The contributions of neonatal inhalation of copper to air pollution-induced neurodevelopmental outcomes in mice.

Exposures to ambient ultrafine particle (UFP) air pollution (AP) during the early postnatal period in mice (equivalent to human third trimester brain development) produce male-biased changes in brain structure, including ventriculomegaly, reduced brain myelination, alterations in neurotransmitters and glial activation, as well as impulsive-like behavioral characteristics, all of which are also features characteristic of male-biased neurodevelopmental disorders (NDDs). The purpose of this study was to ascertain the extent to which inhaled Cu, a common contaminant of AP that is also dysregulated across multiple NDDs, might contribute to these phenotypes. For this purpose, C57BL/6J mice were exposed from postnatal days 4-7 and 10-13 for 4 hr/day to inhaled copper oxide (CuxOy) nanoparticles at an environmentally relevant concentration averaging 171.9 ng/m3. Changes in brain metal homeostasis and neurotransmitter levels were determined following termination of exposure (postnatal day 14), while behavioral changes were assessed in adulthood. CuxOy inhalation modified cortical metal homeostasis and produced male-biased disruption of striatal neurotransmitters, with marked increases in dopaminergic function, as well as excitatory/inhibitory imbalance and reductions in serotonergic function. Impulsive-like behaviors in a fixed ratio (FR) waiting-for-reward schedule and a fixed interval (FI) schedule of food reward occurred in both sexes, but more prominently in males, effects which could not be attributed to altered locomotor activity or short-term memory. Inhaled Cu as from AP exposures, at environmentally relevant levels experienced during development, may contribute to impaired brain function, as shown by its ability to disrupt brain metal homeostasis and striatal neurotransmission. In addition, its ability to evoke impulsive-like behavior, particularly in male offspring, may be related to striatal dopaminergic dysfunction that is known to mediate such behaviors. As such, regulation of air Cu levels may be protective of public health.

Effects of mammary cancer and chemotherapy on neuroimmunological markers and memory function in a preclinical mouse model.

Treatment modalities for breast cancer, including cyclophosphamide chemotherapy, have been associated with the development of cognitive decline (CRCD), which is characterized by impairments in memory, concentration, attention, and executive functions. We and others have identified a link between inflammation and decreased cognitive performance in patients with breast cancer receiving chemotherapy. In order to better understand the inflammation-associated molecular changes within the brain related to tumor alone or in combination with chemotherapy, we orthotopically implanted mouse mammary tumors (E0771) into female C57BL/6 mice and administered clinically relevant doses of cyclophosphamide and doxorubicin intravenously at weekly intervals for four weeks. We measured serum cytokines and markers of neuroinflammation at 48 h and up to one month post-treatment and tested memory using a reward-based delayed spatial alternation paradigm. We found that breast tumors and chemotherapy altered systemic inflammation and neuroinflammation. We further found that the presence of tumor and chemotherapy led to a decline in memory over time at the longest delay, when memory was the most taxed, compared to shorter delay times. These findings in a clinically relevant mouse model shed light on possible biomarkers for CRCD and add to the growing evidence that anti-inflammatory strategies have the potential to mitigate cancer- or treatment-related side effects.

Cumulative Risk Evaluation of Phthalates Under TSCA.

The U.S. Environmental Protection Agency (EPA) is currently conducting separate Toxic Substances Control Act (TSCA) risk evaluations for seven phthalates: dibutyl phthalate (DBP), butyl benzyl phthalate (BBP), di(2-ethylhexyl) phthalate (DEHP), diisobutyl phthalate (DIBP), dicyclohexyl phthalate (DCHP), di-isodecyl phthalate (DIDP), and diisononyl phthalate (DINP). Phthalates are highly abundant plastic additives used primarily to soften materials and make them flexible, and biomonitoring shows widespread human exposure to a mixture of phthalates. Evidence supports biological additivity of phthalate mixture exposures, including the enhancement of toxicity affecting common biological targets. Risk estimates based on individual phthalate exposure may not be protective of public health. Thus, a cumulative risk approach is warranted. While EPA initially did not signal that it would incorporate cumulative risk assessment (CRA) as part of its current risk evaluation for the seven phthalates, the agency recently announced that it is reconsidering if CRA for phthalates would be appropriate. Based on our review of existing chemical mixtures risk assessment guidance, current TSCA scoping documents for the seven phthalates, and pertinent peer-reviewed literature, we delineate a CRA approach that EPA can easily implement for phthalates. The strategy for using CRA to inform TSCA risk evaluation for existing chemicals is based upon integrative physiology and a common adverse health outcome algorithm for identifying and grouping relevant nonchemical and chemical stressors. We recommend adjustments for how hazard indices (HIs) or margins of exposure (MOEs) based on CRA are interpreted for determining "unreasonable risk" under TSCA.

Making the invisible visible: Using a qualitative system dynamics model to map disparities in cumulative environmental stressors and children's neurodevelopment.

BACKGROUND: The combined effects of multiple environmental toxicants and social stressor exposures are widely recognized as important public health problems, likely contributing to health inequities. However, US policy makers at state and federal levels typically focus on one stressor exposure at a time and have failed to develop comprehensive strategies to reduce multiple co-occurring exposures, mitigate cumulative risks and prevent harm. This research aimed to move from considering disparate environmental stressors in isolation to mapping the links between environmental, economic, social and health outcomes as a dynamic complex system using children's exposure to neurodevelopmental toxicants as an illustrative example. Such a model can be used to support a broad range of child developmental and environmental health policy stakeholders in improving their understanding of cumulative effects of multiple chemical, physical, biological and social environmental stressors as a complex system through a collaborative learning process. METHODS: We used system dynamics (SD) group model building to develop a qualitative causal theory linking multiple interacting streams of social stressors and environmental neurotoxicants impacting children's neurodevelopment. A 2 1/2-day interactive system dynamics workshop involving experts across multiple disciplines was convened to develop the model followed by qualitative survey on system insights. RESULTS: The SD causal map covered seven interconnected themes: environmental exposures, social environment, health status, education, employment, housing and advocacy. Potential high leverage intervention points for reducing disparities in children's cumulative neurotoxicant exposures and effects were identified. Workshop participants developed deeper level of understanding about the complexity of cumulative environmental health risks, increased their agreement about underlying causes, and enhanced their capabilities for integrating diverse forms of knowledge about the complex multi-level problem of cumulative chemical and non-chemical exposures. CONCLUSION: Group model building using SD can lead to important insights to into the sociological, policy, and institutional mechanisms through which disparities in cumulative impacts are transmitted, resisted, and understood.

Air Pollution-Related Neurotoxicity Across the Life Span.

Air pollution is a complex mixture of gases and particulate matter, with adsorbed organic and inorganic contaminants, to which exposure is lifelong. Epidemiological studies increasingly associate air pollution with multiple neurodevelopmental disorders and neurodegenerative diseases, findings supported by experimental animal models. This breadth of neurotoxicity across these central nervous system diseases and disorders likely reflects shared vulnerability of their inflammatory and oxidative stress-based mechanisms and a corresponding ability to produce brain metal dyshomeo-stasis. Future research to define the responsible contaminants of air pollution underlying this neurotoxicity is critical to understanding mechanisms of these diseases and disorders and protecting public health.

The potential involvement of inhaled iron (Fe) in the neurotoxic effects of ultrafine particulate matter air pollution exposure on brain development in mice.

BACKGROUND: Air pollution has been associated with neurodevelopmental disorders in epidemiological studies. In our studies in mice, developmental exposures to ambient ultrafine particulate (UFP) matter either postnatally or gestationally results in neurotoxic consequences that include brain metal dyshomeostasis, including significant increases in brain Fe. Since Fe is redox active and neurotoxic to brain in excess, this study examined the extent to which postnatal Fe inhalation exposure, might contribute to the observed neurotoxicity of UFPs. Mice were exposed to 1 µg/m3 Fe oxide nanoparticles alone, or in conjunction with sulfur dioxide (Fe (1 µg/m3) + SO2 (SO2 at 1.31 mg/m3, 500 ppb) from postnatal days 4-7 and 10-13 for 4 h/day. RESULTS: Overarching results included the observations that Fe + SO2 produced greater neurotoxicity than did Fe alone, that females appeared to show greater vulnerability to these exposures than did males, and that profiles of effects differed by sex. Consistent with metal dyshomeostasis, both Fe only and Fe + SO2 exposures altered correlations of Fe and of sulfur (S) with other metals in a sex and tissue-specific manner. Specifically, altered metal levels in lung, but particularly in frontal cortex were found, with reductions produced by Fe in females, but increases produced by Fe + SO2 in males. At PND14, marked changes in brain frontal cortex and striatal neurotransmitter systems were observed, particularly in response to combined Fe + SO2 as compared to Fe only, in glutamatergic and dopaminergic functions that were of opposite directions by sex. Changes in markers of trans-sulfuration in frontal cortex likewise differed in females as compared to males. Residual neurotransmitter changes were limited at PND60. Increases in serum glutathione and Il-1a were female-specific effects of combined Fe + SO2. CONCLUSIONS: Collectively, these findings suggest a role for the Fe contamination in air pollution in the observed neurotoxicity of ambient UFPs and that such involvement may be different by chemical mixture. Translation of such results to humans requires verification, and, if found, would suggest a need for regulation of Fe in air for public health protection.

Both parents matter: a national-scale analysis of parental race/ethnicity, disparities in prenatal PM2.5 exposures and related impacts on birth outcomes.

BACKGROUND: Most U.S. studies that report racial/ethnic disparities in increased risk of low birth weight associated with air pollution exposures have been conducted in California or northeastern states and/or urban areas, limiting generalizability of study results. Few of these studies have examined maternal racial/ethnic groups other than Non-Hispanic Black, non-Hispanic White and Hispanic, nor have they included paternal race. We aimed to examine the independent effects of PM2.5 on birth weight among a nationally representative sample of U.S. singleton infants and how both maternal and paternal race/ethnicity modify relationships between prenatal PM2.5 exposures and birth outcomes. METHODS: We used data from the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B), a longitudinal nationally representative cohort of 10,700 U.S. children born in 2001, which we linked to U.S.EPA's Community Multi-scale Air Quality (CMAQ)-derived predicted daily PM2.5 concentrations at the centroid of each Census Bureau Zip Code Tabulation Area (ZCTA) for maternal residences. We examined relationships between term birthweight (TBW), term low birthweight rate (TLBW) and gestational PM2.5 pollutant using multivariate regression models. Effect modification of air pollution exposures on birth outcomes by maternal and paternal race was evaluated using stratified models. All analyses were conducted with sample weights to provide national-scale estimates. RESULTS: The majority of mothers were White (61%). Fourteen percent of mothers identified as Black, 21% as Hispanic, 3% Asian American and Pacific Islander (AAPI) and 1% American Indian and Alaskan Native (AIAN). Fathers were also racially/ethnically diverse with 55% identified as White Non-Hispanic, 10% as Black Non-Hispanic, 19% as Hispanic, 3% as AAPI and 1% as AIAN. Results from the chi-square and ANOVA tests of significance for racial/ethnic differences indicate disparities in prenatal exposures and birth outcomes by both maternal and paternal race/ethnicity. Prenatal PM2.5 was associated with reduced birthweights during second and third trimester and over the entire gestational period in adjusted regression models, although results did not reach statistical significance. In models stratified by maternal race and paternal race, one unit increase in PM2.5 was statistically significantly associated with lower birthweights among AAPI mothers, -5.6 g (95% CI:-10.3, -1.0 g) and AAPI fathers, -7.6 g (95% CI: -13.1, -2.1 g) during 3rd trimester and among births where father's race was not reported, -14.2 g (95% CI: -24.0, -4.4 g). CONCLUSIONS: These data suggest that paternal characteristics should be used, in addition to maternal characteristics, to describe the risks of adverse birth outcomes. Additionally, our study suggests that serious consideration should be given to investigating environmental and social mechanisms, such as air pollution exposures, as potential contributors to disparities in birth outcomes among AAPI populations.

Protracted Impairment of Maternal Metabolic Health in Mouse Dams Following Pregnancy Exposure to a Mixture of Low Dose Endocrine-Disrupting Chemicals, a Pilot Study.

Pregnancy, a period of increased metabolic demands coordinated by fluctuating steroid hormones, is an understudied critical window of disease susceptibility for later-life maternal metabolic health. Epidemiological studies have identified associations between exposures to various endocrine-disrupting chemicals (EDCs) with an increased risk for metabolic syndrome, obesity, and diabetes. Whether such adverse outcomes would be heightened by concurrent exposures to multiple EDCs during pregnancy, consistent with the reality that human exposures are to EDC mixtures, was examined in the current pilot study. Mouse dams were orally exposed to relatively low doses of four EDCs: (atrazine (10 mg/kg), bisphenol-A (50 µg/kg), perfluorooctanoic acid (0.1 mg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (0.036 µg/kg)), or the combination (MIX), from gestational day 7 until birth or for an equivalent 12 days in non-pregnant females. Glucose intolerance, serum lipids, weight, and visceral adiposity were assessed six months later. MIX-exposed dams exhibited hyperglycemia with a persistent elevation in blood glucose two hours after glucose administration in a glucose tolerance test, whereas no such effects were observed in MIX-exposed non-pregnant females. Correspondingly, MIX dams showed elevated serum low-density lipoprotein (LDL). There were no statistically significant differences in weight or visceral adipose; MIX dams showed an average visceral adipose volume to body volume ratio of 0.09, while the vehicle dams had an average ratio of 0.07. Collectively, these findings provide biological plausibility for the epidemiological associations observed between EDC exposures during pregnancy and subsequent maternal metabolic dyshomeostasis, and proof of concept data that highlight the importance of considering complex EDC mixtures based of off common health outcomes, e.g., for increased risk for later-life maternal metabolic effects following pregnancy.

Early Low-Level Arsenic Exposure Impacts Post-Synaptic Hippocampal Function in Juvenile Mice.

Arsenic is a well-established carcinogen known to increase mortality, but its effects on the central nervous system are less well understood. Epidemiological studies suggest that early life exposure is associated with learning deficits and behavioral changes. Studies in arsenic-exposed rodents have begun to shed light on potential mechanistic underpinnings, including changes in synaptic transmission and plasticity. However, previous studies relied on extended exposure into adulthood, and little is known about the effect of arsenic exposure in early development. Here, we studied the effects of early developmental arsenic exposure in juvenile mice on synaptic transmission and plasticity in the hippocampus. C57BL/6J females were exposed to arsenic (0, 50 ppb, 36 ppm) via drinking water two weeks prior to mating, with continued exposure throughout gestation and parturition. Electrophysiological recordings were then performed on juvenile offspring prior to weaning. In this paradigm, the offspring are exposed to arsenic indirectly, via the mother. We found that high (36 ppm) and relatively low (50 ppb) arsenic exposure both decreased basal synaptic transmission. A compensatory increase in pre-synaptic vesicular release was only observed in the high-exposure group. These results suggest that indirect, ecologically relevant arsenic exposure in early development impacts hippocampal synaptic transmission and plasticity that could underlie learning deficits reported in epidemiological studies.

Confronting Racism in Environmental Health Sciences: Moving the Science Forward for Eliminating Racial Inequities.

BACKGROUND: The twin pandemics of COVID-19 and systemic racism during 2020 have forced a conversation across many segments of our society, including the environmental health sciences (EHS) research community. We have seen the proliferation of statements of solidarity with the Black Lives Matter movement and commitments to fight racism and health inequities from academia, nonprofit organizations, governmental agencies, and private corporations. Actions must now arise from these promises. As public health and EHS scientists, we must examine the systems that produce and perpetuate inequities in exposure to environmental pollutants and associated health effects. OBJECTIVES: We outline five recommendations the EHS research community can implement to confront racism and move our science forward for eliminating racial inequities in environmental health. DISCUSSION: Race is best considered a political label that promotes inequality. Thus, we should be wary of equating race with biology. Further, EHS researchers should seriously consider racism as a plausible explanation of racial disparities in health and consider structural racism as a factor in environmental health risk/impact assessments, as well as multiple explanations for racial differences in environmental exposures and health outcomes. Last, the EHS research community should develop metrics to measure racism and a set of guidelines on the use and interpretation of race and ethnicity within the environmental sciences. Numerous guidelines exist in other disciplines that can serve as models. By taking action on each of these recommendations, we can make significant progress toward eliminating racial disparities. https://doi.org/10.1289/EHP8186.

Defining and Intervening on Cumulative Environmental Neurodevelopmental Risks: Introducing a Complex Systems Approach.

BACKGROUND: The combined effects of multiple environmental toxicants and social stressor exposures are widely recognized as important public health problems contributing to health inequities. However cumulative environmental health risks and impacts have received little attention from U.S. policy makers at state and federal levels to develop comprehensive strategies to reduce these exposures, mitigate cumulative risks, and prevent harm. An area for which the inherent limitations of current approaches to cumulative environmental health risks are well illustrated is children's neurodevelopment, which exhibits dynamic complexity of multiple interdependent and causally linked factors and intergenerational effects. OBJECTIVES: We delineate how a complex systems approach, specifically system dynamics, can address shortcomings in environmental health risk assessment regarding exposures to multiple chemical and nonchemical stressors and reshape associated public policies. DISCUSSION: Systems modeling assists in the goal of solving problems by improving the "mental models" we use to make decisions, including regulatory and policy decisions. In the context of disparities in children's cumulative exposure to neurodevelopmental stressors, we describe potential policy insights about the structure and behavior of the system and the types of system dynamics modeling that would be appropriate, from visual depiction (i.e., informal maps) to formal quantitative simulation models. A systems dynamics framework provides not only a language but also a set of methodological tools that can more easily operationalize existing multidisciplinary scientific evidence and conceptual frameworks on cumulative risks. Thus, we can arrive at more accurate diagnostic tools for children's' environmental health inequities that take into consideration the broader social and economic environment in which children live, grow, play, and learn. https://doi.org/10.1289/EHP7333.

Paraquat Inhalation, a Translationally Relevant Route of Exposure: Disposition to the Brain and Male-Specific Olfactory Impairment in Mice.

Epidemiological and experimental studies have associated oral and systemic exposures to the herbicide paraquat (PQ) with Parkinson's disease. Despite recognition that airborne particles and solutes can be directly translocated to the brain via olfactory neurons, the potential for inhaled PQ to cause olfactory impairment has not been investigated. This study sought to determine if prolonged low-dose inhalation exposure to PQ would lead to disposition to the brain and olfactory impairment, a prodromal feature of Parkinson's disease. Adult male and female C57BL/6J mice were exposed to PQ aerosols in a whole-body inhalation chamber for 4 h/day, 5 days/week for 4 weeks. Subsets of mice were sacrificed during and after exposure and PQ concentrations in various brain regions (olfactory bulb, striatum, midbrain, and cerebellum) lung, and kidney were quantified via mass spectrometry. Alterations in olfaction were examined using an olfactory discrimination paradigm. PQ inhalation resulted in an appreciable burden in all examined brain regions, with the highest burden observed in the olfactory bulb, consistent with nasal olfactory uptake. PQ was also detected in the lung and kidney, yet PQ levels in all tissues returned to control values within 4 weeks post exposure. PQ inhalation caused persistent male-specific deficits in olfactory discrimination. No effects were observed in females. These data support the importance of route of exposure in determination of safety estimates for neurotoxic pesticides, such as PQ. Accurate estimation of the relationship between exposure and internal dose is critical for risk assessment and public health protection.

Developmental exposure to methylmercury and resultant muscle mercury accumulation and adult motor deficits in mice.

Developmental methylmercury (MeHg) exposure can have lasting consequences on neural development and motor function across the lifespan. Recent evidence for MeHg targeting of myogenic pathways has drawn attention to the possibility that developing skeletal muscle plays a role in the motor deficits stemming from early life MeHg exposure. In this study we examined a potential role for muscle in influencing MeHg developmental toxicity in offspring of female mice exposed to MeHg via drinking water. Dams had access to 0, 0.5 or 5.0 ppm MeHg chloride in drinking water from two weeks prior to mating through weaning. Blood, brain and muscle tissue was harvested from dams at weaning and pups at postnatal days (PND) 6, 21 and 60 for analysis of total Hg. Muscle tissue sections were examined with histological stains. Behavioral testing of offspring was conducted at PND 60 and included locomotor activity, inverted screen, grip strength and rotarod tests to assess motor function. Total Hg (tHg) levels in dam muscles at weaning were 1.7-3-fold higher than Hg levels in blood or brain. In PND6 male and female pups, muscle and brain tHg levels were 2 to 4-fold higher than blood tHg. Brain tHg levels decreased more rapidly than muscle tHg levels between PND 6 and 21. Premised on modeling of growth dilution, brain tissue demonstrated an elimination of tHg while muscle tissue exhibited a net uptake of tHg between PND 6 and 21. Despite overall elevated Hg levels in developing muscle, no gross morphological or cytological phenotypes were observed in muscle at PND 60. At the higher MeHg dose, grip strength was reduced in both females and males at PND 60, whereas only male specific deficits were observed in locomotor activity and inverted screen tests with marginally significant deficits on rotarod. These findings highlight a potential role for developing skeletal muscle in mediating the neuromuscular insult of early life MeHg exposure.

Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease.

The etiologic pathways leading to neuropsychiatric diseases remain poorly defined. As genomic technologies have advanced over the past several decades, considerable progress has been made linking neuropsychiatric disorders to genetic underpinnings. Interest and consideration of nongenetic risk factors (e.g., lead exposure and schizophrenia) have, in contrast, lagged behind heritable frameworks of explanation. Thus, the association of neuropsychiatric illness to environmental chemical exposure, and their potential interactions with genetic susceptibility, are largely unexplored. In this review, we describe emerging approaches for considering the impact of chemical risk factors acting alone and in concert with genetic risk, and point to the potential role of epigenetics in mediating exposure effects on transcription of genes implicated in mental disorders. We highlight recent examples of research in nongenetic risk factors in psychiatric disorders that point to potential shared biological mechanisms-synaptic dysfunction, immune alterations, and gut-brain interactions. We outline new tools and resources that can be harnessed for the study of environmental factors in psychiatric disorders. These tools, combined with emerging experimental evidence, suggest that there is a need to broadly incorporate environmental exposures in psychiatric research, with the ultimate goal of identifying modifiable risk factors and informing new treatment strategies for neuropsychiatric disease.

Potential frameworks to support evaluation of mechanistic data for developmental neurotoxicity outcomes: A symposium report.

A key challenge in systematically incorporating mechanistic data into human health assessments is that, compared to studies of apical health endpoints, these data are both more abundant (mechanistic studies routinely outnumber other studies by several orders of magnitude) and more heterogeneous (e.g. different species, test system, tissue, cell type, exposure paradigm, or specific assays performed). A structured decision-making process for organizing, integrating, and weighing mechanistic DNT data for use in human health risk assessments will improve the consistency and efficiency of such evaluations. At the Developmental Neurotoxicology Society (DNTS) 2016 annual meeting, a symposium was held to address the application of existing organizing principles and frameworks for evaluation of mechanistic data relevant to interpreting neurotoxicology data. Speakers identified considerations with potential to advance the use of mechanistic DNT data in risk assessment, including considering the context of each exposure, since epigenetics, tissue type, sex, stress, nutrition and other factors can modify toxicity responses in organisms. It was also suggested that, because behavior is a manifestation of complex nervous system function, the presence and absence of behavioral change itself could be used to organize the interpretation of multiple complex simultaneous mechanistic changes. Several challenges were identified with frameworks and their implementation, and ongoing research to develop these approaches represents an early step toward full evaluation of mechanistic DNT data for assessments.

Lineage- and Sex-Dependent Behavioral and Biochemical Transgenerational Consequences of Developmental Exposure to Lead, Prenatal Stress, and Combined Lead and Prenatal Stress in Mice.

BACKGROUND: Lead (Pb) exposure and prenatal stress (PS) during development are co-occurring risk factors with shared biological substrates. PS has been associated with transgenerational passage of altered behavioral phenotypes, whereas the transgenerational behavioral or biochemical consequences of Pb exposure, and modification of any such effects by PS, is unknown. OBJECTIVES: The present study sought to determine whether Pb, PS, or combined Pb and PS exposures produced adverse transgenerational consequences on brain and behavior. METHODS: Maternal Pb and PS exposures were carried out in F0 mice. Outside breeders were used at each subsequent breeding, producing four F1-F2 lineages: [F1 female-F2 female (FF), FM (male), MF, and MM]. F3 offspring were generated from each of these lineages and examined for outcomes previously found to be altered by Pb, PS, or combined Pb and PS in F1 offspring: behavioral performance [fixed-interval (FI) schedule of food reward, locomotor activity, and anxiety-like behavior], dopamine function [striatal expression of tyrosine hydroxylase (Th)], glucocorticoid receptor (GR) and plasma corticosterone, as well as brain-derived neurotrophic factor (BDNF) and total percent DNA methylation of Th and Bdnf genes in the frontal cortex and hippocampus. RESULTS: Maternal F0 Pb exposure produced runting in F3 offspring. Considered across lineages, F3 females exhibited Pb-related alterations in behavior, striatal BDNF levels, frontal cortical Th total percentage DNA methylation levels and serum corticosterone levels, whereas F3 males showed Pb- and PS-related alterations in behavior and total percent DNA methylation of hippocampal Bdnf. However, numerous lineage-specific effects were observed, most of greater magnitude than those observed across lineages, with outcomes differing by F3 sex. DISCUSSION: These findings support the possibility that exposures of previous generations to Pb or PS may influence the brain and behavior of future generations. Observed changes were sex-dependent, with F3 females showing multiple changes through Pb-exposed lineages. Lineage effects may occur through maternal responses to pregnancy, altered maternal behavior, epigenetic modifications, or a combination of mechanisms, but they have significant public health ramifications regardless of mechanism. https://doi.org/10.1289/EHP4977.

Selective memory and behavioral alterations after ambient ultrafine particulate matter exposure in aged 3xTgAD Alzheimer's disease mice.

BACKGROUND: A growing body of epidemiological literature indicates that particulate matter (PM) air pollution exposure is associated with elevated Alzheimer's disease (AD) risk and may exacerbate AD-related cognitive decline. Of concern is exposure to the ultrafine PM (UFP) fraction (≤100 nm), which deposits efficiently throughout the respiratory tract, has higher rates of translocation to secondary organs, like brain, and may induce inflammatory changes. We, therefore, hypothesize that exposure to UFPs will exacerbate cognitive deficits in a mouse model of AD. The present study assessed alterations in learning and memory behaviors in aged (12.5 months) male 3xTgAD and non-transgenic mice following a 2-week exposure (4-h/day, 4 days/week) to concentrated ambient UFPs using the Harvard ultrafine concentrated ambient particle system (HUCAPS) or filtered air. Beginning one month following exposure, locomotor activity, spatial learning and memory, short-term recognition memory, appetitive motivation, and olfactory discrimination were assessed. RESULTS: No effects on locomotor activity were found following HUCAPS exposure (number concentration, 1 × 104-4.7 × 105 particles/cm3; mass concentration, 29-132 µg/m3). HUCAPS-exposed mice, independent of AD background, showed a significantly decreased spatial learning, mediated through reference memory deficits, as well as short-term memory deficits in novel object recognition testing. AD mice displayed diminished spatial working memory, potentially a result of olfactory deficits, and short-term memory. AD background modulated HUCAPS-induced changes on appetitive motivation and olfactory discrimination, specifically enhancing olfactory discrimination in NTg mice. Modeling variation in appetitive motivation as a covariate in spatial learning and memory, however, did not support the conclusion that differences in motivation significantly underlie changes in spatial learning and memory. CONCLUSIONS: A short-term inhalation exposure of aged mice to ambient UFPs at human-relevant concentrations resulted in protracted (testing spanning 1-6.5 months post-exposure) adverse effects on multiple memory domains (reference and short-term memory) independent of AD background. Impairments in learning and memory were present when accounting for potential covariates like motivational changes and locomotor activity. These results highlight the need for further research into the potential mechanisms underlying the cognitive effects of UFP exposure in adulthood.

The Impact of Inhaled Ambient Ultrafine Particulate Matter on Developing Brain: Potential Importance of Elemental Contaminants.

Epidemiological studies report associations between air pollution (AP) exposures and several neurodevelopmental disorders including autism, attention deficit disorder, and cognitive delays. Our studies in mice of postnatal (human third trimester brain equivalent) exposures to concentrated ambient ultrafine particles (CAPs) provide biological plausibility for these associations, producing numerous neuropathological and behavioral features of these disorders, including male-biased vulnerability. These findings raise questions about the specific components of AP that underlie its neurotoxicity, which our studies suggest could involve trace elements as candidate neurotoxicants. X-ray fluorescence analyses of CAP chamber filters confirm contamination of AP exposures by multiple elements, including iron (Fe) and sulfur (S). Correspondingly, laser ablation inductively coupled plasma mass spectrometry of brains of male mice indicates marked postexposure elevations of Fe and S and other elements. Elevations of brain Fe and S in particular are consistent with potential ferroptotic, oxidative stress, and altered antioxidant capacity-based mechanisms of CAPs-induced neurotoxicity, supported by observations of increased serum oxidized glutathione and increased neuronal cell death in nucleus accumbens with no corresponding significant increase in caspase-3, in male brains following postnatal CAP exposures. Understanding the role of trace element contaminants of particulate matter AP as a source of neurotoxicity is critical for public health protection.