Developmental dyslexia genes are selectively targeted by diverse environmental pollutants

Background Developmental dyslexia, a complex neurodevelopmental disorder, not only affects children’s academic performance but is also associated with increased healthcare costs, lower employment rates, and reduced productivity. The pathogenesis of dyslexia remains unclear and it is generally considered to be caused by the overlap of genetic and environmental factors. Systematically exploring the close relationship between exposure to environmental compounds and susceptibility genes in the development of dyslexia is currently lacking but high necessary. Methods In this study, we systematically compiled 131 publicly reported susceptibility genes for dyslexia sourced from DisGeNET, OMIM, and GeneCards databases. Comparative Toxicogenomics Database database was used to explore the overlap between susceptibility genes and 95 environmental compounds, including metals, persistent organic pollutants, polycyclic aromatic hydrocarbons, and pesticides. Chemical bias towards the dyslexia risk genes was taken into account in the observation/expectation ratios > 1 and the corresponding P value obtained by hypergeometric probability test. Results Our study found that the number of dyslexia risk genes targeted by each chemical varied from 1 to 109. A total of 35 chemicals were involved in chemical reactions with dyslexia-associated genes, with significant enrichment values (observed/expected dyslexia risk genes) ranging from 1.147 (Atrazine) to 66.901 (Dibenzo(a, h)pyrene). Conclusion The results indicated that dyslexia-associated genes were implicated in certain chemical reactions. However, these findings are exploratory, and further research involving animal or cellular experiments is needed. Supplementary Information The online version contains supplementary material available at 10.1186/s12888-024-05952-4.


Introduction
Developmental dyslexia is a specific learning disability that is characterized by difficulties with accurate and/or fluent word recognition and by poor spelling and decoding abilities.Due to differences in language and writing systems, the prevalence of reading disorders varies among different countries, generally ranging from 3.45 to 17.5% [1,2].Dyslexia not only affects children's academic performance, but is also associated with increased healthcare costs, lower employment rates, and reduced productivity.As a complex neurodevelopmental disorder, the pathogenesis of dyslexia is still unclear and is generally considered to be caused by the interaction of genetic and environmental factors [3].
Researchers have focused on the neurodevelopmental impacts of chemical exposures in children, as children are more sensitive to exposure to chemicals due to their physiological characteristics, such as faster metabolism, higher relative exposure per unit body weight than adults, and incomplete immune function [4].Agency for Toxic Substances and Disease Registry (ATSDR) has reported peer-reviewed toxicological profiles for 185 classes of chemicals [5], of which organophosphate (OP) pesticides, air pollutants, polybrominated diphenyl ether flame retardants, lead, mercury, and polychlorinated biphenyls were common chemicals that could increase the risk of neurodevelopmental disorders in children [6].Increasing numbers of epidemiologic, clinical, and animal studies have demonstrated that early chemical exposures were associated with several adverse outcomes, such as autism spectrum disorder (ASD) [7,8], attention-deficit hyperactivity disorder (ADHD) [9,10], and intellectual disability [11].Neurotoxic chemicals could impact brain development through multiple mechanisms, including oxidative stress effects, neurotransmitter effects, neuroendocrine effects, immune effects, and behavioral phenotype [12].For example, exposure to poly chlorinated biphenyls (PCBs) and dibenzo-p-dioxins could change thyroid function and reduce the level of thyroid hormone, an important regulator of brain development, resulting in abnormal brain development [13].Arsenic exposure may change the central pathways involved in regulating learning and memory in hippocampus, such as Ras-MAPK/ ERK pathway, which may be the basis of arsenic-induced behavioral defects, thus leading to abnormal brain development [14].
An increasing number of studies are beginning to explore the association between exposure to chemicals and dyslexia.So far, eight epidemiological studies have suggested a significant association between exposure to metals [15][16][17][18], organophosphate (OP) insecticides [19], propylene oxide [20], and sodium iodide symporter (NIS) inhibitors [21] with the risk of dyslexia (summarized in Table S1).However, no similar results have been found for air pollutants [22].The mechanism by which chemical compound exposure led to dyslexia was still unclear, but it was possible that these compounds could overlap with genes, thereby affecting the normal development and function of the nervous system and cognitive function.Zinc, a trace element that plays an important role in neurological disorders, was associated with dyslexia risk mediated by the GRIN2B gene polymorphism rs1805502 [23].Similarly, mutation in SLC6A3 rs27072 could impact the association between urine manganese levels and the risk of dyslexia [18].Systematically exploring the close relationship between exposure to environmental compounds and susceptibility genes in the development of dyslexia is currently lacking but high necessary, which may contribute a lot to the etiological research of dyslexia.
Thus, in our current study, we systematically compiled publicly reported susceptibility genes for dyslexia and used the Comparative Toxicogenomics Database (CTD) [24] database to explore the overlap between susceptibility genes and environmental compounds, including metals, persistent organic pollutants (POPs), polycyclic aromatic hydrocarbons (PAHs), and pesticides.We aimed to identify chemical compounds involved in dyslexia susceptibility genes.

Dyslexia risk genes
The dyslexia risk genes were derived from DisGeNET [25] (n = 110), OMIM (n = 7), and GeneCards databases (n = 72).DisGeNET integrates data from expert curated repositories, GWAS catalogues, animal models, and the scientific literature.The current version of DisGeNET (v7.0) contains 1,134,942 gene-disease associations, between 21,671 genes and 30,170 diseases, disorders, characteristics, and clinical or abnormal human phenotypes.OMIM is a comprehensive and authoritative outline of human genes and genetic phenotypes, which is provided free of charge and updated daily.After removing duplicates, a total of 131 dyslexia risk genes were included in this study (0.69%) from a human genome of 19,000 protein-coding genes [26].The detail information of genes was shown in Table S2.

Chemical-gene overlap
The gene symbols were uploaded to the CTD database [24] (http://ctdbase.org/).There are 14,489 unique chemicals in CTD, with 2,674,978 curated chemical-gene overlap (2023 data).The genes influenced by each chemical in CTD are determined using curated data from diverse studies, including gene expression studies, protein-protein interaction assays, gene knockout experiments, and computational analyses.After downloading the results, we focused on three types of data.One is the number of genes involved in chemical reactions, the other is the number of dyslexia-related genes involved in chemical reactions, and the last is how many chemical reactions each dyslexia-related gene may participate in.We obtained the chemical list from United States Environmental Protection Agency (https://www.epa.gov/) and National Pesticide Information Center (http://npic.orst.edu/).We removed chemicals that lacked relevant information or evidence of gene involvement in chemical reactions.A total of 95 chemicals in 7 classes were included in this study, including metals (n = 19), POPs (n = 12), PAHs (n = 23), herbicides (n = 9), insecticides (n = 10), fungicides (n = 15), and rodenticides (n = 7) (Table 1).For the joint effect between the compounds we were interested in and susceptibility genes for dyslexia, the evidence from studies in CTD showed that there were 51,281 cases (48.9%) involving Homo sapiens, 25,317 cases (24.1%) involving Mus musculus, and Rattus norvegicus data ranked third, totaling 9525 cases (9.0%).

Gene enrichment analysis
If N genes were involved in a chemical reaction, one would expect an equal proportion of dyslexia risk genes (0.69%) to be contained within gene set (Expected = N × (131/19,000).Chemical bias towards the dyslexia risk genes was taken into account in the observation/expectation ratios > 1 and the corresponding P value obtained by hypergeometric probability test.P value was corrected for false discovery within each category group of chemicals, with a final cut-off at P < 0.05.Analyses were conducted using R software version 4.1.0(R Foundation for Statistical Computing).

Sensitivity analysis
Considering that dyslexia involves brain-mediated effects, we restricted the analysis to genes expressed in the brain.We obtained gene expression data from the Genotype-Tissue Expression Project (GTEx) and discovered that all 131 dyslexia-related genes were expressed in various regions of the brain, except for the STATH gene.The STATH gene, located in the 4q13.3region and consisting of 5 exons, encodes a protein called statherin, which possesses antibacterial properties and is expressed in saliva, the upper respiratory tract, and nasal secretions [27].

Polycyclic aromatic hydrocarbons
Of 23 PAHs, 7 medicals did not target any dyslexia genes.The enrichment value of dibenzo(a, h)pyrene had reached 69, but it should be viewed with caution because it could only target two protein-coding genes in the genome, one of which was a dyslexia risk gene.Anthracene (number of dyslexia genes/ all targeted genes: 3/21, 19.115 fold, P FDR   5).

Sensitivity analysis
After excluding STATH from the list of dyslexia risk genes, we meticulously analyzed the data.Remarkably, the results remained consistent, demonstrating that 35 chemicals exhibited a significant bias towards dyslexia risk genes (detailed data not shown in the Tables).

Discussion
The present study aimed to evaluate the overlap effect between 95 chemicals and 131 dyslexia risk genes.Findings from this study added some evidence that chemicals may act on dyslexia-related genes and thus play a role in the occurrence of the condition.We found that the dyslexia-related genes have significant chemical reactions  Research on metals and their potential role in dyslexia has been growing in recent years.Previous populationbased studies have identified several metals, including lead, copper, zinc, selenium, and argentum as potential contributors to the risk of dyslexia [16,17].Heavy metals are known to be neurotoxic and could have negative effects on neurodevelopment [28].Studies have shown that prenatal and early childhood exposure to heavy metals could impair cognitive development, language skills, attention, and behavior [29].Children exposed to lead, for example, showed neurobehavioral deficits in several areas, such as intelligence, attention, and executive function [30].Arsenic exposure has been linked to reduced cognitive function and increased risk of ADHD [31].While other metals, such as selenium and zinc, have been implicated in exerting neuroprotective effects through their involvement in defense mechanisms against oxidative stress [17].Metals could affect normal brain development by interfering with the formation and function of neurons, glial cells, and synapses [4].The overlapping effect between environment and gene has been established to be a strong determinant of neurodevelopmental disorders.The synergistic impact of excessive manganese exposure and a genetic modification in the GSTP1 gene may potentiate the incidence of mitochondrial dysfunction and oxidative stress, both of which have been documented as underlying mechanisms contributing to ASD [28].Excessive Cu exposure could lead to the accumulation of Cu in the brain tissue of mice.Cu damages synaptic plasticity through CREB/BDNF pathway, stimulates copper proliferation, promotes cell death, and causes learning and memory disorders in mice [32].This current study adds to this body of existing research by identifying additional metals, including chromium, cobalt, copper, zinc, arsenic, selenium, and barium.Susceptible dyslexia genes may be involved in the reaction of these metals.The findings suggest that these metals may contribute to the occurrence of dyslexia by altering the expression of relevant genes.
Our study revealed a potential association between a group of 5 POPs and dyslexia-associated genes.The 109 dyslexia-associated genes may be involved in the chemical reaction of polychlorinated dibenzo-p-dioxins, although the P value obtained by hypergeometric probability test is not significant.PCDDs are unintentionally by-products generated during the manufacture and combustion process involving chlorine or chlorine-derived chemicals [33].We observed significant biases towards dyslexia risk genes in the case of chlordane, dichlorodiphenyl trichloroethane, dieldrin, heptachlor, and toxaphene.Epidemiological research has indicated that higher maternal levels of POP exposures during pregnancy were associated with increased autism-related behaviors, poorer cognitive function, and reduced adaptive function [34].POPs could affect the symptom domain of ASD by acting on SNP site of ESR1 gene [35,36].Synapse appears to be a common susceptible target of POPs, altering dendrite and dendritic spine morphology, as well as synaptic function during sensitive developmental periods, leading to cognitive and behavioral dysfunction [37].Research has provided evidence indicating that prenatal exposure to p, p'-DDT and DDE may have detrimental effects on the neurological development of children.High levels of DDE detected in maternal serum or umbilical cord blood serum during pregnancy were believed to be associated with reduced cognitive function, including language skills, spatial orientation, and memory.Additionally, Dieldrin has been found to induce oxidative stress and trigger mitochondrial-mediated apoptosis [38].Heptachlor, functioning as a direct neurotoxic agent, could impact dopaminergic neurons, resulting in damage to both dopaminergic neurons and brain nerve function.Its pathogenesis may be associated with the overlap of the dyslexia gene DRD2, although further investigation is required to confirm this relationship [39].Our findings provide valuable insights into the potential association between POPs and dyslexia, suggesting a role for these substances in dyslexia pathogenesis.Further investigations are warranted to elucidate the underlying mechanisms and overlaps between these POPs and dyslexia.Understanding how these substances influence the expression and function of dyslexia-associated genes will contribute to a comprehensive understanding of dyslexia pathogenesis and provide scientific evidence for preventive and therapeutic interventions.Additionally, it is crucial to consider the interplay of other potential factors, such as genetic and environmental factors, to comprehensively assess the risk of dyslexia occurrence.
Our study showed that 3 of the PAH compounds exhibited a significant bias against dyslexia genes.Previous studies have shown that the widespread use of synthetic chemicals (including fuels, refrigerants, lubricants, and solvents, among others) has significantly increased in recent years, potentially contributing to the rise in neurodevelopmental disorders such as ASD and ADHD [40].PAHs may impact cognitive function by reducing plasma levels of brain-derived neurotrophic factor (BDNF) [41].BDNF is one of the most plentiful neurotrophic factors in the central nervous system [42,43].Synthesized and secreted by neurons in the brain, it plays a vital role in neuronal survival, differentiation, development, hippocampal neurogenesis, synaptic plasticity, and cognitive function regulation [41].PAHs might decrease the expression of BDNF mRNA by potentially influencing the negative regulation of the BDNF-AS gene on BDNF.These effects may lead to abnormalities in synaptic function associated with cognitive functions in the brain, resulting in impaired transmission of nerve impulses and subsequent cognitive impairment, and may also increase the risk of ADHD [44].These alterations may be observed as reductions in the surface area of children's white matter, as well as decreases in their head circumference, birth weight, and birth length [45].However, the specific mechanism underlying these effects remains unclear, highlighting the need for further research in this area.
We also identified potential biases against dyslexiarelated genes in 6 out of the 9 herbicides studied.Glyphosate, the active ingredient in glyphosate-based herbicides (GBHs), such as Roundup™, is widely used worldwide as an herbicide.Experimental evidence suggests that exposure to glyphosate can impact synaptic transmission and induce morphological and biochemical changes, which may contribute to cognitive impairment [46].Studies have demonstrated that the molecular mechanism of glyphosate-induced neurotoxicity may be linked to the imbalance of miRNA expression.The miRNA regulates the target mRNA, thus affecting the activities of various cells and tissues.Glyphosate, the active ingredient in glyphosate-based herbicides (GBHs), such as Roundup™, is widely used worldwide as an herbicide.Experimental evidence suggests that exposure to glyphosate can impact synaptic transmission and induce morphological and biochemical changes, which may contribute to cognitive impairment [46].The SCL6A3 gene may react with glyphosate exposed to zebrafish, and the expression of SCL6A3 is down-regulated, and the oxidative stress in zebrafish is increased, thus showing obvious damage to exploration and social behavior [47].Studies have demonstrated that the molecular mechanism of glyphosate-induced neurotoxicity may be linked to the imbalance of miRNA expression.The miRNA regulates the target mRNA, thus affecting the activities of various cells and tissues.Forkhead box G1 (FOXG1) is one of the target genes implicated in these processes through miR-34b-5β [48].FOXG1, along with FOXP2, a gene associated with dyslexia, belongs to the FOX gene family, and its encoded transcription factor is specifically expressed in fetal and adult brain tissues.Mutation of FOXP2 gene could also affect general language ability, which lead to speech and facial dyskinesia [49].Moreover, an experiment demonstrated that exposure of both young and old mice to Atrazine resulted in the production of proinflammatory cytokines in the prefrontal cortex and hippocampus, accompanied by a significant decrease in interleukin-10 release.Additionally, exposure to varying levels of Atrazine was found to potentially modify the neurodevelopment of zebrafish by altering protein abundance [50].The exposure of children to pesticides affects their brain development, leading to impaired cognitive functions.This pathogenesis may be associated with dyslexia-related gene expression or changes in protein abundance.These findings provide valuable insights for further research on developmental dyslexia.
Significant biases towards dyslexia-related genes in 5 out of the 10 pesticide species examined were identified.Current research provides evidence that exposure to various pesticides (including organophosphorus and parathyroid pesticides) during pregnancy could disrupt gene pathways at the placental and brain levels, potentially impacting fetal brain development and increase the risk of mental illness such as ASD and intellectual disability (ID) [51,52].Epidemiological studies have shown that early childhood exposure to pesticides was associated with cognitive decline and behavioral problems [53].Pesticides exposure could increase the activity of PARP1 expression, promote the death of nerve cells, affect the signal transduction of neurons, and lead to synaptic and behavioral changes related to neurodevelopmental disorders (NDDs) [52].Organophosphorus pesticides, a commonly used pesticide group, could inhibit the activity of cholinesterase, thereby disrupting nerve signal transmission and causing dysfunction in the nervous system.Children affected by pesticide poisoning may experience difficulties in concentration, verbal IQ, and cognitive impairment related to graphics.Dimethoate, like other organophosphorus pesticides, inhibits acetylcholinesterase, leading to an accumulation of acetylcholine at synapses and neuromuscular junctions, resulting in over-activation of nicotine and noxious alkali receptors and disruption of neurotransmitters.Lambda-cyhalothrin induces a significant increase in malondialdehyde levels, a metabolite associated with oxidative stress, in kidney and brain tissues, leading to tissue damage [54].Among the 15 fungicides studied, 4 displayed significant biases against dyslexia genes.The high manganese concentration in Maneb, which could be neurotoxic to exposed individuals, may be related to altered patterns of brain activation in the prefrontal cortex, an area involved in working memory [55].Two out of the 7 rodenticides examined exhibited significant biases against dyslexia risk genes.Rodenticide poisoning could result in symmetrical lesions in the white matter and corpus callosum of the brain, leading to cognitive impairment [56].Our findings suggest that different pesticides have distinct mechanisms of action in the pathogenesis of brain nerves, which could damage the brain by altering gene expression, inducing oxidative stress, and impairing mitochondrial function.These findings provide some insights into the potential relationship between pesticides and dyslexia.Pesticides may contribute to the pathogenesis of dyslexia, but further research is needed to clarify this association.
Our findings suggested a potential correlation between exposure to environmental compounds and susceptibility genes in the onset of dyslexia.Prior research has hinted at the potential involvement of neuro/immune biological mechanisms in mediating these effects [57].Through examining dyslexia susceptibility genes that were notably enriched with chemical-related genes, we delved into their possible roles within neuro/immune biological processes.Our results revealed that 14 genes, constituting 10.7% of the total, significantly influenced various aspects of these pathways.For instance, BDNF may be associated with the chemical reaction of copper, potentially leading to learning and memory disorders by destroying synaptic plasticity [32].Additionally, in PAH reactions, reduced BDNF expression could lead to abnormal synaptic function related to brain cognition, resulting in cognitive impairment [41].SCL6A3 may react with glyphosate, leading to decreased expression and increased oxidative stress in zebra fish, thus causing damage to exploration and social behavior [47].Hence, it implies that the engagement of dyslexia-related genes in chemical reactions could contribute to dyslexia development via neuro/immune biological pathways.Further investigation is warranted to elucidate this mechanism thoroughly.
Our findings could be partially generalized to neurodevelopmental disorders, given that dyslexia risk genes are frequently expressed in the brain and contribute to brain development [58].Based on gene expression data from the GTEx project across various tissues, dyslexia often involves susceptibility genes expressed throughout different regions of the brain [59,60] (Table S2).Dysregulation of these genes typically results in compromised brain development [61].For instance, alterations in the COMT gene have been linked to differences in brain structure evident at birth, potentially disrupting neurodevelopment and affecting cognitive abilities [62].In addition, compounds could enter the body through various exposure routes, which also have an impact on the brain.Concurrently, we gathered 2229 ADHD susceptibility genes, 819 ID genes and 639 ASD susceptibility genes from database such as GeneCards, OMIM, NCBI, and other related sources.Upon comparing whether dyslexia risk genes were also susceptibility genes for other neurodevelopmental conditions, such as ASD, ADHD and ID, we found that the GRIN2B gene was a susceptibility gene for these three conditions.The GRIN2B gene plays a crucial role in the normal development of neurons.Mutations in human GRIN2B were distributed through the entire gene in a number of patients with varied neuropsychology and developmental disorders [63].There were also 18 dyslexia susceptibility genes, two of which were concurrently susceptible.For example, DRD3 gene may be related to the clinical significance of ASD and ADHD [64,65].Genes related to dyslexia and neurodevelopment usually share a common mechanism in influencing brain development, including synaptic plasticity, neuronal migration, and neurotransmitter transmission [66].It is also common for dyslexia to co-occur with ADHD, ASD, and ID [61,67,68].The joint action of relevant compounds and susceptibility genes for conditions may contribute to other neurodevelopmental disorders, but further research exploration is still needed.
A strength of our study is that, to our knowledge, it is the first to systematically investigate the overlaps between many compounds and a wide range of dyslexia risk genes.Our study may provide new links between certain chemicals and dyslexia, which could help further research on the mechanisms underlying this condition.Some limitations exist in this study.Firstly, this study only explored 95 compounds, and there may be other links between chemicals and dyslexia that have not been investigated.Secondly, the study was based on theoretical analysis and did not conduct actual clinical research, so it was uncertain if the associations between these chemicals and susceptibility genes had clinical significance.Further experimental research is needed to validate the findings.
In conclusion, our study systematically explored the overlaps between several compounds and a wide range of dyslexia susceptibility genes, providing a new perspective on the potential link between chemicals and the development of dyslexia.This study suggested that dyslexiarelated genes may participate in chemical reactions of some chemicals, which may contribute to the occurrence of the condition.However, our findings are exploratory, further research is needed to validate these findings and to elucidate the mechanisms involved.Going forward, it is crucial to continue investigating the potential links between environmental factors and the development of dyslexia.This includes conducting additional animal and cellular experiments to explore the potential mechanism of dyslexia-related genes involved in chemical reactions.Additionally, further clinical research is needed to determine the clinical significance of these findings and to develop effective prevention and intervention strategies for individuals who may be at risk for dyslexia.

Table 1
Chemicals involved in the current study

Table 2
The number of dyslexia risk genes affected by metals a If a chemical affects N genes, one would expect an equal proportion of dyslexia risk gene (0.69%) to be contained within this gene set (Expected = N × (131/19,000)) b Representing the enrichment value which was obtained by dividing the observed value by the expected value c The corresponding P value of observed/expected ratios derived from the hypergeometric probability test d P value was corrected for false discovery P FDR value was bold if P FDR was less than 0.05

Table 4
The number of dyslexia risk genes affected by polycyclic aromatic hydrocarbons (PAHs) a If a chemical affects N genes, one would expect an equal proportion of dyslexia risk gene (0.69%) to be contained within this gene set (Expected = N × (131/19,000)) b Representing the enrichment value which was obtained by dividing the observed value by the expected value c The corresponding P value of observed/expected ratios derived from the hypergeometric probability test d P value was corrected for false discovery P FDR value was bold if P FDR was less than 0.05

Table 5
The number of dyslexia risk genes affected by pesticides

Pesticides Numbers of all genes affected Numbers of dyslexia risk genes affected Expected a Ratio b P value c P FDR value d
b Representing the enrichment value which was obtained by dividing the observed value by the expected value c The corresponding P value of observed/expected ratios derived from the hypergeometric probability test d P value was corrected for false discovery P FDR value was bold if P FDR was less than 0.05