PBDE – Polybrominated Diphenyl ethers. Which hormone do these EDCs mimic the most?  PCBs can interfere with the action of TH during development at numerous stages, resulting in learning and memory disorders. Developmental articulation disorder: - Mispronunciation of speech sounds. Developmental expressive language Disorder: - Difficulty in expression. Developmental receptive language Disorder: Three broad categories - Difficulty in understanding. PCB (Polychlorinated biphenyl) :  USES: Coolants and fluids for transformers and capacitors, stabilizing additives in flexible PVC coatings of electrical wiring.  Higher chlorinated PCBs are associated with the neurological damage. EDCs such as PBDEs are known to affect TH levels. TH affects neuronal differentiation, migration, myelination, synaptogenesis and dendritic branching. PBDE - Polybrominated diphenyl ethers Stem cells differentiate to produce different types of nerve cells.  Thyroid Hormone Disruptors Can Cause Neurodevelopmental Disorders High-dose exposure can cause acute poisoning Exposure to EDCs during pregnancy to lower doses can cause: Small head circumference Low birth weight Developmental delays ADHD Developmental disorders, and autism Newborn Screening Normal  WHAT IS AUTISM? Very complex developmental disability. First described by Leo Kanner in 1943 as early infantile autism. “Auto” – children are “locked within themselves.” CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network  About 1 in 54 children has been identified with autism spectrum disorder (ASD) according to estimates from ADDM Network.  ASD is reported to occur in all racial, ethnic, and socioeconomic groups.  ASD is almost 5 times more common among boys (1 in 42) than among girls (1 in 189).  About 1 in 6 children in the US has a developmental disability, ranging from mild disabilities such as speech and language impairments to serious developmental disabilities, such as intellectual disabilities, cerebral palsy, and autism.  EDCs and autism  A nationwide study found a doubled autism risk among children of women exposed to high levels of particulate air pollution during pregnancy.  The association was strongest when the exposure occurred during the third trimester. The greater the exposure, the greater the risk.  The researchers saw no increased autism risk if the pollution exposure occurred after birth or before conception. The ten funded monitoring centers include:  Colorado Department of Public Health and Environment  Johns Hopkins University  Rutgers, The State University of New Jersey  The University of Wisconsin- Madison  University of Arizona  University of Arkansas for Medical Sciences  University of Minnesota  University of North Carolina at Chapel Hill  Vanderbilt University  Washington University in St. Louis Why should we care about Autism?  Why should we care about Autism? It is estimated that worldwide one in 160 children has an ASD. Prevalence in the U.S is estimated at 1 in 36 births (CDC, 2020) Over 5.4 million U.S. adults have a diagnosed autism spectrum disorder. Prevalence of autism in U.S. children increased by 119.4 percent from 2000 (1 in 150) to 2010 (1 in 68). (CDC, 2014) Autism is the fastest- growing developmental disability (CDC, 2008) or “different ability”. According to the CDC, children with autism can need anywhere between $17,000 and $21,000 per year in extra care compared to neurotypical kids. A majority of costs in the U.S. are in adult services – $175-196 billion, compared to $61-66 billion for children (Buescher et al., 2014) The U.S. cost of autism over the lifespan is about $2.4 million for a person with an intellectual disability, or $1.4 million for a person without intellectual disability. (Buescher et al., 2014) Autism Symptoms Usually high tolerance to pain Sensitive to certain lights, odors, sounds, textures Lack of communication and social skills Poor voluntary control of speech muscles Lack of eye contact Inability to connect emotionally  EDCs and Autism  Both ASD and ADHD typically are diagnosed during childhood, and their causes are not well understood.  Lead, methylmercury and PCBs are known to cause ASD and ADHD- Attention Deficit Hyperactivity Disorder.  The fetal period is the most critical period in development.  Brain development is regulated by THYROID HORMONES (TH)  TH are essential for normal embryonal and fetal neurogenesis.  EDCs are known to affect TH function in particular.  Disruption of THs by EDCs during specific time periods may have adverse effects on neurodevelopment. Lead Can Cause Neurodevelopmental Disorders  Principal source is lead paint and lead paint dust  Other sources – toys, imported dinnerware  15-20% of cases associated with home renovation  *Decreased IQ, shortened attention span, inability to concentrate, dyslexia and school failure  Any amount of lead is dangerous – No level is safe Lead Testing  Lead Cumulative occupational exposure ↑ cognitive impairment Shih 2007 2x risk Parkinson’s Coon 2006 Cumulative community exposure ↑cognitive impairment Shih 2006 Animal studies of early life exposure Late-life Alzheimer’s markers Basha 2005, Lahiri 2007 GABA – Gama Aminobutyric acid; inhibitory neurotransmitter – reduces CNS (central nervous system) excitability  TH-Receptor mutations Reduced GABAergic neurons Reduced GABA Hyppocampus & Amygdala control emotion and memory.  In mice with a mutation of the TH-Rα1, a reduced density of GABAergic neurons in the hippocampus (emotion & memory) is observed, which was accompanied by more depressive and anxious behaviour. GABA is an inhibitory neurotransmitter in the adult. During the embryonic and perinatal period, GABA is important for nerve cell proliferation, migration, differentiation, and synapse maturation. In children with AUTISM, dysfunction of GABAergic signaling is observed. What are the functions of GABA in children and adult brains? Describe the correlation between GABA and autism. Hippocampus: TRE 1. memory formation, 2. organization, and 3. storage. Bisphenol-A (BPA) & PCBs: 1. BPA inhibits GABAaR-mediated response. 2. BPA affects development of GABAergic and dopaminergic systems. 3. PCBs affect the GABAa response. 4. EDCs are risk factors for neurodevelopmental disorders through the modification of GABAergic systems. γ-Aminobutyric acid – GABA (regulating neural excitability) g-aminobutyric acid type A receptor - (GABAAR) Describe the connections between GABA-ergic system and EDCs. Mention two EDCs that affect GABA-ergic system:  BPA has been found in the urine of more than 93% of Americans tested.  BPA was first synthesized in 1891. Early evidence of its hormonal action came from animal experiments on rats carried out in the 1930s, but it was not until 1997 that the adverse effects of low-dose exposure on laboratory animals were first reported.  BPA is a synthetic estrogen widely used since the 1960s specifically to make polycarbonate plastic for plastics such as baby bottles. 1. What is the EDC found in  It's used to line metal cans such as soup cans, dental sealants cash register and eyeglasses as well as a coating for cash register receipts receipts? and hundreds of other household items. 2. In which year BPA was  BPA is an “endocrine disruptor” (EDC), linked to neurological synthesized first? defects, breast and prostate cancer, and heart disease & male infertility.  Campbell’s Soup company announced that they would be removing BPA from the inner lining of their soup cans.  In June 2009, researcher Dr. Bernard Weiss, a professor of Environmental Medicine and Pediatrics at the University of Rochester School of Medicine and Dentistry made a startling discovery.  He found that families living in Sweden who lived in homes with vinyl flooring–with poor ventilation–had higher incidences of children with autism.  Infants raised in bedrooms with vinyl or PVC flooring were twice as likely to be diagnosed with autism by age 5 than those with other types of flooring.  EDC in the vinyl and PVC are phthalates–the plasticizers found in consumer products, from bath toys and teethers to lotions and nail polish.  In homes with poor ventilation, Weiss suggested that phthalates in household dust which the infants inhaled in the course of day-to-day life. 1. Describe Dr. Weiss’ findings on autism and EDCs; 2. What is the EDC found in vinyl and PVC products? 3. Which neuro developmental disease in children was found to be higher when they live in homes with vinyl flooring–with poor ventilation?  Attention deficit hyperactivity disorder A neurological condition that involves problems with inattention and hyperactivity-impulsivity that are developmentally inconsistent with the age of the child. ADHD is a function of developmental failure in the brain circuitry that monitors inhibition and self-control. This loss of self-regulation impairs other important brain functions crucial for maintaining attention. Source: Identifying and Treating Attention Deficit Hyperactivity Disorder: A Resource for School and Home (2003). U.S. Department of Education. Phthalates in toys ADHD Current data – ADHD range from 3 to 10% of all school-age children. Resistance to thyroid hormone (RTH) is an autosomal disease - mutation in the human TH receptor-gene on chromosome three. Seventy percent (70%) of children with RTH also have ADHD. RTH mutation decreases IQ (on average 10-12 points lower than unaffected siblings); Abnormalities of myelin formation Language disorders Abnormalities of brain metabolism and brain morphology. Q: Describe Resistance to Thyroid Hormone (RTH) N Engl J Med 2012; 366:243-249  THs exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors.  The authors describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels.  Using whole-exome sequencing, the authors identified a mutation in a gene encoding thyroid hormone receptor alpha (THRα)  The observations are consistent with defective human TRα-mediated thyroid hormone resistance. Phthalates are endocrine disruptors. Health impacts of phthalates: early puberty, infertility & autism. Phthalates are produced at a rate of about one billion pounds per year. Some cosmetic industries are making $18 billion turn over. Concerns about phthalates have prompted both states and retailers to call for their removal from children’s products. Walmart, and Target first voluntarily removed phthalate-containing kids’ toys and teething products.  Attention deficit hyperactivity disorder A neurological condition that involves problems with inattention and hyperactivity-impulsivity that are developmentally inconsistent with the age of the child. ADHD is a function of developmental failure in the brain circuitry that monitors inhibition and self-control. This loss of self-regulation impairs other important brain functions crucial for maintaining attention. Source: Identifying and Treating Attention Deficit Hyperactivity Disorder: A Resource for School and Home (2003). U.S. Department of Education.  Association between EDCs, autism and ADHD De Cock et al., Acta Paediatr, 2012: Positive associations were found for Autism and exposure to hazardous air pollutants, pesticides and BPA. Increased risks of ADHD were found for exposure to PCBs, dialkyl phosphate (DAP) and chlorpyrifos (insecticides). BPA, polybrominated diphenylethers (PBDEs) and phthalates were positively associated with externalizing behavior (Externalizing behaviors: physical aggression, verbal bullying, relational aggression, defiance, theft and vandalism). Perinatal exposure to EDCs appears to be associated with autism and ADHD. Make a chart! List the EDCs that cause autism and ADHD. What are the EDCs that could increase autism? ANSWER: Bisphenol-A (BPA), phthalates, polychlorinated biphenyls (PCBs) and certain pesticides. Which EDCs are associated with externalizing behavior? BPA, polybrominated diphenylethers (PBDEs) and phthalates were positively associated with externalizing behavior  Association between EDCs, autism and ADHD An interesting study about farmers in Mexico: Subjects Compared: Use of pesticides on their crops vs. similar families who did not use pesticides. Objective: health and behavior of the children. Conclusion: Pesticides-exposed Children, 4-5 years of age had no ability to draw, hyperactive, less coordinated physically, and had increased incidence of illness, infections, compromised immunity. In utero exposure to several pesticides, lead, phthalate, methylmercury, PCBs, and dioxin, adversely affect the brain development and causes learning disabilities and ADHD. Prenatal exposure to EDCs – disrupts early brain development. Neuro-developmental toxicity in utero manifests as psychosocial deficits later in childhood. Prenatal phthalate exposure was associated with childhood social impairment in a multiethnic urban population. 1. What was the outcome of a study in children in Mexico who were exposed to pesticides? 2. In utero exposure to which EDCs were found to cause learning disabilities and ADHD? 3. Mention any 4 EDCs associated with learning disabilities and ADHD.  ADHD Statistics  3-5% of all U.S. school-age children are estimated to have this disorder.  5-10% of the entire U.S. population  Males are 3 to 6 times more likely to have ADHD than are females.  At least 50% of ADHD sufferers have another diagnosable mental disorder.  Prevalence  3-5 % of School Age Children (1:25)  2 % of Adolescents (1:50)  0.8 % of 20 year-olds (1:125)  0.2 % of 30 year olds (1:500)  0.05 % of 40 year olds (1:2000)  Diagnosing ADHD 1. Lacks attention to detail; makes  Inattentiveness: careless mistakes 2. has difficulty sustaining attention 3. doesn’t seem to listen Has a minimum of 6 4. fails to follow through to finish symptoms regularly for projects the past six months. 5. has difficulty organizing tasks 6. avoids tasks requiring mental effort Symptoms are present at 7. often loses items necessary for abnormal levels for stage completing a task of development 8. easily distracted 9. is forgetful in daily activities Diagnosing ADHD 10. Fidgets or squirms excessively 11.leaves seat when inappropriate 12. runs about/climbs extensively  Hyperactivity/ when inappropriate Impulsivity: 13. has difficulty playing quietly 14. often “on the go” or “driven by a motor”  Has a minimum of 6 symptoms regularly 15. talks excessively for the past six 16. blurts out answers before months. question is finished 17. cannot await turn  Symptoms are 18. interrupts or intrudes on present at others abnormal levels for stage of development  ADHD and the Human Brain Portions of brain’s frontal lobe are responsible for “Executive” functions: Consolidating information from other areas of the brain “Considers” potential consequences and implications of behaviors Puts “brakes” on (inhibits) impulsive reactions Initiates appropriate response to environment  Brain Functions : Frontal Lobe Location: Functions in the typical Behind the forehead brain: Motivation Controls attention Judgment Problem solving Decision making Guide/control social behavior Emotional responses/control Expressive language Motor integration Voluntary movements  Comparison of normal brain (left) and ADHD and the Human Brain brain of ADHD patient.  Diminished arousal of the Nervous System  Decreased blood flow to prefrontal cortex and pathways connecting to hippocampus and amygdala (emotion and memory).  PET scan shows decreased glucose metabolism throughout the brain.  ADHD and the Human Brain (Contd.)  Research suggests that in children with ADHD, these “executive” areas of the brain are under- active.  Therapeutically increasing the activity level in these areas of the ADHD brain decrease behavioral symptoms.  This is the logic behind using Stimulant medications as a first line treatment for the disorder. Increase both norepinephrine and dopamine in the prefrontal cortex. These drugs are used to treat ADHD.  The Limbic System The limbic system is a complex set of structures that lies on both sides of the thalamus, just under the cerebral cortex. It mainly includes the hypothalamus, the hippocampus, the amygdala. It is primarily responsible for our emotional life, and formation of memories. **** What are the 3 parts of the brain where the blood flow is affected in ADHD? Frontal lobe; hippocampus and amygdala (limbic system)  What causes ADHD?  Underlying cause of these Dopamine, differences is still unknown; norepinephrine, and  Strong evidence of genetic epinephrine are known as component catecholamines.  Predominant theory: Catecholamine neurotransmitter dysfunction or imbalance  decreased dopamine and/or norepinephrine uptake in brain  theory supported by positive response to stimulant treatment  Use of drugs/alcohol or exposure to EDCs during pregnancy  Catecholamines include three well known hormones: Epinephrine (adrenaline), Norepinephrine (noradrenaline), and Dopamine. Therapeutic agents for ADHD are psychostimulants such as methylphenidate (Ritalin) and amphetamine, drugs that increase both dopamine and norepinephrine levels in the brain.  Pesticides  Parkinson’s Disease  Human studies showed increased risks for PD in humans exposed to pesticides  Animal models with PD had damaged dopaminergic neurons in striatal region of brain.  Prenatal EDC exposure “primes/reprograms” the brain, increasing adult susceptibility.  Cognitive decline/dementia  Low level/dose fungicides in vineyards 3.5x poor attention, poor memory.  Occupational exposure to fungicides in men associated with 2x risk of developing Alzheimer's.  Eat USDA-Certified Organic   Prevention in the Home - The Value of Eating Organic “Consumption of organic produce appears to provide a relatively simple way for parents to reduce their children's exposure to pesticides.” “Families who consume an organic diet can reduce their pesticide exposure levels by 90% as compared to families who consume conventional supermarket food.”  Prevention in the Community  Integrated pest management  Pesticide neighbor notification laws  Green schools  Plant trees  Maintain parks and play spaces  Prevention Works Example: The removal of lead from gasoline  In 1976, US EPA began phase-out of lead from gasoline Lead use in gasoline declined from 1976 through 1980 Lead used In gasoline 110 100 90 (1000 tons) 80 Gasoline lead 70 60 50 40 30 1975 1976 1977 1978 1979 1980 1981 Year Annest, Pirkle, Makuc, et al., Chronological trend in blood lead levels between 1976 and 1980. NEJM 1983; 308;1373-7. Environmental Disease is Preventable Declining Blood Lead Levels in the U.S. [1976–1999] 18 (µg/dL) 16 14 Blood Lead Levels 12 10 8 6 4 2.7 2.0 2 0 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 Year