The influence of environmental particulate matter exposure during late gestation and early life on the risk of neurodevelopmental disorders: A systematic review of experimental evidences.

Particulate matter (PM) is a major component of ambient air pollution (AAP), being widely associated with adverse health effects. Epidemiological and experimental studies point towards a clear implication of AAP on the development of central nervous system (CNS) diseases. In this sense, the period of most CNS susceptibility is early life, when the CNS is maturing. In humans the last trimester of gestation is crucial for brain maturation while in rodents, due to the shorter gestational period, the brain is still immature at birth, and early postnatal development plays a significant role. The present systematic review provides an updated overview and discusses the existing literature on the relationship between early exposure to PM and neurodevelopmental outcomes in experimental studies. We included 11 studies with postnatal exposure and 9 studies with both prenatal and postnatal exposure. Consistent results between studies suggest that PM exposure could alter normal development, triggering impairments in short-term memory, sociability, and impulsive-like behavior. This is also associated with alterations in synaptic plasticity and in the immune system. Interestingly, differences have been observed between sexes, although not all studies included females. Furthermore, the developmental window of exposure seems to be crucial for effects to be observed in the future. In summary, air pollution exposure during development affects subjects in a time- and sex-dependent manner, the postnatal period being more important and being males apparently more sensitive to exposure than females. Nevertheless, additional experimental investigations should prioritize the examination of learning, impulsivity, and biochemical parameters, with particular attention provided to disparities between sexes.

Uncovering the link between air pollution and neurodevelopmental alterations during pregnancy and early life exposure: A systematic review.

Air pollution plays, nowadays, a huge role in human's health and in the personal economy. Moreover, there has been a rise in the prevalence of neurodevelopmental disorders like the Autism Spectrum Disorder (ASD) in recent years. Current scientific studies have established a link between prenatal or perinatal exposure to environmental pollutants and ASD. This systematic review summarizes the current literature available about the relationship between exposure to air pollutants (particulate matter [PM], Second Organic Aerosols [SOA], Diesel Exhaust [DE], and Traffic Related Air Pollution [TRAP]) and neurodevelopmental disorders in preclinical models using rats and mice. The articles were selected and filtered using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, and bias-evaluated using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool. Overall, our findings suggest that air pollutants are associated with negative developmental outcomes characterized by ASD-like behaviors, abnormal biochemical patterns, and impaired achievement of developmental milestones in rodents. However, there is not sufficient information in certain domains to establish a clear relationship. Short phrases for indexing terms: Air pollution affects neurodevelopment; PM exposure modifies glutamate system; Prenatal exposure combined with postnatal affect more to behavioral / cognitive domain; Air pollution modifies social behavior in rodents; Cognitive deficits can be detected after gestational exposure to air pollution.

Particulate Matter in Human Elderly: Higher Susceptibility to Cognitive Decline and Age-Related Diseases.

This review highlights the significant impact of air quality, specifically particulate matter (PM), on cognitive decline and age-related diseases in the elderly. Despite established links to other pathologies, such as respiratory and cardiovascular illnesses, there is a pressing need for increased attention to the association between air pollution and cognitive aging, given the rising prevalence of neurocognitive disorders. PM sources are from diverse origins, including industrial activities and combustion engines, categorized into PM10, PM2.5, and ultrafine PM (UFPM), and emphasized health risks from both outdoor and indoor exposure. Long-term PM exposure, notably PM2.5, has correlated with declines in cognitive function, with a specific vulnerability observed in women. Recently, extracellular vesicles (EVs) have been explored due to the interplay between them, PM exposure, and human aging, highlighting the crucial role of EVs, especially exosomes, in mediating the complex relationship between PM exposure and chronic diseases, particularly neurological disorders. To sum up, we have compiled the pieces of evidence that show the potential contribution of PM exposure to cognitive aging and the role of EVs in mediating PM-induced cognitive impairment, which presents a promising avenue for future research and development of therapeutic strategies. Finally, this review emphasizes the need for policy changes and increased public awareness to mitigate air pollution, especially among vulnerable populations such as the elderly.

Emptiness in the study of emotions in the teaching-learning process of reading-writing during the COVID-19 pandemic.

The teaching-learning process of reading and writing has great relevance in the psycho-emotional and socio-psychological development of school-age children. This is an exercise in which they develop imagination, attention and memory capacity and through this process the management of emotions and sensitivity and capacity of apprehension of reality. The crisis derived from the COVID-19 pandemic transformed reality in an unprecedented way in the recent history of humanity and the educational context was shaken by all these changes. With confinement, the teaching-learning process of reading and writing, which is designed to take place in person, had to be developed in a hybrid or online way, which was a major challenge for teachers and families and, of course, also for children who were in the process of learning. One of the aspects that was blurred in this context was the role of the teacher, which in this case is one of the most important elements, to achieve adequate learning of reading and writing. On one hand, the teacher is in charge of helping to manage the emotions derived from the learning process itself and, on the other hand, he is a key figure so that this is not only technical learning but also contributes to the child's socio-emotional development. The aim of this study was to analyze the impact of the socio-psychological changes that have occurred in the educational context since the COVID-19 pandemic on the emotions linked to the teaching process, learning of reading and writing through a systematic review of the studies carried out on the subject, in order to provide recommendations for face-to-face learning in the post-COVID-19 era. A systematic review strategy was devised and the literature search was conducted. The search was conducted using ERIC, Dialnet, Scopus, WoS, EBSCO, and Google Scholar databases. This systematic review took place during the month of May 2022. The results show that given the scarce presence of empirical studies on the subject, the objective has only been partially met. However, a systematic review of the studies carried out on the subject. For the identification of recommendations in the development of face-to-face learning in the post-covid era, it has been possible to identify some ideas of interest for future curricular designs in primary school students who are immersed in learning to read and write.

BXD Recombinant Inbred Mice as a Model to Study Neurotoxicity.

BXD recombinant inbred (RI) lines represent a genetic reference population derived from a cross between C57BL/6J mice (B6) and DBA/2J mice (D2), which through meiotic recombination events possesses recombinant chromosomes containing B6 or D2 haplotype segments. The quantitative trait loci (QTLs) are the locations of segregating genetic polymorphisms and are fundamental to understanding genetic diversity in human disease susceptibility and severity. QTL mapping represents the typical approach for identifying naturally occurring polymorphisms that influence complex phenotypes. In this process, genotypic values at markers of known genomic locations are associated with phenotypic values measured in a segregating population. Indeed, BXD RI strains provide a powerful tool to study neurotoxicity induced by different substances. In this review, we describe the use of BXD RI lines to understand the underlying mechanisms of neurotoxicity in response to ethanol and cocaine, as well as metals and pesticide exposures.

The BXD21/TyJ recombinant inbred strain as a model for innate inflammatory response in distinct brain regions.

Oxidative stress and inflammatory cytokines affect the human brain, increasing the risk for mood and cognitive disorders. Such risk might be selective to brain-specific regions. Here, we determined whether BXD recombinant inbred (RI) mice strains are more suitable than C57BL/6J mice for the understanding of the relationship between antioxidant response and inflammatory responses. We hypothesized that inflammatory responses could be independent of antioxidant response and be inherent to brain-specific regions. This hypothesis will be addressed by the analyses of mRNA expression. We explored, at 7-months-of-age, the innate activation of proinflammatory cytokines (tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6), as well as Kelch-like ECH-associating protein 1 (Keap1), nuclear factor erythroid 2 related factor 2 (Nrf2) and glutathione peroxidase 1 (Gpx1) mRNA in both male and female BXD84/RwwJ RI, BXD21/TyJ RI and control strain (C57BL/6J mice). We report that: (1) The cerebellum is more sensitive to antioxidant response in the BXD21/TyJ RI strain; (2) The cerebellum, hippocampus and striatum show increased levels of cytokines in the BXD21/TyJ RI strain; (3) The BXD RI strain has lower brain weight relative to control strain (C57BL/6 mice). In conclusion, our novel data show the utility of the BXD21/TyJ RI strain mice in offering mechanistic insight into Nrf2's role in the inflammatory system.

Oxidative stress, caspase-3 activation and cleavage of ROCK-1 play an essential role in MeHg-induced cell death in primary astroglial cells.

Methylmercury is a toxic environmental contaminant that elicits significant toxicity in humans. The central nervous system is the primary target of toxicity, and is particularly vulnerable during development. Rho-associated protein kinase 1 (ROCK-1) is a major downstream effector of the small GTPase RhoA and a direct substrate of caspase-3. The activation of ROCK-1 is necessary for membrane blebbing during apoptosis. In this work, we examined whether MeHg could affect the RhoA/ROCK-1 signaling pathway in primary cultures of mouse astrocytes. Exposure of cells with 10 µM MeHg decreased cellular viability after 24 h of incubation. This reduction in viability was preceded by a significant increase in intracellular and mitochondrial reactive oxygen species levels, as well as a reduced NAD+/NADH ratio. MeHg also induced an increase in mitochondrial-dependent caspase-9 and caspase-3, while the levels of RhoA protein expression were reduced or unchanged. We further found that MeHg induced ROCK-1 cleavage/activation and promoted LIMK1 and MYPT1 phosphorylation, both of which are the best characterized ROCK-1 downstream targets. Inhibiting ROCK-1 and caspases activation attenuated the MeHg-induced cell death. Collectively, these findings are the first to show that astrocytes exposed to MeHg showed increased cleavage/activation of ROCK-1, which was independent of the small GTPase RhoA.

BXD recombinant inbred strains participate in social preference, anxiety and depression behaviors along sex-differences in cytokines and tactile allodynia.

Depression and anxiety are the most common psychiatric disorders, representing a major public health concern. Dysregulation of oxidative and inflammatory systems may be associated with psychiatric disorders, such as depression and anxiety. Due to the need to find appropriate animal models to the understanding of such disorders, we queried whether 2 BXD recombinant inbred (RI) mice strains (BXD21/TyJ RI and BXD84/RwwJ RI mice) and C57BL/6 wild-type mice show differential performance in depression and anxiety related behaviors and biomarkers. Specifically, we assessed social preference, elevated plus maze, forced swim, and Von Frey tests at 3-4 months-of-age, as well as activation of cytokines and antioxidant mRNA levels in the cortex at 7 months-of-age. We report that (1) the BXD84/RwwJ RI strain exhibits anxiety disorder and social avoidance-like behavior (2) BXD21/TyJ RI strain shows a resistance to depression illness, and (3) sex-dependent cytokine profiles and allodynia with elevated inflammatory activity were inherent to male BXD21/TyJ RI mice. In conclusion, we provide novel data in favor of the use of BXD recombinant inbred mice to further understand anxiety and depression disorders.

Methylmercury and brain development: A review of recent literature.

Methylmercury (MeHg) is a potent environmental pollutant, which elicits significant toxicity in humans. The central nervous system (CNS) is the primary target of toxicity, and is particularly vulnerable during development. Maternal exposure to MeHg via consumption of fish and seafood can have irreversible effects on the neurobehavioral development of children, even in the absence of symptoms in the mother. It is well documented that developmental MeHg exposure may lead to neurological alterations, including cognitive and motor dysfunction. The neurotoxic effects of MeHg on the developing brain have been extensively studied. The mechanism of toxicity, however, is not fully understood. No single process can explain the multitude of effects observed in MeHg-induced neurotoxicity. This review summarizes the most current knowledge on the effects of MeHg during nervous system development considering both, in vitro and in vivo experimental models. Considerable attention was directed towards the role of glutamate and calcium dyshomeostasis, mitochondrial dysfunction, as well as the effects of MeHg on cytoskeletal components/regulators.

Chronic dietary chlorpyrifos causes long-term spatial memory impairment and thigmotaxic behavior.

Little is known about the long-term effects of chronic exposure to low-level organophosphate (OP) pesticides, and the role of neurotransmitter systems, other than the cholinergic system, in mediating OP neurotoxicity. In this study, rats were administered 5mg/kg/day of chlorpyrifos (CPF) for 6 months commencing at 3-months-of-age. The animals were examined 7 months later (at 16-months-of-age) for spatial learning and memory in the Morris water maze (MWM) and locomotor activity. In addition, we assessed the chronic effects of CPF on glutamatergic and gamma-aminobutyric acid (GABAergic) function using pharmacological challenges with dizocilpine (MK801) and diazepam. Impaired performance related to altered search patterns, including thigmotaxis and long-term spatial memory was noted in the MWM in animals exposed to CPF, pointing to dietary CPF-induced behavioral disturbances, such as anxiety. Twenty-four hours after the 31st session of repeated acquisition task, 0.1mg/kg MK801, an N-methyl-d-aspartate (NMDA) antagonist was intraperitoneally (i.p.) injected for 4 consecutive days. Decreased latencies in the MWM in the control group were noted after two sessions with MK801 treatment. Once the MWM assessment was completed, animals were administered 0.1 or 0.2mg/kg of MK801 and 1 or 3mg/kg of diazepam i.p., and tested for locomotor activity. Both groups, the CPF dietary and control, displayed analogous performance in motor activity. In conclusion, our data point to a connection between the long-term spatial memory, thigmotaxic response and CPF long after the exposure ended.

Comparative study on short- and long-term behavioral consequences of organophosphate exposure: relationship to AChE mRNA expression.

Organophosphates (OPs) affect behavior by inhibiting acetylcholinesterase (AChE). While the cognitive short-term effects may be directly attributed to this inhibition, the mechanisms that underlie OP's long-term cognitive effects remain controversial and poorly understood. Accordingly, two experiments were designed to assess the effects of OPs on cognition, and to ascertain whether both the short- and long-term effects of are AChE-dependent. A single subcutaneous dose of 250 mg/kg chlorpyrifos (CPF), 1.5mg/kg diisopropylphosphorofluoridate (DFP) or 15 mg/kg parathion (PTN) was administered to male Wistar rats. Spatial learning was evaluated 72 h or 23 weeks after exposure, and impulsive choice was tested at 10 and 30 weeks following OPs administration (experiment 1 and 2, respectively). Brain soluble and membrane-bound AChE activity, synaptic AChE-S mRNA, read-through AChE-R mRNA and brain acylpeptide hydrolase (APH) activity (as alternative non-cholinergic target) were analyzed upon completion of the behavioral testing (17 and 37 weeks after OPs exposure). Both short- and long-term CPF treatment caused statistically significant effects on spatial learning, while PTN treatment led only to statistically significant short-term effects. Neither CPF, DFP nor PTN affected the long-term impulsivity response. Long-term exposure to CPF and DFP significantly decreased AChE-S and AChE-R mRNA, while in the PTN treated group only AChE-S mRNA levels were decreased. However, after long-term OP exposure, soluble and membrane-bound AChE activity was indistinguishable from controls. Finally, no changes were noted in brain APH activity in response to OP treatment. Taken together, this study demonstrates long-term effects of OPs on AChE-S and AChE-R mRNA in the absence of changes in AChE soluble and membrane-bound activity. Thus, changes in AChE mRNA expression imply non-catalytic properties of the AChE enzyme.

Chronic dietary exposure to chlorpyrifos causes behavioral impairments, low activity of brain membrane-bound acetylcholinesterase, and increased brain acetylcholinesterase-R mRNA.

Chlorpyrifos (CPF) is an organophosphate (OP) insecticide that is metabolically activated to the highly toxic chlorpyrifos oxon. Dietary exposure is the main route of intoxication for non-occupational exposures. However, only limited behavioral effects of chronic dietary exposure have been investigated. Therefore, male Wistar rats were fed a dose of 5mg/kg/day of CPF for thirty-one weeks. Animals were evaluated in spatial learning and impulsivity tasks after 21 weeks of CPF dietary exposure and one week after exposure ended, respectively. In addition, the degree of inhibition of brain acetylcholinesterase (AChE) was evaluated for both the soluble and particulate forms of the enzyme, as well as AChE gene expression. Also, brain acylpeptide hydrolase (APH) was investigated as an alternative target for OP-mediated effects. All variables were evaluated at various time points in response to CPF diet and after exposure ended. Results from behavioral procedures suggest cognitive and emotional disorders. Moreover, low levels of activity representing membrane-bound oligomeric forms (tetramers) were also observed. In addition, increased brain AChE-R mRNA levels were detected after four weeks of CPF dietary exposure. However, no changes in levels of brain APH were observed among groups. In conclusion, our data point to a relationship between cognitive impairments and changes in AChE forms, specifically to a high inhibition of the particulate form and a modification of alternative splicing of mRNA during CPF dietary exposure.

Dose-dependent regional brain acetylcholinesterase and acylpeptide hydrolase inhibition without cell death after chlorpyrifos administration.

Organophosphates (OPs) are important toxic compounds commonly used for a variety of purposes in agriculture, industry and household settings. It has been well established that the main mechanism of acute toxic action of OP is the inhibition of acetylcholinesterase (AChE). However, we observed long term deficit after acute subcutaneous exposure to Chlorpyrifos (CPF) even when AChE activity is restored. In fact, besides AChE inhibition, non-AChE targets have also been proposed as an alternative mechanism involved in the acute lethal action and side effects of short or long-term exposure. In this context, our main aim in this research was to establish a dose-response curve of Acylpeptide hydrolase (APH) and AChE regional brain activity after acute CPF administration that could explain these long term effects observed in the literature. Moreover, since available data suggest that long term effects of OPs exposure could involve neuronal cell death, our second aim was to evaluate, assessing by Fluoro-Jade B (FJB) staining, whether CPF produces induced cell death. Our results show that an acute exposure to 250 mg/kg CPF does not induce neuronal death as measured by FJB but produces highest AChE regional brain inhibition after administration. In addition, APH seems to be more sensitive than AChE to CPF exposure because after 31 days of exposure, complete recovery was seen only for APH activity at Frontal Cortex, Cerebellum and Brain Stem.

Chlorpyrifos-, diisopropylphosphorofluoridate-, and parathion-induced behavioral and oxidative stress effects: are they mediated by analogous mechanisms of action?

Exposure to organophosphates (OPs) can lead to cognitive deficits and oxidative damage. Little is known about the relationship between behavioral deficits and oxidative stress within the context of such exposures. Accordingly, the first experiment was carried out to address this issue. Male Wistar rats were administered 250 mg/kg of chlorpyrifos (CPF), 1.5 mg/kg of diisopropylphosphorofluoridate (DFP), or 15 mg/kg of parathion (PTN). Spatial learning in the water maze task was evaluated, and F(2)-isoprostanes (F(2)-IsoPs) and prostaglandin (PGE(2)) were analyzed in the hippocampus. A second experiment was designed to determine the degree of inhibition of brain acetylcholinesterase (AChE) activity, both the soluble and particulate forms of the enzyme, and to assess changes in AChE gene expression given evidence on alternative splicing of the gene in response to OP exposures. In addition, brain acylpeptide hydrolase (APH) activity was evaluated as a second target for OP-mediated effects. In both experiments, rats were sacrificed at various points to determine the time course of OPs toxicity in relation to their mechanism of action. Results from the first experiment suggest cognitive and emotional deficits after OPs exposure, which could be due to, at least in part, increased F(2)-IsoPs levels. Results from the second experiment revealed inhibition of brain AChE and APH activity at various time points post OP exposure. In addition, we observed increased brain read-through splice variant AChE (AChE-R) mRNA levels after 48 h PTN exposure. In conclusion, this study provides novel data on the relationship between cognitive alterations and oxidative stress, and the diverse mechanisms of action along a temporal axis in response to OP exposures in the rat.