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Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop (2020)

Chapter: 4 Chemical Toxicants as Drivers of Abnormal Neurodevelopment and Neurodegeneration

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Suggested Citation:"4 Chemical Toxicants as Drivers of Abnormal Neurodevelopment and Neurodegeneration." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Suggested Citation:"4 Chemical Toxicants as Drivers of Abnormal Neurodevelopment and Neurodegeneration." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Page 30
Suggested Citation:"4 Chemical Toxicants as Drivers of Abnormal Neurodevelopment and Neurodegeneration." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
×
Page 31
Suggested Citation:"4 Chemical Toxicants as Drivers of Abnormal Neurodevelopment and Neurodegeneration." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
×
Page 32
Suggested Citation:"4 Chemical Toxicants as Drivers of Abnormal Neurodevelopment and Neurodegeneration." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
×
Page 33
Suggested Citation:"4 Chemical Toxicants as Drivers of Abnormal Neurodevelopment and Neurodegeneration." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
×
Page 34
Suggested Citation:"4 Chemical Toxicants as Drivers of Abnormal Neurodevelopment and Neurodegeneration." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
×
Page 35
Suggested Citation:"4 Chemical Toxicants as Drivers of Abnormal Neurodevelopment and Neurodegeneration." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
×
Page 36
Suggested Citation:"4 Chemical Toxicants as Drivers of Abnormal Neurodevelopment and Neurodegeneration." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
×
Page 37
Suggested Citation:"4 Chemical Toxicants as Drivers of Abnormal Neurodevelopment and Neurodegeneration." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
×
Page 38

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

4 Chemical Toxicants as Drivers of Abnormal Neurodevelopment and Neurodegeneration HIGHLIGHTS • Early life exposure to neurotoxicants can impact brain devel- opment in later life, possibly by reducing an individual’s ability to respond to neurological insults (Bellinger). • Childhood lead exposure has cascading downstream effects on multiple behavioral domains and quality of life (Bellinger). • Exposure to lead and polychlorinated biphenyls may increase a child’s risk of developing attention-deficit hyperactivity dis- order (Richardson). • Studies in mouse models and humans indicate that the pyrethroid insecticide deltamethrin may be associated with increased hyperactivity and impulsivity (Richardson). • Exposure to the pesticides Paraquat and Maneb is associ- ated with an increased risk of Parkinson’s disease (PD), which appears to be modified by function of the dopamine trans- porter (Ritz). • There are variants of paraoxonase that differ in their ability to detoxify organophosphate pesticides that increase risk of developing PD (Ritz). • Individuals exposed to traffic-related air pollution are at a much more increased risk of PD when they are carriers of a variant in an inflammatory gene interleukin-1β (Ritz). 29 PREPUBLICATION COPY—Uncorrected Proofs

30 ENVIRONMENTAL NEUROSCIENCE • Exposure to air pollution and cigarette smoke may increase the risk of age-related brain volume loss and cognitive impairment (Finch). • Multiple studies show that both heritability and environmental exposures—particularly chlorinated pesticides—are implicated as causes of amyotrophic lateral sclerosis (Feldman). NOTE: These points were made by the individual speakers identified above; they are not intended to reflect a consensus among workshop participants. Early life exposure to neurotoxicants can impact a child’s develop- mental trajectory in multiple and sometimes unexpected domains, said David Bellinger. It can affect how well an individual is able to respond to neurological insults even later in life, possibly by reducing resilience or cognitive reserve, which may provide a link between neurodevelopment and neurodegeneration, he added. Bellinger noted, however, that effects at the individual level may be small and affected by many other factors, including the extent and time course of the exposure. Thus, in order to estimate the societal impact of neurotoxicant exposure, studies must look at the popula- tion rather than individual level, he said. Bellinger also noted that the effects of neurotoxicants on brain devel- opment have been recapitulated in animal models. For example, a study in rats showed that animals that were exposed to lead recovered more poorly to an induced brain injury (Schneider, 2007). NEURODEVELOPMENT, AUTISM, AND ATTENTION- DEFICIT HYPERACTIVITY DISORDER As discussed in Chapters 2 and 3, exposure to neurotoxicants such as lead and pesticides has been associated with increased rates of neurodevel- opmental disorders such as autism and attention-deficit hyperactivity disor- der (ADHD). With about 1 in 68 individuals affected by autism, according to Mark Zylka, this has become a major health problem. The linkages between environmental exposures and autism have already been discussed extensively; here we explore in more detail the association with ADHD. In addition to effects of lead exposure on IQ, which was discussed in Chapter 2, lead exposure has also been reliably linked to other domains of neurodevelopment, such as attention, executive function, and impulse control, said Bellinger (Braun et al., 2006). Children with higher levels PREPUBLICATION COPY—Uncorrected Proofs

CHEMICAL TOXICANTS AS DRIVERS 31 of lead exposure in early life do less well in school, are more likely to be classified as learning or behaviorally exceptional, and less likely to be considered advanced or intellectually gifted (Miranda et al., 2007, 2010). Bellinger added that the impact of the same level of lead exposure on school achievement and behavior was considerably greater for children already at risk of having these problems due to low socioeconomic status and low parental education levels. As adults, children with higher blood lead levels achieve lower socioeconomic status (Reuben et al., 2017). Putting this all together, said Bellinger, suggests that childhood lead exposure has cascading downstream effects with real consequences on quality of life, including, for some children, greater criminal activity later in life (Boutwell et al., 2017; Coulton et al., 2020; Emer et al., 2020; Nkomo et al., 2017). Bellinger acknowledged that the effect sizes are small at an individual level, but noted that on a population level, lead has a huge impact on cumulative IQ loss and thus is responsible for a substantial loss of societal intellectual resources (Bellinger, 2012). Difficulties with attention and impulse control manifest in many chil- dren as a diagnosis of ADHD. Indeed, according to Jason Richardson, ADHD affects about 8 to 12 percent of children in the United States, with boys diagnosed about three to four times as often as girls. Like other neu- rodevelopmental and neurodegenerative disorders, ADHD has a strong genetic basis, but is also associated with multiple other factors, including environmental exposures, he said. In a recent meta-analysis of twin stud- ies, the heritability of ADHD was estimated to be more than 70 percent (Faraone and Larsson, 2019), said Richardson, but factors such as low birthweight, perinatal hypoxia, and lead exposure are also associated with increased risk of ADHD. Environmental toxicants such as polychlorinated biphenyls (PCBs) may also be linked to ADHD, but have been less well studied, he added. Richardson and colleagues used a gestational lactational exposure par- adigm to study the behavioral and neurobiological effects of the pyrethroid insecticide deltamethrin in mice (Richardson et al., 2015). Using doses from 4- to 40-fold lower than the “no observable adverse effect level” estab- lished by the Environmental Protection Agency, pregnant mice were fed deltamethrin in peanut butter starting at gestation day 6 through weaning on postnatal day 22. At 6 weeks of age (equivalent to early adolescence in humans), a dose-related increase in locomotor activity was observed in males, which was attenuated by treatment with methylphenidate. Male mice also scored significantly higher on a task assessing impulsivity, said Richardson. The behavioral findings in mice were recapitulated in a sepa- rate human study, where pyrethroid pesticide exposure in children (assessed by measuring urinary levels of a pyrethroid metabolite) was shown to be PREPUBLICATION COPY—Uncorrected Proofs

32 ENVIRONMENTAL NEUROSCIENCE associated with ADHD, particularly in boys with hyperactive-impulsive symptoms (Wagner-Schuman et al., 2015). In an effort to understand the mechanism underlying the effect of pyre- throids on locomotor activity, Richardson and colleagues showed signifi- cantly increased locomotor activity in male mice exposed to deltamethrin and given a dopamine-1 (D1) receptor agonist. This increase in activity was reduced to control levels by administration of a D1 receptor antagonist. Using receptor autoradiography, they also demonstrated increases in D1 receptors in the nucleus accumbens of these mice, a brain region associated with impulse control and substance abuse (Richardson et al., 2015). They also observed increases in D1 and dopamine transporter mRNA, which per- sisted through 1 year of age and suggested a possible epigenetic effect, said Richardson. His lab has proceeded to show in cell culture that knocking down DNA methyltransferase increases D1 receptor mRNA, which further supports an epigenetic mechanism. NEURODEGENERATIVE DISORDERS: ALZHEIMER’S DISEASE, PARKINSON’S DISEASE, AND AMYOTROPHIC LATERAL SCLEROSIS A complex combination of genetic and environmental factors is thought to contribute to the pathogenesis of neurodegenerative disorders such Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), although what initiates the process of neurodegen- eration may be different from what drives it subsequently, said J. Timothy Greenamyre. Indeed, several of the mechanisms associated with neuro- toxicant exposure that were discussed in Chapter 3, including effects on synaptic function and endolysosomal pathways, oxidative stress, epigenetic changes, and cellular mosaicism, have been linked to neurodegenerative disorders. Greenamyre and Jason Cannon have suggested that common mechanisms may underlie most neurodegenerative disorders (Cannon and Greenamyre, 2011). Alzheimer’s Disease Accumulating data indicate that exposure to high levels of air pollu- tion increase the risk for all-cause dementia, said Andrew Petkus (Peters et al., 2019). Indeed, according to Caleb Finch, ARCO Professor and Wil- liam F. Kieschnick Chair in the Neurobiology of Aging at the University of Southern California, half of individual AD risk may be environmental (Gatz et al., 2006). Finch and Alexander Kulminski of the Duke Popula- tion Research Institute and Duke’s Biodemography Research Unit, recently proposed an AD exposome as a framework for understanding endogenous PREPUBLICATION COPY—Uncorrected Proofs

CHEMICAL TOXICANTS AS DRIVERS 33 and exogenous environmental factors that may contribute to AD as well as gene–environment interactions (Finch and Kulminski, 2019). Finch’s research focuses on the role of air pollution and cigarette smoke as risk factors for accelerated aging and AD. He calls both of these “sterile gerogens”—sterile because they are toxicants rather than pathogens, and gerogens because they accelerate aspects of aging processes. Both air pollu- tion and cigarettes shorten life span by about 5 to 10 years and accelerate disease of aging, said Finch. He noted that both contain fine and ultrafine particles that are deposited in the lungs as well as incompletely burned carbon particles, carcinogens, neurotoxicants, polyaromatic hydrocarbons, and the toxic metals iron and lead. In the Vietnam Era Twin Study of Aging (VETSA), cigarette smoking was associated in a dose-dependent manner with brain volume loss (Prom-Wormley et al., 2015); and in the Women’s Health Initiative Memory Study (WHIMS), exposure to particulate matter from air pollution was associated with accelerated loss of both gray and white matter as well as with a decline in episodic memory (Casanova et al., 2016; Younan et al., 2020). Gene–environment interactions have been demonstrated as well, said Finch. In the Washington Heights-Inwood Columbia Aging Project (WHICAP) cohort, higher concentrations of air pollution were associated with more rapid cognitive decline, particularly in carriers of the APOE4 allele, which is the strongest genetic risk factor for AD (Kulick et al., 2020). Finch’s lab is exploring in mouse models the mechanisms underlying this association. In APOE4-carrying mice, they have shown that oxidative stress from exposure to nano-sized, traffic-related air pollution particulate matter (nPM) results in accelerated production of the amyloid-β protein by reor- ganizing key enzymes involved in processing the amyloid precursor protein (Cacciottolo et al., 2020). They have also demonstrated that the effects of nPM on gene transcription differ depending on sex as well as APOE allele (Haghani et al., 2020). Finch also noted “remarkable overlap” in the developmental impact of air pollution, cigarette smoke, and lead exposure (Finch and Morgan, 2020). Synergistic effects from exposure to cigarette smoke and air pollu- tion also have been demonstrated for multiple morbidities, including cogni- tive aging, he said (Forman and Finch, 2018). The oxidative stress and inflammation triggered by air pollution con- tribute to the accumulation of hallmark neuropathologies associated with AD, including amyloid β and tau tangles, brain atrophy, cognitive decline, and eventually dementia, said Petkus. A decline in episodic memory is typically the first cognitive sign of AD, he said (Petkus et al., 2020). Pet- kus added that air pollution induces variable effects on different aspects of episodic memory; for example, fine particulate matter (referred to as PM2.5) appears to be more strongly associated with the encoding aspect PREPUBLICATION COPY—Uncorrected Proofs

34 ENVIRONMENTAL NEUROSCIENCE FIGURE 4-1  Paraquat and maneb are both widely used in the Central Valley of California. SOURCES: Presented by Beate Ritz, June 25, 2020; California Department of Pes- ticide Regulation. PREPUBLICATION COPY—Uncorrected Proofs

CHEMICAL TOXICANTS AS DRIVERS 35 FIGURE 4-1  Continued PREPUBLICATION COPY—Uncorrected Proofs

36 ENVIRONMENTAL NEUROSCIENCE of episodic memory compared to retrieval and long-term recall aspects, suggesting that it may be impacting brain regions associated with learning new material versus long-term recall (Petkus et al., 2020). However, imag- ing studies using structural MRI to assess brain atrophy have produced mixed findings, he said. Parkinson’s Disease Pesticides have long been linked to onset of PD, although until recently it has been difficult to determine which specific pesticide exposures may be associated with PD, said Beate Ritz. For the past two decades, Ritz and Jeff Bronstein, director of the Movement Disorders Program at the University of California, Los Angeles, have collected biosamples and data on pesticide use in California in the Parkinson’s Environment and Gene Study. By combining data on the timing and geo-location of pesticide application with lifelong address data, they have been able to determine long-term pesticide exposure across a large population. These modeled exposures have been validated against biomarkers of exposure (Paul et al., 2018b; Ritz and Costello, 2006). For example, they estimated levels of two pesticides—paraquat and maneb (see Figure 4-1). They also determined that when these two agents come together, there is an approximately 75 percent increase in risk of develop- ing PD (Costello et al., 2009). The results of their study supported earlier work indicating that exposure to paraquat and maneb increase the risk of PD amongst those who carry risk alleles in the dopamine transporter (DAT) by as much as five-fold, said Ritz (Kelada et al., 2006; Ritz et al., 2009). Ritz described another way that gene–environment interactions con- tribute to the development of PD. Organophosphates (OPs) are another widely used class of pesticides that have been linked to an increased risk of PD. Ritz and colleagues have shown that this risk is affected by vari- ants in the gene for paraoxonase (PON1), an enzyme that detoxifies OP pesticides. These gene variants determine how fast a person metabolizes OPs: those who are slow metabolizers have a much greater increased risk of developing PD, said Ritz (Lee et al., 2013). For example, people who frequently use OPs in their households and are slow metabolizers have about 2.5-fold increased risk of developing PD compared to people who are slow metabolizers, but do not use OPs frequently (Narayan et al., 2013). In other words, said Ritz, genetic susceptibility alone does not increase the risk of PD in the absence of exposure. She added that the combination of PON1 slow metabolizers and OP exposure also contributes to a decline in cognitive function over time, both in populations with ambient residential and occupational exposures from agricultural applications in a population of older Mexican Americans (Paul et al., 2017, 2018a). PREPUBLICATION COPY—Uncorrected Proofs

CHEMICAL TOXICANTS AS DRIVERS 37 Ritz and colleagues have also been investigating the impact of air pol- lution on the development of PD. A study in Denmark combined sophis- ticated traffic-related exposure data over a 40-year period with incidence of PD and showed that people highly exposed to traffic had an increased risk of PD (Ritz et al., 2016). They also demonstrated a gene–environment interaction by showing that those exposed to traffic-related air pollution who also carried a polymorphism in the interleukin-1β gene, which is known to increase inflammatory responses in the brain, was associated with a three-fold increased risk of PD in those with high exposure to traffic (Lee et al., 2016). Amyotrophic Lateral Sclerosis ALS is a progressive, incurable degenerative disease of the motor neu- rons in the brain, brainstem, and spinal cord, which has a prevalence in North America of approximately 3.5 per 100,000. Eva Feldman, the Rus- sell N. DeJong Professor of Neurology and director of the ALS Center of Excellence at the University of Michigan, said that while heritability clearly plays a role, multiple studies show there is an environmental component as well. Scientists believe that in ALS as in other neurodegenerative diseases, a clear genetic load or genetic predisposition combines with aging and cell damage and with environmental exposures to initiate a self-perpetuating decline to death, she said (Al-Chalabi and Hardiman, 2013). Michigan is a hotspot with a high prevalence of ALS cases, said Feld- man, which she suggested may result from the large number of uncleaned Superfund sites in the state (see Figure 4-2). Against this backdrop, Feldman has been collaborating with Stephen Goutman, director of the Pranger ALS Clinic at Michigan Medicine, on a project designed to identify environmental and occupational toxic expo- sures, the sources of these exposures, and the effects of these exposures on the metabolome of 156 individuals with ALS compared to 128 controls. Using whole blood gas chromatography and mass spectrometry, they mea- sured levels of three groups of chemicals: chlorinated pesticides, brominated flame retardants, and PCBs. In addition to being highly toxic, Feldman noted that these chemicals are also highly persistent in the environment, sometimes lasting for decades before dissipating. Their results, published in 2016, reported an association between persistent environmental pollutants and ALS. Chlorinated pesticides were associated with the greatest risk of developing ALS, said Feldman (Su et al., 2016). Because they also saw that organic pollutants were highly correlated with each other in terms of case exposure, Goutman, Feldman, and col- leagues collaborated with Stuart Batterman and Bhramar Mukherjee from the University of Michigan School of Public Health to assess exposures to PREPUBLICATION COPY—Uncorrected Proofs

38 ENVIRONMENTAL NEUROSCIENCE FIGURE 4-2 Identifying environmental risk factors for amyotrophic lateral scle- rosis in Michigan. The map on the left depicts age-adjusted death rates for motor neuron disease, while the map on the right indicates locations of major emissions of toxic substances. Note the substantial overlap and the particularly high prevalence near the Leelanau Peninsula (red arrows), which has an extremely toxic uncleaned Superfund site. SOURCE: Presented by Eva Feldman, June 25, 2020. multiple pollutants. Using a mathematical model, they showed that the cumulative environmental risk score for mixtures of pollutants in ALS patients was more than seven times that of controls. They also showed that exposure to persistent organic pollutants influence survival. Individuals with the lowest environmental risk scores survived twice as long as those with the highest scores, said Feldman (Goutman et al., 2019). Feldman and colleagues, led by Manish Aurora at Mount Sinai in New York City have also explored how exposures during childhood and ado- lescence affect ALS risk. Using laser analysis of metals in teeth, this joint collaboration showed that 11 metal toxicants present in teeth—including zinc, chromium, and manganese, but not lead—were clearly associated with increased ALS risk (Curtin et al., 2020; Figueroa-Romero et al., 2020). Feldman added that metabolomics studies conducted by her lab have also demonstrated a significant difference in the metabolome of ALS patients associated with exposure to the chlorinated pesticide pentachlorobenzene. She noted that more environmental studies are needed to advance this research, especially in regard to recruiting and maintaining cohorts to later support more hypothesis-based studies. PREPUBLICATION COPY—Uncorrected Proofs

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Humans are potentially exposed to more than 80,000 toxic chemicals in the environment, yet their impacts on brain health and disease are not well understood. The sheer number of these chemicals has overwhelmed the ability to determine their individual toxicity, much less potential interactive effects. Early life exposures to chemicals can have permanent consequences for neurodevelopment and for neurodegeneration in later life. Toxic effects resulting from chemical exposure can interact with other risk factors such as prenatal stress, and persistence of some chemicals in the brain over time may result in cumulative toxicity. Because neurodevelopmental and neurodegenerative disorders - such as attention-deficit hyperactivity disorder and Parkinson's disease - cannot be fully explained by genetic risk factors alone, understanding the role of individual environmental chemical exposures is critical.

On June 25, 2020, the National Academies of Sciences, Engineering, and Medicine's Forum on Neuroscience and Nervous System Disorders hosted a workshop to lay the foundation for future advances in environmental neuroscience. The workshop was designed to explore new opportunities to bridge the gap between what is known about the genetic contribution to brain disorders and what is known, and not known, about the contribution of environmental influences, as well as to discuss what is known about how genetic and environmental factors interact. This publication summarizes the presentation and discussion of the workshop.

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