Neurotoxic Exposure Research Articles

Therapeutic potential of astrocyte-derived extracellular vesicles in mitigating cytotoxicity and transcriptome changes in human brain endothelial cells

This study investigates the therapeutic effect of astrocyte-derived extracellular vesicles (EVs) in mitigating neurotoxicity-induced transcriptome changes, mitochondrial function, and base excision repair mechanisms in human brain endothelial cells (HBECs). Neurodegenerative disorders are marked by inflammatory processes impacting the blood–brain barrier (BBB) that involve its main components- HBECs and astrocytes. Astrocytes maintain homeostasis through various mechanisms, including EV release. The effect of these EVs on mitigating neurotoxicity in HBECs has not been investigated. This study assesses the impact of astrocyte-derived EVs on global transcriptome changes, cell proliferation, cytotoxicity, oxidative DNA damage, and mitochondrial morphology in HBECs exposed to the neurotoxic reagent Na2Cr2O7. Exposure to Na2Cr2O7 for 5 and 16 h induced oxidative DNA damage, measured by an increase in genomic 8OHdG, while the EVs reduced the accumulation of the adduct. A neurotoxic environment caused a non-statistically significant upregulation of the DNA repair enzyme OGG1 while the addition of astrocyte-derived EVs was associated with the same level of expression. EVs caused increased cell proliferation and reduced cytotoxicity in Na2Cr2O7-treated cells. Mitochondrial dysfunction associated with a reduced copy number and circular morphology induced by neurotoxic exposure was not reversed by astrocyte-derived EVs. High-throughput RNA sequencing revealed that exposure to Na2Cr2O7 suppressed immune response genes. The addition of astrocyte-derived EVs resulted in the dysregulation of long noncoding RNAs impacting genes associated with brain development and angiogenesis. These findings reveal the positive impact of astrocytes-derived EVs in mitigating neurotoxicity and as potential therapeutic avenues for neurodegenerative diseases.

Polycyclic aromatic hydrocarbon exposure effects on trajectories of maternal and adolescent mental health

BackgroundParental psychological distress is a well-known risk factor for developmental psychopathology, with longer term parental distress associated with worse youth mental health. Neurotoxicant exposure during pregnancy is a risk factor for both poor maternal and youth mental health. The impact of one class of pollutant, polycyclic aromatic hydrocarbons (PAH), on long-term trajectories of maternal distress and youth self-reported mental health symptoms in adolescence has been understudied.MethodsPAH exposure was measured by DNA adducts in maternal blood sampled during the third trimester of pregnancy. Maternal distress, operationalized as maternal demoralization, was measured at 11 timepoints (prenatal to child age 16). Adolescent mental health symptoms were measured at age 13–15. Follow up analyses examined a subset of measures available at age 15–20 years. Structural equation modeling examined associations between PAH exposure during pregnancy and latent growth metrics of maternal distress, and between maternal distress (intercept and slope) and youth mental health symptoms in a prospective longitudinal birth cohort (N = 564 dyads).ResultsHigher prenatal PAH exposure was associated with higher concurrent maternal distress. Prenatal maternal distress was associated with adolescent’s self-reported anxiety, depression, and externalizing problems. On average, maternal distress declined over time; a slower decline in mother’s distress across the course of the child’s life was associated with greater self-reported anxiety and externalizing problems in youth.ConclusionsOur findings are consistent with an intergenerational framework of environmental effects on mental health: PAH exposure during pregnancy affects maternal mental health, which in turn influences mental health outcomes for youth well into adolescence. Future research is necessary to elucidate the possible social and biological mechanisms (e.g., parenting, epigenetics) underlying the intergenerational transmission of the negative effects of pollution on mental health in caregiver-child dyads.

A single-cell transcriptomic landscape of cadmium-hindered brain development in mice

The effects of neurotoxicant cadmium (Cd) exposure on brain development have not been well elucidated. To investigate this, we have herein subjected pregnant mice to low-dose Cd throughout gestation. Using single-cell RNA sequencing (scRNA-seq), we explored the cellular responses in the embryonic brain to Cd exposure, and identified 18 distinct cell subpopulations that exhibited varied responses to Cd. Typically, Cd exposure impeded the development and maturation of cells in the brain, especially progenitor cells such as neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). It also caused significant cell subpopulation shifts in almost all the types of cells in the brain. Additionally, Cd exposure reduced the dendritic sophistication of cortical neurons in the offspring. Importantly, these changes led to aberrant Ca2+ activity in the cortex and neural behavior changes in mature offspring. These data contribute to our understanding of the effects and mechanisms of Cd exposure on brain development and highlight the importance of controlling environmental neurotoxicant exposure at the population level.

Tracking Childhood Lead Exposure in Early Industrial Romanians

Childhood lead exposure has been linked to severe adverse health outcomes throughout life. Measurements of lead in teeth have established that individuals living in contaminated environments show higher levels compared to individuals living further away, although less is known about when individuals are most susceptible to these exposures. We examined lead (Pb208) concentrations (ppm) in teeth over the first 2.5 years of life in 16 children born in the late 19th to early 20th century throughout Romania. This period of intense industrialization was characterized by increases in mining, coal burning, and oil refining—activities that contaminate air, water, and food with Pb. We hypothesized the distance from an operational mine or oil refinery, or being born in a city, would be positively associated with cumulative dentine Pb exposure (CDPE). We also predicted that Pb exposures would peak in the first six months of life when gastrointestinal (GI) absorption of Pb is likely highest. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) of sectioned tooth dentine followed by Bayesian statistical analyses revealed that living 30 km or more from a mine or oil refinery did not explain CDPE. However, being born in a city explained 42% of CDPE. All individuals showed maximum Pb exposures after six months of age, likely due to contaminated solid food and/or non-milk liquids. This research demonstrates how tooth formation can be coupled with comprehensive elemental mapping to analyse the context and timing of early-life neurotoxicant exposures, which may be extended to well-preserved teeth from clinical and historic populations.

PON1 Status in Relation to Gulf War Illness: Evidence of Gene-Exposure Interactions from a Multisite Case-Control Study of 1990-1991 Gulf War Veterans.

Deployment-related neurotoxicant exposures are implicated in the etiology of Gulf War illness (GWI), the multisymptom condition associated with military service in the 1990-1991 Gulf War (GW). A Q/R polymorphism at position 192 of the paraoxonase (PON)-1 enzyme produce PON1192 variants with different capacities for neutralizing specific chemicals, including certain acetylcholinesterase inhibitors. We evaluated PON1192 status and GW exposures in 295 GWI cases and 103 GW veteran controls. Multivariable logistic regression determined independent associations of GWI with GW exposures overall and in PON1192 subgroups. Exact logistic regression explored effects of exposure combinations in PON1192 subgroups. Hearing chemical alarms (proxy for possible nerve agent exposure) was associated with GWI only among RR status veterans (OR = 8.60, p = 0.014). Deployment-related skin pesticide use was associated with GWI only among QQ (OR = 3.30, p = 0.010) and QR (OR = 4.22, p < 0.001) status veterans. Exploratory assessments indicated that chemical alarms were associated with GWI in the subgroup of RR status veterans who took pyridostigmine bromide (PB) (exact OR = 19.02, p = 0.009) but not RR veterans who did not take PB (exact OR = 0.97, p = 1.00). Similarly, skin pesticide use was associated with GWI among QQ status veterans who took PB (exact OR = 6.34, p = 0.001) but not QQ veterans who did not take PB (exact OR = 0.59, p = 0.782). Study results suggest a complex pattern of PON1192 exposures and exposure-exposure interactions in the development of GWI.

Prefrontal cortical network dysfunction from acute neurotoxicant exposure.

Prefrontal cortical (PFC) dysfunction has been linked to disorders exhibiting deficits in cognitive performance, attention, motivation, and impulse control. Neurons of the PFC are susceptible to glutamatergic excitotoxicity, an effect associated with cortical degeneration in frontotemporal disorders (FTDs). PFC susceptibility to environmental toxicant exposure, one possible contributor to sporadic FTD, has not been systematically studied. Here, we tested the ability of a well-known environmental neurotoxicant, methylmercury (MeHg), to induce hyperexcitability in medial prefrontal cortex (mPFC) excitatory pyramidal neurons, using whole cell patch-clamp recording. Acute MeHg exposure (20 μM) produced significant mPFC dysfunction, with a shift in the excitatory to inhibitory (E-I) balance toward increased excitability. Both excitatory postsynaptic current (EPSC) and inhibitory postsynaptic current (IPSC) charges were significantly increased after MeHg exposure. MeHg increased EPSC frequency, but there was no observable effect on IPSC frequency, EPSC amplitude or IPSC amplitude. Neither evoked AMPA receptor- nor NMDA receptor-mediated EPSC amplitudes were affected by MeHg. However, excitatory synapses experienced a significant reduction in paired-pulse depression and probability of release. In addition, MeHg induced temporal synchrony in spontaneous IPSCs, reflecting mPFC inhibitory network dysfunction. MeHg exposure also produced increased intrinsic excitability in mPFC neurons, with an increase in action potential firing rate. The observed effects of MeHg on mPFC reflect key potential mechanisms for neuropsychological symptoms from MeHg poisoning. Therefore, MeHg has a significant effect on mPFC circuits known to contribute to cognitive and emotional function and might contribute to etiology of neurodegenerative diseases, such as FTD.NEW & NOTEWORTHY Prefrontal cortical neurons are highly susceptible to glutamatergic excitotoxicity associated with neuronal degeneration in frontal dementia and to environmental toxicant exposure, one potential contributor to FTD. However, this has not been systematically studied. Our results demonstrate that methylmercury exposure leads to hyperexcitability of prefrontal cortical neurons by shifting excitatory to inhibitory (E-I) balance and raising sensitivity for spiking. Our results provide a mechanism by which environmental neurotoxicants may contribute to pathogenesis of diseases such as FTD.

Persistent environmental lead exposures disrupting black children’s neurodevelopment and quality of life trajectories: an under-recognized ACE in the hole

Persistent environmental lead exposures disrupting black children’s neurodevelopment and quality of life trajectories: an under-recognized ACE in the hole

Petunidin-3-glucoside supplementation causes sex-specific effects on the lifespan and motor function in \(\textit{Drosophila melanogaster}\)

Petunidin-3-glucoside (P3G), an anthocyanin prevalent in vegetables, fruits, and wine, possesses noteworthy antioxidant properties attributed to its capacity to scavenge free radicals. This property has sparked interest in the potential for anthocyanins to confer benefits on longevity and age-related motor dysfunctions. In this study, the impact of petunidin-3-glucoside (P3G) on the lifespan and motor function in Drosophila melanogaster was examined, both in the presence and absence of neurotoxic substances, such as glyphosate or ethanol. Varying concentrations of P3G were incorporated into the flies' diet immediately after hatching. Subsequently, distinct sets of flies were subjected to diverse conditions, including a stress-free environment, ethanol exposure, and glyphosate exposure. The survival rate of the flies was monitored daily, and their motor function was assessed using a negative geotaxis assay on days 1, 5, 10, and 15 post-eclosion. Only male flies exhibited an extended lifespan under normal and ethanol-exposed conditions. While P3G did not induce significant alterations in overall motor function for male and female flies across various conditions, intriguing variations were observed at different time points. In female flies, low concentrations of P3G seemed to exacerbate motor function decline during mid to late adulthood, particularly in the presence of glyphosate. Conversely, middle P3G concentration improved motor function in male flies during early to mid-adulthood, a trend consistent regardless of neurotoxic exposures. Taken together, the findings underscore the potential sex-specific effects of P3G on both lifespan and motor function, with observed benefits predominantly applicable to male flies. Nonetheless, while suggestive, a more in-depth investigation is imperative to comprehensively determine whether the advantageous impact of P3G on motor function is exclusive to the early to mid-adult stage. As such, this study presents a foundation that warrants further investigation.

B-esterases activities in several tissues of the marine fish: sea bass and hake, as potential biomarkers of bisphenol A derivatives

In the marine environment, a new threat linked to plastic pollution relates to plastic additives. This threat encompasses multiple chemical compound groups with a high bioaccumulation potential for these chemical mixtures. Hence, informative biomarkers are needed to indicate the effects of environmentally realistic mixtures of these additives. This study proposes an in vitro approach using tissue homogenates of two marine fish, the European sea bass and hake, which are both of interest in aquaculture and fisheries. The selected biomarkers are B-esterase activities comprising acetylcholinesterase (AChE) and carboxylesterases (CEs). The physiological role of AChE in brain and muscle is mainly neural transmission, while CEs participate in liver detoxification processes. However, B-esterases are also widely distributed in other tissues/organs, where their role is yet to be determined, but their inhibition may have undesired biological consequences. Here, we compared the interaction of the plastic additives, bisphenol A and some of its derivatives, like tetrabromobisphenol A (TBBPA), with B-esterase activities. We particularly focused not only on the robust and broadly distributed CE enzymes in brain, gonad, liver, kidney, and plasma tissues of two marine fish, but also on the use of two commercial substrates, p-nitrophenyl butyrate and α-naphthyl butyrate, tentatively representing two CE isoforms. The results evidenced specific species and tissue responses that could be due to a diverse isoform composition. They identified sea bass as better protected against neurotoxic exposures, at least in terms of B-esterase composition. The flame retardant TBBPA was the most reactive to B-esterases inhibition, although Bisphenol A bis (2,3-dihydroxy propyl) ether and Bisphenol F bis (3-chloro-2-hydroxypropyl) ether warrant further toxicology assessments.

MicroRNA-29b-3p degenerates terminally differentiated dopaminergic SH-SY5Y cells by perturbation of mitochondrial functions.

Mitochondrial dysfunction is the main cause of gradual deterioration of structure and function of neuronal cells, eventually resulting in neurodegeneration. Studies have revealed a complex interrelationship between neurotoxicant exposure, mitochondrial dysfunction, and neurodegenerative diseases. Alteration in the expression of microRNAs (miRNAs) has also been linked with disruption in mitochondrial homeostasis and bioenergetics. In our recent research (Cellular and Molecular Neurobiology (2023) https://doi.org/10.1007/s10571-023-01362-4), we have identified miR-29b-3p as one of the most significantly up-regulated miRNAs in the blood of Parkinson's patients. The findings of the present study revealed that neurotoxicants of two different natures, that is, arsenic or rotenone, dramatically increased miR-29b-3p expression (18.63-fold and 12.85-fold, respectively) in differentiated dopaminergic SH-SY5Y cells. This dysregulation of miR-29b-3p intricately modulated mitochondrial morphology, induced oxidative stress, and perturbed mitochondrial membrane potential, collectively contributing to the degeneration of dopaminergic cells. Additionally, using assays for mitochondrial bioenergetics in live and differentiated SH-SY5Y cells, a reduction in oxygen consumption rate (OCR), maximal respiration, basal respiration, and non-mitochondrial respiration was observed in cells transfected with mimics of miR-29b-3p. Inhibition of miR-29b-3p by transfecting inhibitor of miR-29b-3p prior to exposure to neurotoxicants significantly restored OCR and other respiration parameters. Furthermore, we observed that induction of miR-29b-3p activates neuronal apoptosis via sirtuin-1(SIRT-1)/YinYang-1(YY-1)/peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α)-regulated Bcl-2 interacting protein 3-like-dependent mechanism. Collectively, our studies have shown the role of miR-29b-3p in dysregulation of mitochondrial bioenergetics during degeneration of dopaminergic neurons via regulating SIRT-1/YY-1/PGC-1α axis.

Carbon disulfide induces accumulation of TDP-43 in the cytoplasm and mitochondrial dysfunction in rat spinal cords.

The relationship between environmental neurotoxicant exposure and neurodegenerative diseases is being extensively investigated. Carbon disulfide, a classic neurotoxicant and prototype of dithiocarbamates fungicides and anti-inflammatory agents, has been detected in urban adults, raising questions about whether exposure to carbon disulfide is associated with a high incidence of neurodegenerative diseases. Here, using rat models and SH-SY5Y cells, we investigated the possible mechanistic linkages between carbon disulfide neurotoxicity and the expression of TDP-43 protein, a marker of amyotrophic lateral sclerosis/frontotemporal lobar degeneration. Our results showed that rats exhibited severe dyskinesia and increased TDP-43 expression in the spinal cord following carbon disulfide exposure. Moreover, carbon disulfide exposure induced abnormal cytoplasmic localization and phosphorylation of TDP-43 in motor neurons. Importantly, carbon disulfide treatment led to the accumulation of TDP-43 in the mitochondria of motor neurons and resulted in subsequent mitochondrial damage, including mitochondrial structural disruption, mitochondrial respiratory chain complex I inhibition, and impaired VCP/p97-dependent mitophagy. In summary, our study provides support for carbon disulfide exposure-mediated TDP-43 mislocalization and mitochondrial dysfunction, contributes to understanding the pathogenesis of environmental neurotoxin-induced neurodegeneration, and provides inspiration for potential therapeutic strategies.

Effect of altered production and storage of dopamine on development and behavior in C. elegans.

The nematode, Caenorhabditis elegans (C. elegans), is an advantageous model for studying developmental toxicology due to its well-defined developmental stages and homology to humans. It has been established that across species, dopaminergic neurons are highly vulnerable to neurotoxicant exposure, resulting in developmental neuronal dysfunction and age-induced degeneration. C. elegans, with genetic perturbations in dopamine system proteins, can provide insight into the mechanisms of dopaminergic neurotoxicants. In this study, we present a comprehensive analysis on the effect of gene mutations in dopamine-related proteins on body size, development, and behavior in C. elegans. We studied C. elegans that lack the ability to sequester dopamine (OK411) and that overproduce dopamine (UA57) and a novel strain (MBIA) generated by the genetic crossing of OK411 and UA57, which both lack the ability to sequester dopamine into vesicles and, additionally, endogenously overproduce dopamine. The MBIA strain was generated to address the hypothesis that an endogenous increase in the production of dopamine can rescue deficits caused by a lack of vesicular dopamine sequestration. These strains were analyzed for body size, developmental stage, reproduction, egg laying, motor behaviors, and neuronal health utilizing multiple methods. Our results further implicate proper dopamine synthesis and sequestration in the regulation of C. elegans body size, development through larval stages into gravid adulthood, and motor functioning. Furthermore, our analyses demonstrate that body size in terms of length is distinct from the developmental stage as fully developed gravid adult C. elegans with disruptions in the dopamine system have decreased body lengths. Thus, body size should not be used as a proxy for the developmental stage when designing experiments. Our results provide additional evidence that the dopamine system impacts the development, growth, and reproduction in C. elegans. Furthermore, our data suggest that endogenously increasing the production of dopamine mitigates deficits in C. elegans lacking the ability to package dopamine into synaptic vesicles. The novel strain, MBIA, and novel analyses of development and reproduction presented here can be utilized in developmental neurotoxicity experiments.

Leveraging MODEL‐AD mouse strains to understand the role of toxicant exposures on LOAD risk

AbstractBackgroundLate‐onset Alzheimer’s disease (LOAD) is caused by interactions between genes and environment. However, current mouse models do not fully recapitulate LOAD phenotypes, limiting translatability to clinical needs. To address this, MODEL‐AD (Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease) Consortium was established to create and phenotype new mouse models. The IU/JAX/PITT MODEL‐AD Center focuses on developing models with combinations of genetic risk factors, as well as humanizing APP (hAb) and MAPT. One use of these models is to determine the contribution of environmental factors to LOAD risk. Studies show associations between LOAD risk and exposure to ubiquitous environmental neurotoxicants, including arsenic (As), lead (Pb), and cadmium (Cd). All three are ranked in the “Top 10 Toxicants” of public health concern (As #1, Pb #2, Cd #7; ATSDR Toxic Substance Priority List). However, mechanisms driving increased risk are unknown.MethodNovel mouse models were created by genetic engineering or editing in C57BL/6J. Four to 24 months old mice and controls were phenotyped using a human‐relevant battery that includes cognitive performance, imaging, biometrics, transcriptomics, proteomics, metabolomics, neuropathology, and fluid biomarkers. Toxicants (As, Pb, Cd) were delivered using human‐relevant doses in drinking water. Exogenous toxicants (Pb, Cd, As) and endogenous biometals (Zn, Cu, Fe) in brain and blood samples were analyzed by elemental mass spectrometry mapping.ResultMore than 40 mouse models have been created carrying combinations of genetic risk factors in genes including APOE, Trem2, Abca7 and Mthfr. One strain, LOAD2 (triple homozygous for APOE4, Trem2*R47H, and hAb) shows molecular and transcriptomic changes associated with human LOAD. Short‐term exposure to As, Cd, or Pb also modified expression of LOAD‐relevant genes in LOAD2 mice and controls, including App and Vgf, in a toxicant‐specific manner. Elevated toxicant levels were detected in both brain and blood samples from exposed mice.ConclusionThese data indicate that exposure to common environmental toxicants may increase LOAD risk by modifying expression of specific genes and molecular pathways previously implicated in human LOAD. Studies are underway using additional MODEL‐AD models to determine the long‐term effects of neurotoxicant exposures.

Sex difference of pre- and post-natal exposure to six developmental neurotoxicants on intellectual abilities: a systematic review and meta-analysis of human studies

BackgroundEarly life exposure to lead, mercury, polychlorinated biphenyls (PCBs), polybromide diphenyl ethers (PBDEs), organophosphate pesticides (OPPs), and phthalates have been associated with lowered IQ in children. In some studies, these neurotoxicants impact males and females differently. We aimed to examine the sex-specific effects of exposure to developmental neurotoxicants on intelligence (IQ) in a systematic review and meta-analysis.MethodWe screened abstracts published in PsychINFO and PubMed before December 31st, 2021, for empirical studies of six neurotoxicants (lead, mercury, PCBs, PBDEs, OPPs, and phthalates) that (1) used an individualized biomarker; (2) measured exposure during the prenatal period or before age six; and (3) provided effect estimates on general, nonverbal, and/or verbal IQ by sex. We assessed each study for risk of bias and evaluated the certainty of the evidence using Navigation Guide. We performed separate random effect meta-analyses by sex and timing of exposure with subgroup analyses by neurotoxicant.ResultsFifty-one studies were included in the systematic review and 20 in the meta-analysis. Prenatal exposure to developmental neurotoxicants was associated with decreased general and nonverbal IQ in males, especially for lead. No significant effects were found for verbal IQ, or postnatal lead exposure and general IQ. Due to the limited number of studies, we were unable to analyze postnatal effects of any of the other neurotoxicants.ConclusionDuring fetal development, males may be more vulnerable than females to general and nonverbal intellectual deficits from neurotoxic exposures, especially from lead. More research is needed to examine the nuanced sex-specific effects found for postnatal exposure to toxic chemicals.

22 Neuropsychological Outcomes Vary by Sex in Neurotoxicant Exposed Veterans with Gulf War Illness

Objective:More than 30 years after the 199091 Gulf War (GW), approximately 200,000 veterans are still suffering from Gulf War Illness (GWI). Veterans who have this multi-symptom disorder experience impaired cognition, chronic pain, sustained fatigue, and gastrointestinal issues. GWI is believed to be associated with neurotoxicant exposures during the war. Prior research has shown cognitive deficits in combined samples of male and female GW veterans with GWI. These studies have shown that veterans with GWI have cognitive decrements in memory, learning and sustained attention. Studies have yet to compare neuropsychological outcomes by sex. This is mainly due to the lack of collected data on women GW veterans in the past. This study aims to analyze neuropsychological differences in males compared with female veterans with GWI and in those with neurotoxicant exposures from the Boston, Biorepository and Integrative Network (BBRAIN) for GWI repository dataset.Participants and Methods:The total sample included 297 veterans with GWI (women n=50, men n=247) who were deployed to the 1990-91 Gulf War with an average age of 52 years. GWI case status was defined by the Kansas GWI criteria. Neuropsychological data including the Conners Continuous Performance Test Third Edition (CPT3), Delis-Kaplan Executive Function System (D-KEFS) Color-Word Interference Test, and the California Verbal Learning Test (CVLT-II) were combined from the BBRAIN repository datasets. War-related exposures, including chemical weapons, anti-nerve gas pills and pesticides were measured by a self-reported survey. Multiple linear regression was used to analyze the association between sex, war-related exposures, and neuropsychological test score outcomes.Results:After adjusting for age, education level and PTSD, men had a significantly lower number of words correct in the CVLT-II learning Trials 1-5, short delay recall and long delay recall compared with women veterans (p&lt;0.05). The two groups also differed significantly in CPT3 commission scores, and total time on the D-KEFs Color-Word Inference total times in Trials 1 and 2 with men performing worse (p&lt;0.05). Reported exposure to chemical weapons, pesticides, pyridostigmine bromide (PB) anti-nerve gas pills or smoke from oil well fires were all significantly associated with fewer words correctly recalled on all learning trials of the CVLT-II, long delay, and short delay to a greater degree in men as compared to women (p&lt;0.05). Reported exposure to chemical weapons or smoke from oil well fires were significantly associated with more commission errors on CPT3 in men with GWI (p&lt;0.05). Chemical alarms, smoke from oil well fires and PB were associated with slower response time on the Color-Word Interference test Trial 1 in men compared with women veterans.Conclusions:In this study, men with GWI demonstrated significantly poorer performance in verbal memory, learning, response speed and attention. Male veterans reporting neurotoxicant exposures during the war also showed worse learning and verbal memory, impulsivity and response speed decrements compared to exposed women veterans. Future research should consider men and women separately when examining outcomes from war-related exposures.

16 Longitudinal Cognitive Functioning in Gulf War veterans with and without Gulf War Illness: Data Mining from the BBRAIN Repository

Objective:Veterans from the 1991 Gulf War (GW) experienced several neurotoxicant exposures, including chemical weapons, pesticide sprays and creams, oil well fires and pyridostigmine bromide anti-nerve gas pills during the war. Research has shown these exposures to affect cognition and mood. Moreover, MR diffusion imaging has shown microstructural changes in the white matter that may be related to psychomotor slowing. Over a third of all GW veterans suffer from a chronic multi-symptom disorder called Gulf War Illness (GWI). The Kansas Criteria for GWI consists of six distinct criteria including symptoms of fatigue/sleep problems, pain symptoms, neurologic/cognitive/mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms. The Boston Gulf War Illness Consortium (GWIC) was a multi-site study designed to assess symptoms of GWI. After the conclusion of the GWIC study, the Boston Biorepository Recruitment and Integrative Network for Gulf War Illness (BBRAIN) was developed to harmonize retrospectively collected GW Veteran data while simultaneously collecting Time 2 data and samples from GW veterans who participated in the original study. This analysis includes the first 58 participants who have completed the GWIC study and the BBRAIN study.Participants and Methods:We conducted a longitudinal analysis of cognitive outcomes from the BBRAIN data repository. Verbal learning, memory, attention, and executive functioning were assessed using neuropsychological tests including the Continuous Performance Test (CPT3), Trail Making Test A, Delis-Kaplan Executive Function System (DKEFS), California Verbal Learning Test (CVLT-II). A total of 58 participants were re-evaluated from the original GWIC cohort with a total of 47 cases and 11 controls. Paired t-tests for the cognitive measures were completed separately for GWI cases and healthy GW veteran controls for each of the neuropsychological test measures. Average time between assessments was four years.Results:The overall sample was on average 56 years old, 84% male and 75% White. The average level of education was 15 years. GWI cases showed significantly more commission errors and slower reaction times on the CPT3 at Time 2 compared to Time 1 (p &lt; 0.05). Cases also showed a slowing in time to completion on Trails A at the second time point (p&lt;0.05). On the other hand, controls only showed significantly slower reaction times on the CPT3 at Time 2 (p&lt;0.05).Conclusions:These results showed that veterans with GWI are showing more decline over time in cognitive functioning particularly on psychomotor slowing and impulsivity than control veterans. It is important to document illness trajectories for veterans with GWI in order to devise strategies for interventions and treatments. The importance of studying longitudinal cohorts is to document changes in the same individuals over time. The next steps are to assess if this accelerated aging develops into neurodegenerative conditions by using brain imaging and other biomarkers in addition to cognitive evaluations. This could identify individuals who should be the focus of targeted treatment strategies while there is still time to intervene.

Symposium 02: Current Directions in Women’s Neuropsychology Research

Summary Abstract:A longstanding trend of underrepresentation of women in pre-clinical and clinical research limits our understanding of women’s issues across several scientific fields, including neuropsychology and related disciplines. Highlighting this trend is the fact that only 2-6% of studies across major neuroscience journals over the last decade were conducted exclusively in women/females. This pattern of research limits our understanding of how women’s unique physiological, hormonal, psychiatric, and psychosocial presentations contribute to their brain health. Inclusion efforts aimed at increasing the study of more diverse populations have resulted in a nascent understanding of sex differences across several neuropsychological conditions, with implications for identification, prevention, and intervention efforts unique to women.In this seminar, we highlight current efforts by neuropsychologists to expand research of women in order to enhance our understanding and clinical care of this population. Of note, we use the standardized term “women” to describe a biological category (females) and/or a self-identified gender trait, which varies depending on the scope of the research and data availability. We highlight five lines of women’s-focused research spanning epilepsy/seizure disorders, traumatic brain injury (TBI), Alzheimer’s Disease (AD), and neurotoxicant exposure. In Dr. Sullivan-Baca’s presentation, ongoing lines of research into the clinical presentations of women with epilepsy are discussed. Findings highlight substantial psychiatric burden and unique medical factors to consider in women within this population. Dr. Jak’s presentation expands on concussion outcomes in women using the national FITBIR database and highlights a sex difference in postconcussive outcomes, with increased cognitive and somatic symptoms in women compared to men. Dr. Rapport and colleagues focus on the experience of menopause after TBI and discuss validation of a menopause symptom survey for TBI survivors. Dr. Sundermann’s presentation covers findings on women’s unique preclinical Alzheimer’s Disease trajectories. Dr. Krengel focuses on health trajectories for women Veterans exposed to neurotoxicants during the Gulf War and underlines sex differences in neuropsychological test performance. Through these presentations, our goal is both to inform and to inspire. Overall, we seek to orient members of our field to current directions in women’s research so they can better understand how women are differentially affected by neurological conditions. Clinically, we hope this knowledge will encourage neuropsychologists to understand how their women patients’ unique experiences of sex and gender contribute to their brain health. For researchers, we hope that attending this symposium will encourage pursuit of women’s-focused lines of inquiry. Furthermore, we hope to inspire training institutions to integrate this type of research more systematically into graduate student didactics and training, particularly for those students in neuropsychology-focused training.

24 Longitudinal Neuropsychological Functioning in Gulf War Veterans Exposed to Neurotoxicants and War-Related Trauma

Objective:Gulf War (GW) veterans were exposed to many neurotoxicants during the 1990-1991 Gulf War. Neurotoxicants included: chemical warfare such as sarin nerve gas, combustion byproducts from oil well fires and diesel fuels from tent heaters, pesticides, and prophylactic anti- nerve gas pyridostigmine bromide pills (PB); all of which have been associated with both cognitive and mood concerns. There are few longitudinal studies that have examined cognitive functioning regarding these toxicant exposures. In our longitudinal Fort Devens cohort, we found decrements over time in the area of verbal learning and memory but no differences in measures of nonverbal memory and executive function. To describe changes more accurately over time in this GW veteran cohort, we examined cognitive functioning in those with probable Post-Traumatic Stress Disorder (PTSD) versus those without.Participants and Methods:The FDC is the longest running cohort of GW veterans with initial baseline cognitive, mood, exposure and trauma assessments in 1997-1998 and follow-up evaluations in 2019-2022. FDC veterans (N=48) who completed both time points were the participants for this study. Veterans were categorized into dichotomous (yes/no) groups of PTSD classification. The PTSD checklist (PCL) was used to determine PTSD case status. Symptom ratings on the PCL were summed (range:17-85) and a cutoff score of 36 or higher was utilized to indicate probable PTSD. Neuropsychological measures of mood (POMS) and memory (Visual Reproductions from the Weschler Memory Scale-R; California Verbal Learning Test Second Edition; CVLT2) and executive function and language; (Delis-Kaplan Executive Function System- Color Word and Verbal fluency- Animals) were compared overtime using Paired T-tests.Results:The study sample (N=48) was 92% male and 96% reported active-duty status at the time of the GW. Mean current age was 58 years. All veterans reported exposure to at least one war-related toxicant. 48% met criteria for probable PTSD (N = 23) while 52% did not (n=25). No differences between groups were found in any of the POMS subscales, nor were differences seen in verbal memory, executive function, or language tasks. There were, however, significant differences in nonverbal memory in those with probable PTSD showing fewer details recalled during delay on the WMS-R Visual Reproductions (p&lt;0.05).Conclusions:In this longitudinal analysis, GW veterans with PTSD showed declines in nonverbal memory and consistent levels of function in all other tasks. Basic mood scales did not show decline; therefore, these results are not due to generalized changes in mood. All participants reported at least one neurotoxicant exposure and we did not have the power to examine the impact of the individual exposures, thus we cannot rule any contributing factors other than PTSD. This study highlights the importance of longitudinal follow up and continual documentation of GW veterans’ memory performance and their endorsement of mood symptoms overtime. Specifically, these findings reveal that future studies should examine the prolonged course of memory and mood symptomatology in GW veterans who have endorsed a traumatic experience.

2 Sex difference of Developmental Neurotoxicants on Intellectual Abilities: A Systematic Review and Meta-Analysis

Objective:Early life exposures to lead, mercury, polychlorinated biphenyls (PCBs), polybromide diphenyl ethers (PBDEs), organophosphate pesticides (OPPs), and phthalates have been associated with diminished IQ scores in children. Some studies suggest that these neurotoxicants impact boys and girls differently. We conducted a systematic review and meta-analysis to identify and quantify sex differences in IQ deficits from pre- and post-natal exposures to these developmental neurotoxicants.Participants and Methods:We used PubMed and PsychINFO to screen abstracts of articles published between January 1, 1950 and December 31, 2021 for empirical studies of six neurotoxicants [lead, mercury, PCBs, PBDEs, OPPs, and/or phthalates] that (1) used an individualized biomarker; (2) measured exposure during the prenatal period or within the first six years of life; and (3) provided different effect estimates on children's intellectual abilities by sex. We assessed each study for risk of bias using Navigation Guide (Woodruff &amp; Sutton, 2014). For studies with combinable data, we performed separate random effects meta-analyses for boys and girls with subgroup analyses by neurotoxicant. To homogenize the magnitude of effect observed in each study, we recalculated results to be expressed as the absolute change in intellectual abilities for a relative change of 1.5 times (i.e., 50% increase) in the exposure variable.Results:Of 3205 studies screened, 53 met inclusion criteria: 34 evaluated prenatal exposure, 11 postnatal exposure, and 8 both pre- and post-natal exposure. We generally rated these studies as "low" to "probably low" risk of bias. Among the studies examining prenatal exposure, 27 reported no significant differences between the sexes, 7 found negative associations in boys, 4 found negative associations in girls, 5 found negative nonsignificant associations in boys and positive nonsignificant associations in girls, and 3 found no clear pattern, where differences by sex depended on the specific phthalate compound or outcome measurement. Among the studies examining postnatal exposure, 14 reported no significant differences between the sexes, 1 found a negative association in boys, 2 found negative associations in girls, and 2 found positive associations for either boys or girls. In our meta-analysis of 16 studies (4 lead, 4 mercury, 2 PBDEs, 2 OPPs, 4 phthalates), we found that prenatal exposure to developmental neurotoxicants was associated with decreased full-scale intelligence in boys (B = -0.26; 95% CI: -0.45, -0.08), but not girls (B = 0.09; 95% CI: -0.14, 0.31). In subgroup analyses by neurotoxicant, prenatal exposure to lead (B = -1.07; 95% CI: -1.63, -0.52), and ZPBDEs (B = -0.57; 95% CI: -1.14, -0.01) were associated with decreased full-scale intelligence in boys, whereas the girls' effect sizes were consistently near zero.Conclusions:During fetal development, boys appear to be more vulnerable than girls to IQ deficits from neurotoxic exposures, and especially from lead and PBDEs. More research is needed to examine the nuanced sex-specific effects found for postnatal exposures to toxic chemicals.

Environmental Neurochemistry and Neurodevelopmental Disorders in Pediatrics

Neurochemistry about environment and neurodevelopmental disorders in children is the interesting part of the analysis of the research paper. This paper focuses on the effects brought on by toxins in the environment such as heavy metals and pesticides to a developing brain and common disorder relating to ADHD as well as autism spectrum disorders. Placing the focus on policy and community intervention, as well as to determine the effective step for intervention, this study examines the biochemical pathways to neurotoxic exposures. Therefore, the aim of this current study is to enhance knowledge on risks to the environment in order to afford optimal neurodevelopment to children.