Developmental Neurotoxicity Research Articles

New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project.

In the European regulatory context, rodent in vivo studies are the predominant source of neurotoxicity information. Although they form a cornerstone of neurotoxicological assessments, they are costly and the topic of ethical debate. While the public expects chemicals and products to be safe for the developing and mature nervous systems, considerable numbers of chemicals in commerce have not, or only to a limited extent, been assessed for their potential to cause neurotoxicity. As such, there is a societal push toward the replacement of animal models with in vitro or alternative methods. New approach methods (NAMs) can contribute to the regulatory knowledge base, increase chemical safety, and modernize chemical hazard and risk assessment. Provided they reach an acceptable level of regulatory relevance and reliability, NAMs may be considered as replacements for specific in vivo studies. The European Partnership for the Assessment of Risks from Chemicals (PARC) addresses challenges to the development and implementation of NAMs in chemical risk assessment. In collaboration with regulatory agencies, Project 5.2.1e (Neurotoxicity) aims to develop and evaluate NAMs for developmental neurotoxicity (DNT) and adult neurotoxicity (ANT) and to understand the applicability domain of specific NAMs for the detection of endocrine disruption and epigenetic perturbation. To speed up assay time and reduce costs, we identify early indicators of later-onset effects. Ultimately, we will assemble second-generation developmental neurotoxicity and first-generation adult neurotoxicity test batteries, both of which aim to provide regulatory hazard and risk assessors and industry stakeholders with robust, speedy, lower-cost, and informative next-generation hazard and risk assessment tools.

Dihalogenated nitrophenols exposure induces developmental neurotoxicity in zebrafish embryo

2,6-Dihalogenated nitrophenols (2,6-DHNPs) are emerging halogenated nitroaromatic pollutants that have been detected in various water environments. However, there is currently limited research available regarding their potential impacts on locomotion behavior and neurotoxicity. Therefore, this study utilized zebrafish embryos to investigate the potential neurotoxic effects of 2,6-DHNPs by examining their impact on the nervous system at a concentration defined as 10% of the median lethal concentration. Our findings demonstrated that exposure to 2,6-DHNPs resulted in a significant 30 % decrease in the total swimming distance of zebrafish larvae, accompanied by notable impairments in motor neuron development and central nervous system. These effects were evidenced by a substantial 25% decrease in axonal growth, as well as disruptions in synapse formation and neuronal differentiation. Additionally, neurotransmitter analysis revealed marked decreases of 40%, 35%, and 30% in dopamine, 5-hydroxytryptamine, and acetylcholine levels respectively, highlighting disturbances in their synthesis, transport, and degradation mechanisms. These results emphasize the considerable neurotoxicity of 2,6-DHNPs at concentrations previously considered safe; thus necessitating a re-evaluation of environmental risk assessments and regulatory standards for such emerging contaminants.

Nanoplastics aggravated TDCIPP-induced transgenerational developmental neurotoxicity in zebrafish depending on the involvement of the dopamine signaling pathway

Plastics pose a hazard to the environment. Although plastics have toxicity, microplastics (MPs) and nanoplastics (NPs) are capable of interacting with the rest pollutants in the environment, so they serve as the carriers and interact with organic pollutants to modulate their toxicity, thus resulting in unpredictable ecological risks. PS-NPs and TDCIPP were used expose from 2 h post-fertilization (hpf) to 150 days post-fertilization (dpf) to determine the bioaccumulation of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and its potential effects on neurodevelopment in F1 zebrafish (Danio rerio) offspring under the action of polystyrene nano plastics (PS-NPs). The exposure groups were assigned to TDCIPP (0, 0.4, 2 or 10 µg/L) alone group and the PS-NPs (100 µg/L) and TDCIPP co-exposed group. F1 embryos were collected and grown in clean water to 5 dpf post-fertilization. PS-NPs facilitated the bioaccumulation of TDCIPP in the gut, gill, head，gonad and liver of zebrafish in a sex-dependent manner and promoted the transfer of TDCIPP to their offspring, thus contributing to PS-NPs aggravated the inhibition of offspring development and neurobehavior of TDCIPP-induced. In comparison with TDCIPP exposure alone, the combination could notably down-regulate the levels of the dopamine neurotransmitter, whereas the levels of serotonin or acetylcholine were not notably different. This result was achieved probably because PS-NPs interfered with the TDCIPP neurotoxic response of zebrafish F1 offspring not through the serotonin or acetylcholine neurotransmitter pathway. The increased transfer of TDCIPP to the offspring under the action of PS-NPs increased TDCIPP-induced transgenerational developmental neurotoxicity, which was proven by a further up-regulation/down-regulation the key gene and protein expression related to dopamine synthesis, transport, and metabolism in F1 larvae, in contrast to TDCIPP exposure alone. The above findings suggested that dopaminergic signaling involvement could be conducive to the transgenerational neurodevelopmental toxicity of F1 larval upon parental early co-exposure to PS-NPs and TDCIPP.

Decreases in the number of microglia and neural circuit dysfunction elicited by developmental exposure to neonicotinoid pesticides in mice.

Neonicotinoids are insecticides widely used in the world. Although neonicotinoids are believed to be toxic only to insects, their developmental neurotoxicity in mammals is a concern. Therefore, we examined the effects of developmental exposure to neonicotinoids on immune system in the brain and post-developmental behaviors in this study. Imidacloprid or clothianidin was orally administered to dams at a dosage of 0.1 mg/kg/day from embryonic day 11 to postnatal day 21. Imidacloprid decreased sociability, and both imidacloprid and clothianidin decreased locomotor activity and induced anxiety, depression and abnormal repetitive behaviors after the developmental period. There was no change in the number of neurons in the hippocampus of mice exposed to imidacloprid. However, the number and activity of microglia during development were significantly decreased by imidacloprid exposure. Imidacloprid also induced neural circuit dysfunction in the CA1 and CA3 regions of the hippocampus during the early postnatal period. Exposure to imidacloprid suppressed the expression of csf1r during development. Collectively, these results suggest that developmental exposure to imidacloprid decreases the number and activity of microglia, which can cause neural circuit dysfunction and abnormal behaviors after the developmental period. Care must be taken to avoid exposure to neonicotinoids, especially during development.

Exploring a mechanism-based approach for the identification of endocrine disruptors using Adverse Outcome Pathways (AOPs) and New Approach Methodologies (NAMs) : A perfluorooctane sulfonic acid case study

Endocrine disruptors (EDs) pose a serious threat to human health and the environment and require a comprehensive evaluation to be identified. The identification of EDs require a substantial amount of data, both in vitro and in vivo, due to the current scientific criteria in the EU. At the same time, the EU strives to reduce animal testing due to concerns regarding animal welfare and sensitivity of animal studies to adequately detect adverse effects relevant for human health. Perfluorooctane sulfonic acid (PFOS) is a persistent organic pollutant that is suspected to be an ED based on academic research, however it is not identified as such from a regulatory perspective. It has previously been shown that PFOS has the potential to cause neurotoxicity as well as affect the thyroid system, and it is known that specific thyroid hormone levels are critical in the development of the brain during. In this work, the aim was to evaluate a mechanism-based approach to identify ED properties of PFOS based on the Adverse Outcome Pathway (AOP) framework and using New Approach Methods (NAMs), by comparing this approach to an ED assessment based on the currently available guidance document. An AOP network (AOPN) was generated for the thyroid modality, and AOPs leading to developmental neurotoxicity (DNT) were identified. A literature search and screening process based on the AOPN, and systematic review methodology, was performed, followed by a rigorous Weight-of-Evidence (WoE) assessment. Evidence was mapped back onto the AOPN used for the literature search, to identify possible endocrine Modes-of-Action (MoAs) for PFOS and data gaps in the two assessments. It could be concluded that PFOS fulfils the criteria for ED classification in the standard ED assessment, but not in the mechanism-based assessment. The need for quantitative information, such as quantitative AOPs, for the mechanism-based approach is discussed. The possibility of a directly neurotoxic alternative MoA was also highlighted based on available in vitro data. Opportunities and challenges with implementing AOPs and NAMs into the regulatory assessment of EDs, and assessing hazard in the Next Generation Risk Assessment, is discussed. This case study exploring the mechanism-based approach to ED identification represents an important step toward more accurate and predictive assessment of EDs based on AOPs and NAMs, and to the Next Generation Risk Assessment (NGRA) concept.

Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity

BackgroundRepeated neonatal sevoflurane exposures led to neurocognitive disorders in young mice. We aimed to assess the role of microglia and complement C1q in sevoflurane-induced neurotoxicity and explore the underlying mechanisms.MethodsNeonatal mice were treated with sevoflurane on postnatal days 6, 8, and 10, and the Morris water maze was performed to assess cognitive functions. For mechanistic explorations, mice were treated with minocycline, C1q-antibody ANX005, and sialidase-inhibitor N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (NADNA) before sevoflurane exposures. Western blotting, RT-qPCR, Golgi staining, 3D reconstruction and engulfment analysis, immunofluorescence, and microglial morphology analysis were performed. In vitro experiments were conducted in microglial cell line BV2 cells.ResultsRepeated neonatal sevoflurane exposures resulted in deficiencies in learning and cognition of young mice, accompanied by microglial activation and synapse loss. Sevoflurane enhanced microglia-mediated synapse elimination through C1q binding to synapses. Inhibition of microglial activation and phagocytosis with minocycline significantly reduced the loss of synapses. We further revealed the involvement of neuronal sialic acids in this process. The enhanced activity of sialidase by sevoflurane led to the loss of sialic acids, which facilitated C1q binding to synapses. Inhibition of C1q with ANX005 or inhibition of sialidase with NADNA significantly rescued microglia-mediated synapse loss and improved neurocognitive function. Sevoflurane enhanced the engulfment of BV2 cells, which was reversed by ANX005.ConclusionsOur findings demonstrated that C1q-mediated microglial synaptic elimination by enhancing desialylation contributed to sevoflurane-induced developmental neurotoxicity. Inhibition of C1q or sialidase may be a potential therapeutic strategy for this neurotoxicity.

Global Trends and Hotspots in Pediatric Anesthetic Neurotoxicity Research: A Bibliometric Analysis From 2000 to 2023.

The impact of general anesthetics on brain function development is one of the top frontier issues of public concern. However, little bibliometric analysis has investigated this territory systematically. Our study aimed to visualize the publications between 2000 and 2023 to inspire the trends and hotspots in anesthetic neurodevelopmental toxicity research. Publications from 2000 to 2023 were collected from the Web of Science Core Collection. CiteSpace was utilized to plot and analyze the network maps of countries, institutions, authors, journals, and keywords associated with these publications. A total of 864 publications, consisting of 786 original articles and 78 reviews, were extracted from 2000 to 2023. The annual publications have increased constantly over the past two decades. The USA and the People's Republic of China were the leading driving forces in this field. Harvard University was the most productive institution. Zhang Y published the most related articles, and Jevtovic-Todorovic V was mostly cited in this field. The most prolific journal was Pediatric Anesthesia, and the most frequently co-cited journal was Anesthesiology. Keywords were divided into nine clusters: "apoptosis", "propofol", "developing brain", "cognitive dysfunction", "neuronal cell degeneration", "brain", "neuroinflammation", "local anesthesia", and "oxygen therapy". The strongest citation bursts in earlier years were "learning disability", "cell death", and "cognitive function". The emerging trends in the coming years were "awake regional anesthesia", "behavioral outcome", and "infancy general anesthesia compared to spinal anesthesia". We concludethat anesthetic-induced neurotoxicity has received growing attention in the past two decades. Our findings evaluated the present status and research trends in this area, which may provide help for exploring further potential prospects on hot topics and frontiers.

Nanoplastic Exposure Mediates Neurodevelopmental Toxicity by Activating the Oxidative Stress Response in Zebrafish (Danio rerio).

The global accumulation and adverse effects of nanoplastics (NPs) are a growing concern for the environment and human health. In recent years, more and more studies have begun to focus on the toxicity of plastic particles for early animal development. Different particle sizes of plastic particles have different toxicities to biological development. Nevertheless, the potential toxicological effects of 20 nm NPs, especially on neurodevelopment, have not been well investigated. In this paper, we used fluorescence microscopy to determine neurotoxicity in zebrafish at different concentrations of NPs. Moreover, the behavioral analysis demonstrated that NPs induced abnormal behavior of zebrafish. The results revealed developmental defects in zebrafish embryos after exposure to different concentrations (0, 0.3, 3, and 9 mg/L) of NPs. The morphological deformities, including abnormal body length and the rates of heart, survival, and hatching, were induced after NP exposure in zebrafish embryos. In addition, the development of primary motor neurons was observed the inhibitory effects of NPs on the length, occurrence, and development of primary motor neurons in Tg(hb9:GFP). Quantitative polymerase chain reaction analysis suggested that exposure to NPs significantly affects the expression of the genes involved in the occurrence and differentiation of primary motor neurons in zebrafish. Furthermore, the indicators associated with oxidative stress and apoptosis were found to be modified in zebrafish embryos at 24 and 48 h following exposure to NPs. Our findings demonstrated that NPs could cause toxicity in primary motor neurons by activating the oxidative stress response and inducing apoptosis, consequently impairing motor performance.

Embryotoxicity Induced by Triclopyr in Zebrafish (Danio rerio) Early Life Stage.

Triclopyr, an auxin-like herbicide that is widely employed for managing weeds in food crops and pastures, has been identified in various environmental settings, particularly aquatic ecosystems. Limited understanding of the environmental fate of this herbicide, its potential repercussions for both the environment and human health, and its insufficient monitoring in diverse environmental compartments has caused it to be recognized as an emerging contaminant of concern. In this study, we have investigated how triclopyr affects zebrafish, considering a new alternative methodology. We focused on the endpoints of developmental toxicity, neurotoxicity, and behavior of zebrafish embryos and larvae. We determined that triclopyr has a 96 h median lethal concentration of 87.46 mg/L (341.01 µM). When we exposed zebrafish embryos to sublethal triclopyr concentrations (0.5, 1, 5, 10, and 50 μM) for up to 144 h, we found that 50 µM triclopyr delayed zebrafish egg hatchability. Yolk sac malabsorption was significant at 0.5, 1, 5, and 10 µM triclopyr. In zebrafish larvae, uninflated swim bladder was significant only at 50 µM triclopyr. Furthermore, zebrafish larvae had altered swimming activity after exposure to 10 µM triclopyr for 144 h. In summary, these comprehensive results indicate that even low triclopyr concentrations can elicit adverse effects during early zebrafish development.

Internalization and toxicity of polystyrene nanoplastics on inmortalized human neural stem cells

Global plastic production has increased exponentially in recent decades, and a significant part of it persists in the environment, where it degrades into microplastics and nanoplastics (MPs and NPs). These can enter in humans by ingestion, inhalation, and dermal routes, and there is scientific evidence that they are able to reach the systemic circulation and penetrate and accumulate in various tissues and organs. Neurodevelopmental toxicity of NPs is one of the most worrying effects, as they can cross the blood-brain barrier. In the following study, we analyzed, by transmission electron microscopy, the in vitro uptake of 30-nm polystyrene nanoplastics (PS-NPs) into human neural stem cells (NSCs), their accumulation and subcellular localization within the cell. Furthermore, we studied the effects of different concentrations of PS-NPs on cell death, proliferation, and cell differentiation using immunocytochemistry and quantitative real time PCR for specific markers. This study demonstrated that PS-NPs were able to enter the cell, probably by endocytosis, accumulate, and aggregated in human NSCs, without being detected in the nucleus, causing cell death by apoptosis and decreased cell proliferation. This study provides new insights into the interaction and effects of PS-NPs in human NSC and supports the scientific evidence for the involvement of nanoplastic in neurodevelopmental disorders.

Early life phenobarbital exposure dysregulates the hippocampal transcriptome.

Introduction: Phenobarbital (PB) and levetiracetam (LEV) are the first-line therapies for neonates with diagnosed seizures, however, a growing body of evidence shows that these drugs given during critical developmental windows trigger lasting molecular changes in the brain. While the targets and mechanism of action of these drugs are well understood-what is not known is how these drugs alter the transcriptomic landscape, and therefore molecular profile/gene expression during these critical windows of neurodevelopment. PB is associated with a range of neurotoxic effects in developing animals, from cell death to altered synaptic development to lasting behavioral impairment. LEV does not produce these effects. Methods: Here we evaluated the effects of PB and Lev on the hippocampal transcriptome by RNA sequencing. Neonatal rat pups were given a single dose of PB, Lev or vehicle and sacrificed 72h later-at time at which drug is expected to be cleared. Results: We found PB induces broad changes in the transcriptomic profile (124 differentially expressed transcripts), as compared to relatively small changes in LEV-treated animals (15 transcripts). PB exposure decreased GABAergic and oligodendrocyte markers pvalb and opalin, and increased the marker of activated microglia, cd68 and the astrocyte- associated gene vegfa. These data are consistent with the existing literature showing developmental neurotoxicity associated with PB, but not LEV. Discussion: The widespread change in gene expression after PB, which affected transcripts reflective of multiple cell types, may provide a link between acute drug administration and lasting drug toxicity.

A Scoping Review of the Mechanisms Underlying Developmental Anesthetic Neurotoxicity.

Although anesthesia makes painful or uncomfortable diagnostic and interventional health care procedures tolerable, it may also disrupt key cellular processes in neurons and glia, harm the developing brain, and thereby impair cognition and behavior in children. Many years of studies using in vitro, animal behavioral, retrospective database studies in humans, and several prospective clinical trials in humans have been invaluable in discerning the potential toxicity of anesthetics. The objective of this scoping review was to synthetize the evidence from preclinical studies for various mechanisms of toxicity across diverse experimental designs and relate their findings to those of recent clinical trials in real-world settings.

Recent advances and current challenges of new approach methodologies in developmental and adult neurotoxicity testing.

Adult neurotoxicity (ANT) and developmental neurotoxicity (DNT) assessments aim to understand the adverse effects and underlying mechanisms of toxicants on the human nervous system. In recent years, there has been an increasing focus on the so-called new approach methodologies (NAMs). The Organization for Economic Co-operation and Development (OECD), together with European and American regulatory agencies, promote the use of validated alternative test systems, but to date, guidelines for regulatory DNT and ANT assessment rely primarily on classical animal testing. Alternative methods include both non-animal approaches and test systems on non-vertebrates (e.g., nematodes) or non-mammals (e.g., fish). Therefore, this review summarizes the recent advances of NAMs focusing on ANT and DNT and highlights the potential and current critical issues for the full implementation of these methods in the future. The status of the DNT in vitro battery (DNT IVB) is also reviewed as a first step of NAMs for the assessment of neurotoxicity in the regulatory context. Critical issues such as (i) the need for test batteries and method integration (from in silico and in vitro to in vivo alternatives, e.g., zebrafish, C. elegans) requiring interdisciplinarity to manage complexity, (ii) interlaboratory transferability, and (iii) the urgent need for method validation are discussed.

Protective effects of docosahexaenoic acid supplementation on cognitive dysfunction and hippocampal synaptic plasticity impairment induced by early postnatal PM2.5 exposure in young rats.

PM2.5 exposure is a challenging environmental issue that is closely related to cognitive development impairment; however, currently, relevant means for prevention and treatment remain lacking. Herein, we determined the preventive effect of docosahexaenoic acid (DHA) supplementation on the neurodevelopmental toxicity induced by PM2.5 exposure. Neonatal rats were divided randomly into three groups: control, PM2.5, and DHA + PM2.5 groups. DHA could ameliorate PM2.5-induced learning and memory dysfunction, as well as reverse the impairment of hippocampal synaptic plasticity, evidenced by enhanced long-term potentiation, recovered synaptic ultrastructure, and increased expression of synaptic proteins. Moreover, DHA increased CREB phosphorylation and BDNF levels and attenuated neuroinflammation and oxidative stress, reflected by lower levels of IBA-1, IL-1β, and IL-6 and increased levels of SOD1 and Nrf2. In summary, our findings demonstrated that supplementation of DHA effectively mitigated the cognitive dysfunction and synaptic plasticity impairment induced by early postnatal exposure to PM2.5. These beneficial effects may be attributed to the upregulation of the CREB/BDNF signaling pathway, as well as the reduction of neuroinflammation and oxidative stress.

Comprehensive mapping of the AOP-Wiki database: identifying biological and disease gaps.

Introduction: The Adverse Outcome Pathway (AOP) concept facilitates rapid hazard assessment for human health risks. AOPs are constantly evolving, their number is growing, and they are referenced in the AOP-Wiki database, which is supported by the OECD. Here, we present a study that aims at identifying well-defined biological areas, as well as gaps within the AOP-Wiki for future research needs. It does not intend to provide a systematic and comprehensive summary of the available literature on AOPs but summarizes and maps biological knowledge and diseases represented by the already developed AOPs (with OECD endorsed status or under validation). Methods: Knowledge from the AOP-Wiki database were extracted and prepared for analysis using a multi-step procedure. An automatic mapping of the existing information on AOPs (i.e., genes/proteins and diseases) was performed using bioinformatics tools (i.e., overrepresentation analysis using Gene Ontology and DisGeNET), allowing both the classification of AOPs and the development of AOP networks (AOPN). Results: AOPs related to diseases of the genitourinary system, neoplasms and developmental anomalies are the most frequently investigated on the AOP-Wiki. An evaluation of the three priority cases (i.e., immunotoxicity and non-genotoxic carcinogenesis, endocrine and metabolic disruption, and developmental and adult neurotoxicity) of the EU-funded PARC project (Partnership for the Risk Assessment of Chemicals) are presented. These were used to highlight under- and over-represented adverse outcomes and to identify and prioritize gaps for further research. Discussion: These results contribute to a more comprehensive understanding of the adverse effects associated with the molecular events in AOPs, and aid in refining risk assessment for stressors and mitigation strategies. Moreover, the FAIRness (i.e., data which meets principles of findability, accessibility, interoperability, and reusability (FAIR)) of the AOPs appears to be an important consideration for further development.

Assessing developmental neurotoxicity of emerging environmental chemicals using multiple in vitro models: A comparative analysis

Newly synthesized chemicals are being introduced into the environment without undergoing proper toxicological evaluation, particularly in terms of their effects on the vulnerable neurodevelopment. Thus, it is important to carefully assess the developmental neurotoxicity of these novel environmental contaminants using methods that are closely relevant to human physiology. This study comparatively evaluated the potential developmental neurotoxicity of 19 prevalent environmental chemicals including neonicotinoids (NEOs), organophosphate esters (OPEs), and synthetic phenolic antioxidants (SPAs) at environment-relevant doses (100 nM and 1 μM), using three commonly employed in vitro neurotoxicity models: human neural stem cells (NSCs), as well as the SK-N-SH and PC12 cell lines. Our results showed that NSCs were more sensitive than SK-N-SH and PC12 cell lines. Among all the chemicals tested, the two NEOs imidaclothiz (IMZ) and cycloxaprid (CYC), as well as the OPE tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), generated the most noticeable perturbation by impairing NSC maintenance and neuronal differentiation, as well as promoting the epithelial-mesenchymal transition process, likely via activating NF-κB signaling. Our data indicate that novel NEOs and OPEs, particularly IMZ, CYC, and TDCIPP, may not be safe alternatives as they can affect NSC maintenance and differentiation, potentially leading to neural tube defects and neuronal differentiation dysplasia in fetuses.

The mystery of methylmercury-perturbed calcium homeostasis: AMPK-DRP1-dependent mitochondrial fission initiates ER-mitochondria contact formation

Methylmercury (MeHg), as a global environmental pollutant, is of concern globally due to its neurodevelopmental toxicity. Mitochondria-associated membranes (MAMs) are highly dynamic sites of endoplasmic reticulum (ER)-haemocyte contact. MAMs are closely associated with the pathophysiology of neurological disorders due to their role in the transfer of calcium ions (Ca2+) between mitochondria and the ER. However, the molecular mechanisms that control these interactions in MeHg-induced neurotoxicity have not yet been characterized. In the current study, MeHg caused increases in the levels of both cytosolic and mitochondrial Ca2+ in PC12 cells and promoted MAMs formation in both in vivo and in vitro experiments. Of note, MeHg perturbed mitochondrial dynamics, promoting a shift toward a fission phenotype, and this was supported by the dysregulation of fission regulators. Interestingly, the MeHg-induced promotion of MAMs formation and increase in Ca2+ levels were effectively attenuated by the inhibition of mitochondrial fission using Mdivi-1, a DRP1 inhibitor. Furthermore, MeHg triggered the AMPK pathway, and most of the aforementioned changes were significantly rescued by Compound C. Mechanistic investigations revealed a reciprocal relationship between AMPK- and Ca2+-mediated mitochondrial fission. The specific inhibitor of Ca2+ uniporter, ruthenium-red (RuR), effectively abolished the feedback regulation of mitochondrial dynamics and MAMs formation mediated by AMPK in response to MeHg-induced Ca2+ overload. This study reveals a novel role of AMPK-DRP1-mediated mitochondrial fragmentation in the coupling of ER-mitochondrial calcium microdomains in MeHg-induced neurotoxicity. The findings provide valuable insights for the development of strategies to regulate mitochondrial imbalances in neurological diseases.

Neurodevelopmental toxicity and molecular mechanism of environmental concentration of tetrabromobisphenol A bis (2- hydroxyethyl) ether exposure to sexually developing male SD rats

Tetrabromobisphenol A bis (2- hydroxyethyl) ether (TBBPA-DHEE), as one of the main derivatives of Tetrabromobisphenol A, been attracted attention for its health risks. In this study, the neurotoxicity, mechanism, and susceptivity of TBBPA-DHEE exposure to sexually developing male rats were systematically studied. Neurobehavioral research showed that TBBPA-DHEE exposure could significantly affect the behavior, learning,and memory abilities of male-developing rats, and aggravate their depression. TBBPA-DHEE exposure could inhibit the secretion of neurotransmitters. Transcriptomics studies show that TBBPA-DHEE can significantly affect gene expression, and a total of 334 differentially expressed genes are enriched. GO function enrichment analysis shows that TBBPA-DHEE exposure can significantly affect the expression of genes related to synapses and cell components. KEGG function enrichment analysis shows that TBBPA-DHEE exposure can significantly affect the expression of signal pathways related to nerves, nerve development, and signal transduction. Susceptibility analysis showed that female rats were more susceptible to TBBPA-DHEE exposure than male rats. Therefore, TBBPA-DHEE exposure has neurodevelopmental toxicity to male developmental rats, and female developmental rats are more susceptible than male developmental rats. Its possible molecular mechanism is that TBBPA-DHEE may inhibit the secretion of neurotransmitters and affect signal pathways related to neurodevelopment and signal transduction.

Impact of Perinatal Arsenic Exposure on Amino Acid Neurotransmitters and Bioenergetics Molecules in the Hippocampus of Rats

Developmental neurotoxicity of Arsenic (As) is a major concern worldwide. High level As exposure is associated with several chronic diseases including adverse pregnancy and birth outcomes. However, very a lack of information on its ability to impair neurodevelopment at lower exposure. To date, there are very few animal studies during the perinatal period of As exposure. Although exposure to As induces developmental neurotoxicity, there is a lack of data regarding its specific effects on amino acid neurotransmitters and bioenergetics biomolecules in the hippocampus of developing rats exposed to As during the perinatal period (GD6-PD21). In continuation of previous studies, rats were exposed to As from gestational day (GD 6) through PD 21 with targeted doses of 0, 2.0, and 4.0 mg/kg/day, respectively. HPLC-UV method was used to estimate the level of amino acid neurotransmitters (aspartate, glutamate, homocysteine, glutamine, serine, and glycine) and the level of Adenosine 5’-Triphosphate (ATP), Adenosine Diphosphate (ADP), Adenosine Monophosphate (AMP), Nicotinamide Mononucleotide (NMN), Nicotinamide Adenine Dinucleotide (NAD+), reduced Nicotinamide Adenine Dinucleotide (NADH) in the hippocampus of rats after the exposure of As. Amino acid neurotransmitter levels, a predictive biomarker of As-induced developmental neurotoxicity were found to be altered. ATP, ADP, and AMP were also significantly impaired in the hippocampus of As-exposed rats. We have observed that the hippocampus is susceptible to As toxicity, both because of the high energy depletion and the alterations in the levels of selected amino acid neurotransmitters. Taken together, our results indicate that perinatal As exposure appears to be critical and vulnerable.

Role of SIRT1 in Potentially Toxic Trace Elements (Lead, Fluoride, Aluminum and Cadmium) Associated Neurodevelopmental Toxicity.

The formation of the central nervous system is a meticulously planned and intricate process. Any modification to this process has the potential to disrupt the structure and operation of the brain, which could result in deficiencies in neurological growth. When neurotoxic substances are present during the early stages of development, they can be exceptionally dangerous. Prenatally, the immature brain is extremely vulnerable and is therefore at high risk in pregnant women associated with occupational exposures. Lead, fluoride, aluminum, and cadmium are examples of possibly toxic trace elements that have been identified as an environmental concern in the aetiology of a number of neurological and neurodegenerative illnesses. SIRT1, a member of the sirtuin family has received most attention for its potential neuroprotective properties. SIRT1 is an intriguing therapeutic target since it demonstrates important functions to increase neurogenesis and cellular lifespan by modulating multiple pathways. It promotes axonal extension, neurite growth, and dendritic branching during the development of neurons. Additionally, it contributes to neurogenesis, synaptic plasticity, memory development, and neuroprotection. This review summarizes the possible role of SIRT1 signalling pathway in potentially toxic trace elements -induced neurodevelopmental toxicity, highlighting some molecular pathways such as mitochondrial biogenesis, CREB/BDNF and PGC-1α/NRF1/TFAM.