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Epigenetics in neurodegenerative disorders induced by pesticides

Genes and Environment volume 43, Article number: 55 (2021) Cite this article

Abstract

Neurodegenerative diseases are becoming major socio-economic burdens. However, most of them still have no effective treatment. Growing evidence indicates excess exposure to pesticides are involved in the development of various forms of neurodegenerative and neurological diseases through trigger epigenetic changes and inducing disruption of the epigenome. This review summaries studies on epigenetics alterations in nervous systems in relation to different kinds of pesticides, highlighting potential mechanism in the etiology, precision prevention and target therapy of various neurodegenerative diseases. In addition, the current gaps in research and future areas for study were also discussed.

Introduction

With aging of the population in worldwide, neurodegenerative diseases, especially Alzheimer’s disease (AD) and Parkinson’s disease (PD) are becoming major socio-economic burdens. Their increasing prevalence and without effective treatment mean these diseases will be a challenge for future generations [1]. Although several cellular mechanisms and genes have been proved implicated in the onset and progression of the disease, the precise molecular underpinnings of these diseases remain unclear [2].

Epigenetics is generally defined as a heritable change in gene function, which can influence gene expression and subsequent protein expression levels without altering DNA sequence [3]. The epigenetic molecular factors include DNA methylation [4], histone modifications [5], non-coding RNA [6], chromatin structure [7], and RNA methylation [8]. Epigenetic dysregulation may induce the development of neurological disorders like Parkinson’s disease, Huntington’s disease, and mood disorders (including depression and anxiety) [9]. Growing evidence indicates that environmental neurotoxicants are involved in the development of various forms of neurodegenerative and neurological diseases through trigger epigenetic changes and inducing disruption of the epigenome [10,11,12,13]. Some sources of environmental pollutants were related to neurotoxic manifestations, such as metals, pesticides, solvent and some other environmental pollutions [14,15,16]. Chemicals could regulate gene expression by influencing gene transcription, mRNA degradation and translation, etc. Abnormal changes in DNA or RNA methylation, non-coding RNA, histone modification can serve as biomarkers for environmental pollutant-induced neurotoxicity [17,18,19,20,21]. Consequently, insight into the epigenetic mechanisms by which environmental contaminants causes neurotoxicity is key to modelling targeted preventions and treatments [22].

Pesticides, including insecticides, herbicides and fungicides, are widely used in agriculture for preventing, destroying, repelling or mitigating harmful or unwanted insects, weeds and fungi. However, most pesticides are not highly selective and generally toxic to many nontarget species, including humans [23]. Particularly, insecticides, which kill insects by disrupting their nervous system, exert neurotoxic effects in humans as well. Neurotoxicity can be induced upon high acute exposure, or by chronic exposure at low doses. Multiple studies have proved chronic exposure to pesticides at a low dose is a risk factor for the development of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and attention deficit hyperactivity disorder (ADHD) etc. [24,25,26,27,28,29,30]. However, nowadays there are still about 25 million workers experience unintentional pesticide poisoning each year, due to inhalation or skin absorption [31]. Therefore, it is very important to study the pathogenic mechanism and preventive measures of neurodegenerative and neurological diseases induced by pesticides. For the past few years, many researchers have concerned the potential role of epigenetic mechanism in pesticide induced neurotoxicity (as shown in Fig. 1).

Fig. 1
figure 1

Schematic representation of the mechanism of epigenetic alterations and neurodegenerative disorders due to exposure to different kind of pesticides

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Here we review details studies on epigenetics alterations in nervous systems in relation to pesticides, highlighting potential mechanism in the etiology of various neurodegenerative diseases (summarized Table 1). We also highlight current gaps and future areas for the studies upon epigenetic neurotoxicity induced by pesticides.

Table 1 Summary of epigenetic changes induced by pesticisdes
Full size table

Mechanism of epigenetics

DNA methylation

DNA methylation is an epigenetic mechanism involving the transfer of a methyl group onto the C5 position of the cytosine to form 5-methylcytosine [56]. Methyl groups to cytosine are added by the DNA methyltransferase (DNMT) enzyme family, namely DNMT3A, DNMT3B, and DNMT1 [57,58,59]. DNA methylation is the most well studied epigenetic regulators in relation to environmental exposures, which can result in altered global and gene-specific DNA methylation [60]. In the nervous system, neuronal activity can also modulate DNA methylation in response to physiological and environmental stimuli [61, 62].

RNA methylation

In addition to genomic DNA modifications, various modifications of nucleosides which form the basis for RNA (including tRNA, rRNA, mRNA etc.) were also appreciated [63,64,65]. N6-methyladenosine (m6A) in mRNA has been the best-characterized mRNA modification so far, with roles in modulating mRNA transcript processing and regulation [66, 67]. The m6A effectors include “writers”, “erasers” and “readers” that respectively install, remove and interpret the methylation [68]. The ‘writer’ methyltransferase enzymes (including METTL3, METTL14, WTAP, and KIAA1429) add a methyl group to the N6 position of adenosine in RNA, and removed by the “erasers” demethylases (including FTO and ALKBH5). The methyl group can be recognized by “reader” proteins (HNRNPC, HNRNPA2B1, YTHDF2, YTHDF1, and eIF3), and influence almost all steps of RNA metabolism, including mRNA translation, degradation, splicing, export and folding, consequently altering target gene expression, influencing the corresponding cell processes and physiological function [69, 70].

Histone modification

Histones (H3, H4, H2A, H2B and H1) are the most abundant proteins in the eukaryotic nuclear DNA structure [71]. Most of the amino acids reside on the N-terminal tails of the histone proteins are subjected to modifications, including acetylation, methylation and ubiquitination on lysine, methylation and citrullination on arginine, etc. [72]. Histone modification can influence all DNA-based processes, including chromatin compaction, nucleosome dynamics, and transcription [73]. Moreover, histone core modifications can also directly regulate transcription, and influence processes of DNA repair, replication, stemness, and changes in cell state [74]. In general, active enhancers are related to the enrichments of both monomethylated H3K4 (H3K4me1) and H3K27ac. Gene bodies of actively transcribed genes are associated with trimethylated H3K36 (H3K36me3), and transcription start sites of actively transcribed genes can be identified by trimethylated H3K4 (H3K4me3) and acetylated H3K27 (H3K27ac) [72].

Non-coding RNAs

Non-coding RNAs (ncRNA) are a relatively recently described but significant subpopulation of the transcriptome [75]. According to their size, non-coding RNAs can be classified to short RNAs which are < 200 nucleotides (nts) in length and long non-coding RNAs (lncRNAs) are longer than 200 nts. Short non-coding RNAs include PIWI-interacting RNAs (piRNAs), microRNAs (miRNAs), small interfering RNAs (siRNAs), circular RNA (circRNA) and small nuclear RNAs (snRNAs). In the last decade, gene expression has been proved to be largely regulated by ncRNAs. A growing number of studies have investigated the involvement of ncRNAs in various physiological processes [75]. Moreover, miRNAs, lncRNAs and circRNAs have been proved to be involved in transcriptional regulation at different level. Therefore, ncRNA is a burgeoning area for all the biology fields, including neurotoxicology [76].

Pesticide induced epigenetic neurotoxic effect

Insecticides

Organophosphate pesticide

Organophosphate pesticide has been known as the most widely used pesticides during the past half century. Number of literatures regard their association with neurodegenerative and neurodevelopmental disorders with respect to epigenetic mechanisms [77, 78].

Chlorpyrifos (CPF) is one of the most widely used organophosphorus pesticide (OP) in the world. However, CPE and its active metabolite chlorpyrifos-oxon (CPO) have been proved involving in several neurodevelopmental disorders. Lee’s work identifies the potential epigenetic mechanism of hlorpyrifos neurotoxicity, founding that miR132/212 was elevated in the CA1 hippocampal region, disrupting the neurotrophin mediated cognitive processes after CPF administration [32]. Zhao’s team observed chlorpyrifos could activate cell pyroptosis and increases susceptibility on oxidative stress-induced toxicity by miR-181/SIRT1/PGC-1α/Nrf2 signaling pathway [33]. In addition, the adverse effects of developmental exposure to the active CPO have been proved to persist into adulthood even future generations [79]. Schmitt et al. demonstrated that early life stage exposures to CPO can lead to epigenetic changes in neurological activity, which may lead to alterations in response to CPO in future generations [34]. Liu’ team also investigated H3K4me3 and DNA methylation levels of the PPARγ gene in the placenta was associated with prenatal chlorpyrifos exposure, and could effect on birth outcomes and neurodevelopment [80].

Organochlorine pesticide

Organochlorine pesticide is another kind of insecticides. Nowadayes, some OCPs are banned in most industrialized countries. However, due to the very long half-life in humans, the circulating levels of the breakdown product of dchlorodiphenyltrichloroethane (DDT), p,p′-DDE (1, 1-dichloro2, 2-bis (p-chlorophenyl) ethylene) are still found in almost all humans in the industrialized world. Moreover, some OCPs, such as DDT is still used to combat malaria in Asia and Africa [81]. Researches in epidemiology showed workers with Parkinson’s disease were related with exposure to organochlorines [77].

DDT is a common environmental organochlorine pesticide with a long half-life. Because it can passes through the placental barrier, DDT exposure during pregnancy may heavily influence lifetime health of the offspring.. An epidemiological study showed that prenatal exposure to DDT is associated with fetal genome-wide DNA methylation [82]. Another cohort study also investigated prenatal exposure to persistent organic pollutants can induce DNA methylation of LINE-1 and imprint genes in placenta [83].

Dieldrin is also a highly toxic organochlorine pesticide. Although it was phased out of commercial use in the 1970s, dieldrin was still persisted in the environment and easily accumulated in lipid-rich tissues like the brain, due to its high stability and lipophilicity [84]. Previous epidemiology studies have shown a positive association between dieldrin exposure and PD [85, 86]. Experimental researches also investigated that developmental dieldrin exposure could alter DNA methylation at genes related to dopaminergic neuron development and Parkinson’s disease [35]. Song’ research revealed that dieldrin induced a time-dependent increase in the acetylation of core histones H3 and H4 in neuronal cells. Moreover, the histone acetylation appeared within 10 min after exposure to dieldrin, suggesting that acetylation is an early event in dieldrin neurotoxicity [36].

Pyrethroid

Pyrethroid insecticides contain natural pyrethrins which are extracted from pyrethrum flowers, and their synthetic derivatives, pyrethroids [87]. Pyrethroids with low mammalian toxicity are now commonly used for household and post-harvest insect control [88]. However, pyrethroid pesticide exposures may be also associated with disruption of neurological functioning [89,90,91,92]. Neonatal exposure to permethrin can induce a Parkinson-like disease.

Permethrin is a synthetic pyrethroid widely used as anti-woodworm agent and for indoor and outdoor pest control. However, early life permethrin exposure induces long-term brain changes [93]. These long-term changes were regulated by early impairment of epigenetic pattern in neurodegeneration, such as DNA methylation or histone alterations [37, 38]. In addition, on the prospective intergenerational effect of this pesticide, parental exposure also leads to global DNA methylation changes and hydroxymethylation impairment in their offspring, providing pivotal evidences on intergenerational effects of postnatal exposure to permethrin [39, 40]. Tevoltage-gated sodium channel (VGSC), a motoneuronal transport protein, is the target of all pyrethroids [94]. In addition, Kubik et al. found miRNA-33 modulates permethrin induced toxicity by regulating VGSC transcripts [95].

Herbicide

Herbicides are essential tool in weed management. The first commercial herbicides were released in the 1940s and hundreds more since then [96]. Among all the herbicides, the neurotoxicity paraquat (PQ) are probably the most conclusive [97]. Paraquat exposure has been linked to an increased risk for Parkinson’s disease [98], and has been used for modeling sporadic Parkinson’s Disease [99]. However, the impacts of PQ exposure on the central nervous system remain unclear. In recent years, epigenetic mechanisms involved paraquat induced neurons damage have been extensively investigated in order to explore new preventive and therapeutic targets of Parkinson’s disease. Our team also do a lot of exploration there [17, 30, 45, 47,48,49,50,51, 100]. The epigenetic molecular mechanisms were summarized in Fig. 2.

Fig. 2
figure 2

Epigenetic regulation in the context ofparaquat induced nerve cell damage. DAN methylation, m6A modification of circRNA,histone acetylation, miRNA, and lncRNAs were involved in the epigenetic regulation process. The details of the molecular mechanisms were descripted in the following text

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As shown in Fig. 2, DNA methylations were found to be causative factors in paraquat induced neurons damage. When pretreated with methyltransferase inhibitor 5′-aza-dC, the level of reactive oxygen species (ROS) increased more significantly. The rate of bcl-2/bax decreased, consequently enhancing the cell apoptosis induced by PQ. This work demonstrated the interaction of DNA methylation and paraquat, providing additional new insights into the pathogenic mechanisms of PD [101].

A major epigenetic change in chromatin can regulate gene expression. Song et al. found that exposure to paraquat could induced histone H3 acetylation in N27 dopaminergic cells in a time dependent manner. These changes were associated with decreased total histone deacetylase (HDAC) activity and HDAC4 and 7 protein expression levels. Additionally, the inhibition of histone acetyltransferase (HAT) activity by anacardic acid can protect against apoptotic cell death induced by PQ, indicating that histone acetylation may represent key epigenetic changes during neurotoxic insults [41].

Evidence indicates that miRNA also play a key role in PQ involved neurodegenerative diseases. Zhou’s team analyzed the impacts of PQ on the miRNome of human neural progenitor cells (hNPCs) during proliferation. Upon PQ treatment, 66 miRNAs were identified as differentially expressed in proliferating hNPCs. With further analysis, the target genes were found enriched in regulation of cell proliferation and differentiation, cell cycle and apoptosis as well as tumor protein 53 (p53), Wnt, Notch and mitogen-activated protein kinases (MAPK) signaling pathways [42]. Furtherly, they found mRNAs and miRNAs expression changes induced by PQ in hNPCs could lead to the alteration of several neurodevelopment related key biological processes and crucial pathways, especially Wnt signaling pathway. The results suggested that PQ could downregulate Wnt signaling pathway via miRNA to induce developmental neurotoxicity [43]. In addition, they also found miR-200a was down regulated in the PQ treated neural stem cell. This process subsequently decreased cell viability, increased epithelial-mesenchymal transition process and the inhibited differential through CTNNB1 pathway [44]. The transcription factor Nrf2 has been proved to regulate the expression of many miRNAs, our previous work also found that Nrf2 can promote the expression of miR-380-3p, which blocks the translation of Sp3 protein and enhances paraquat-induced toxicity in mouse neuroblastoma N2a cells [45]. Interestingly, Narasimhan et al. explained the relationship between Nrf2 and miRNA from a different perspective. Their study showed that PQ induced miR153 dependent hydrogen peroxide (H2O2), and then caused miR153 to bind to and target Nrf2 3′ UTR thereby weakening the cellular antioxidant defense [46].

Emerging evidence showing that oxidative stress and DNA methylation can alter miRNA expression. Our previous work also investigated that PQ can induce DNA methylation variations through ROS production, leading to the downregulation of miR-17-5p expression [17]. The downregulation of miR-17-5p expression contributes to PQ-induced dopaminergic neurodegeneration through influencing the cell proliferation, cell apoptosis and S phase transition of the cell cycle [47]. Subsequently, we found long noncoding RNAs also play a crucial part in PQ induced neurotoxicity. The alteration of the lncRNA expression profile were found in PQ treated mouse, suggesting lncRNAs were involved in PQ- induced neurotoxicity. Further studies displayed PQ caused lncRNA expression profiling alteration in the substantia nigra (SN) through an interaction with Nrf2, thus changing the NR_027648/Zc3h14/ Cybb and NR_030777/Zfp326/Cpne5 mRNA pathways [48]. Latterly, we proved PQ-induced low expression of AK039862 rescued microglia proliferation and migration inhibition via the AK039862/Pafah1b1/Foxa1 pathway [49]. LncRNA NR_030777 is another lncRNA involved in PQ induced neurotoxicity. It is highly conserved among species and was firstly confirmed by our team. Evidence illustrated NR_030777 7 has a vital protective role in neurotoxicity induced by PQ through regulating the expression of Zfp326 and Copine 5 [50]. These novel discoveries suggested lncRNAs could be a potential target for the prevention and treatment of PQ-induced neurodegenerative disorders such as PD. Recently, our team successfully established a positive link between the alteration of circRNAs driven by m6A modification and PQ-induced oxidative stress. Moreover, the alteration of m6A methylated circRNAs upon PQ exposure could be partially reversed by N-acetylcysteine (NAC) pretreatment, providing a new preventive or therapeutic tools for PQ-induced neurodegenerative disorders [51].

Other pesticides

In addition to the pesticides described above, there are still some other pesticides, such as biological insecticides, combination of various pesticides and some other new low toxicity chemical pesticides. The epigenetic mechanisms of their neurotoxicity were also investigated.

Avermectin

Avermectin (AVM) is an effective insecticidal and nematicidal agent, it has been extensively used in agriculture and stock farming areas. Subsequently, the residues of AVM or its active metabolites present a toxic threat through epigenetic mechanisms. Cao et al. reported subchronic exposure to AVM could decrease the mRNA expression levels of DNA methyltransferases (DNMT1 and DNMT3a/3b), and increase the mRNA levels of demethylase methyl-CpG-binding domain protein 2 (MBD2), consequently down regulated the global DNA methylation level decreased in pigeon brain tissues [52].

Fipronil

Fipronil is a broad-spectrum chiral insecticide. It has been documented to induce significant neurotoxicity to nontarget aquatic species. Qian et al. firstly discussed the enantioselective toxicity of chiral pesticide fipronil in central nervous system, and find R-fipronil exhibited more intense neurotoxicity compared with S-fipronil. Further research revealed that R-fipronil disrupted five signaling pathways including MAPK, Calcium signaling, Neuroactive ligand-receptor interaction, Purine metabolism, and Endocytosis. These pathways revealed greater extent than S-fipronil through the hypermethylation of several important neuro-related genes. This study indicated that the fipronil-conducted enantioselective neurotoxicity by the dysregulation of DNA methylation, providing a novel epigenetic insight into the study of enantioselective biological effects [74].

Pesticide mixture

Nowadays, mixed formulation of pesticide is commonly used to reduce insect resistance, achieve-control efficiency and/or economic concers [102]. Xing et al. examined the effect of atrazine (ATR), chlorpyrifos (CPF) and combined ATR/CPF exposure on DNA methylation in the brain of zebra fish. Compared to the control fish, a significant global DNA hypomethylation was observed in the common carp exposed to ATR, CPF and their mixture. Moreover, the MBD2 mRNA expression was up-regulated and the DNMTs mRNA expression was down-regulated in the brain and gonad of the common carp exposed to ATR, CPF and their mixture [75]. Nuclear receptor subfamily 3 group C member 1 (Nr3c1) is a transcription factors necessary for proper dopamine neuron development. Vester et al. also reported combined neurodevelopmental exposure to deltamethrin and corticosterone could induce Nr3c1 hypermethylation in the midbrain of adult male mice [76].

Concluding remarks

The underlying cause of many neurological and neurodegenerative diseases are still unclear. However, it is now widely accepted that the environmental toxicants contribute to many of these disorders. Increasing evidence indicates that the epigenome may be targeted on people at risk for neurodegenerative disorders. Multiple studies have indicated chronic exposure to pesticides at a low dose could increase the risk of neurodegenerative diseases. Epigenetic disruptions induced by pesticides, which can induce neurotoxicity were summarized in this work. Epidemiologic studies and experimental researches performed both in vivo and in vitro provide evidence that exposure to pesticides even at a low dose have long-term effects on central nervous systems, possibly via epigenetic modifications. Individuals, exposure to neurotoxic in the early life and even in the womb could induce epigenetic alterations in adulthood, the aged or even next generations, moreover some of the alterations are sex-depended. Meanwhile, compared with genetic changes, epigenetic aberrations could be more easily reversible. Drugs, even some nutrients, which target the specific epigenetic mechanisms involved in the regulation of gene expression could be emerging preventive or therapeutic tools for disease. In this review, there are some evidences illustrated inhibits the epigenetic modification changes by compounds or regulates the expression of non-coding RNA by genetic tools might alleviate pesticide induced neurological and neurodegenerative impairments. These will shed new light on the precise prevention and targeted treatment for the neurodegenerative diseases. However, a great deal of further investigations is still needed. For instance (1) explore how pesticides exposure leads to epigenetic alteration in specific genes; (2) identify the susceptible genes of human in the epigenetic alterations induced by exposure to pesticides; (3) prove whether epigenetic changes can be used as biomarkers for the early detection and treatment target for neurodegenerative disorders; (4) develop novel epigenetic modification inhibitors; (5) explore the epigenetic mechanisms of some novel and mixtures of pesticides.

Availability of data and materials

Not applicable.

Abbreviations

AD:

Alzheimer’s disease

ADHD:

Attention deficit/hyperactivity disorder

ALS:

Amyotrophic lateral sclerosis

AVM:

Avermectin

circRNA:

Circular RNA

CNS:

Central nervous system

CPF:

Chlorpyrifos

CPO:

Chlorpyrifos-oxon

DDT:

Dchlorodiphenyltrichloroethane

DNMT:

DNA methyltransferase

HAT:

Histone acetyltransferases

HDACs:

Histone deacetylases

hNPCs:

Human neural progenitor cells

lncRNAs:

Long non-coding RNAs

m6A:

N6-methyladenosine

MAPK:

Mitogen-activated protein kinases

MBD2:

Methyl-CpG-binding domain protein 2

miRNA:

Micrornas

ncRNA:

Non-coding RNAs

NAC:

N-acetylcysteine

OP:

Organophosphorus pesticide

PD:

Parkinson’s disease,

piRNAs:

PIWI-interacting RNAs

PQ:

Paraquat

ROS:

Reactive oxygen species

siRNAs:

Small interfering RNAs

SN:

Substantia nigra

snRNAs:

Small nuclear RNAs

References

  1. Dugger BN, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2017;9(7). https://doi.org/10.1101/cshperspect.a028035.

  2. Pavlou MAS, Outeiro TF. Epigenetics in Parkinson's disease. Adv Exp Med Biol. 2017;978:363–90. https://doi.org/10.1007/978-3-319-53889-1_19.

    Article  PubMed  CAS  Google Scholar 

  3. Inbar-Feigenberg M, Choufani S, Butcher DT, Roifman M, Weksberg R. Basic concepts of epigenetics. Fertil Steril. 2013;99(3):607–15. https://doi.org/10.1016/j.fertnstert.2013.01.117.

    Article  PubMed  CAS  Google Scholar 

  4. Holliday R, Pugh JE. DNA modification mechanisms and gene activity during development. Science. 1975;187(4173):226–32. https://doi.org/10.1126/science.187.4173.226.

    Article  PubMed  CAS  Google Scholar 

  5. Turner BM. Histone acetylation as an epigenetic determinant of long-term transcriptional competence. Cell Mol Life Sci. 1998;54(1):21–31. https://doi.org/10.1007/s000180050122.

    Article  PubMed  CAS  Google Scholar 

  6. Lekka E, Hall J. Noncoding RNAs in disease. FEBS Lett. 2018;592(17):2884–900. https://doi.org/10.1002/1873-3468.13182.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Yaniv M. Chromatin remodeling: from transcription to cancer. Cancer Genet. 2014;207(9):352–7. https://doi.org/10.1016/j.cancergen.2014.03.006.

    Article  PubMed  CAS  Google Scholar 

  8. Schaefer M, Pollex T, Hanna K, Tuorto F, Meusburger M, Helm M, et al. RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes Dev. 2010;24(15):1590–5. https://doi.org/10.1101/gad.586710.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Abel T, Zukin RS. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr Opin Pharmacol. 2008;8(1):57–64. https://doi.org/10.1016/j.coph.2007.12.002.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Babenko O, Kovalchuk I, Metz GA. Epigenetic programming of neurodegenerative diseases by an adverse environment. Brain Res. 2012;1444:96–111. https://doi.org/10.1016/j.brainres.2012.01.038.

    Article  PubMed  CAS  Google Scholar 

  11. Berson A, Nativio R, Berger SL, Bonini NM. Epigenetic regulation in neurodegenerative diseases. Trends Neurosci. 2018;41(9):587–98. https://doi.org/10.1016/j.tins.2018.05.005.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Coppedè F, Mancuso M, Siciliano G, Migliore L, Murri L. Genes and the environment in neurodegeneration. Biosci Rep. 2006;26(5):341–67. https://doi.org/10.1007/s10540-006-9028-6.

    Article  PubMed  CAS  Google Scholar 

  13. Brown RC, Lockwood AH, Sonawane BR. Neurodegenerative diseases: an overview of environmental risk factors. Environ Health Perspect. 2005;113(9):1250–6. https://doi.org/10.1289/ehp.7567.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. Front Cell Neurosci. 2015;9:124. https://doi.org/10.3389/fncel.2015.00124.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Iqubal A, Ahmed M, Ahmad S, Sahoo CR, Iqubal MK, Haque SE. Environmental neurotoxic pollutants: review. Environ Sci Pollut Res Int. 2020;27(33):41175–98. https://doi.org/10.1007/s11356-020-10539-z.

    Article  PubMed  CAS  Google Scholar 

  16. Yu G, Guo Z, Li H. Analyses of epigenetic modification in environmental pollutants-induced neurotoxicity. Methods Mol Biol. 2021;2326:123–41. https://doi.org/10.1007/978-1-0716-1514-0_9.

    Article  PubMed  CAS  Google Scholar 

  17. Zhan Y, Guo Z, Zheng F, Zhang Z, Li K, Wang Q, et al. Reactive oxygen species regulate miR-17-5p expression via DNA methylation in paraquat-induced nerve cell damage. Environ Toxicol. 2020;35(12):1364–73. https://doi.org/10.1002/tox.23001.

    Article  PubMed  CAS  Google Scholar 

  18. Forster VJ, McDonnell A, Theobald R, McKay JA. Effect of methotrexate/vitamin B (12) on DNA methylation as a potential factor in leukemia treatment-related neurotoxicity. Epigenomics. 2017;9(9):1205–18. https://doi.org/10.2217/epi-2016-0165.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Neal M, Richardson JR. Epigenetic regulation of astrocyte function in neuroinflammation and neurodegeneration. Biochim Biophys Acta Mol basis Dis. 2018;1864(2):432–43. https://doi.org/10.1016/j.bbadis.2017.11.004.

    Article  PubMed  CAS  Google Scholar 

  20. Logan S, Jiang C, Yan Y, Inagaki Y, Arzua T, Bai X. Propofol alters long non-coding RNA profiles in the neonatal mouse Hippocampus: implication of novel mechanisms in anesthetic-induced developmental neurotoxicity. Cell Physiol Biochem. 2018;49(6):2496–510. https://doi.org/10.1159/000493875.

    Article  PubMed  CAS  Google Scholar 

  21. Gu C, Wen Y, Wu L, Wang Y, Wu Q, Wang D, et al. Arsenite-induced transgenerational glycometabolism is associated with up-regulation of H3K4me2 via inhibiting spr-5 in caenorhabditis elegans. Toxicol Lett. 2020;326:11–7. https://doi.org/10.1016/j.toxlet.2020.03.002.

    Article  PubMed  CAS  Google Scholar 

  22. Jose CC, Wang Z, Tanwar VS, Zhang X, Zang C, Cuddapah S. Nickel-induced transcriptional changes persist post exposure through epigenetic reprogramming. Epigenetics Chromatin. 2019;12(1):75. https://doi.org/10.1186/s13072-019-0324-3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Costa LG, Giordano G, Guizzetti M, Vitalone A. Neurotoxicity of pesticides: a brief review. Front Biosci. 2008;13(13):1240–9. https://doi.org/10.2741/2758.

    Article  PubMed  CAS  Google Scholar 

  24. Paul KC, Chuang YH, Cockburn M, Bronstein JM, Horvath S, Ritz B. Organophosphate pesticide exposure and differential genome-wide DNA methylation. Sci Total Environ. 2018;645:1135–43. https://doi.org/10.1016/j.scitotenv.2018.07.143.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Yan D, Zhang Y, Liu L, Shi N, Yan H. Pesticide exposure and risk of Parkinson's disease: dose-response meta-analysis of observational studies. Regul Toxicol Pharmacol. 2018;96:57–63. https://doi.org/10.1016/j.yrtph.2018.05.005.

    Article  PubMed  CAS  Google Scholar 

  26. Martins R, Carruthers M. Testosterone as the missing link between pesticides, Alzheimer disease, and Parkinson disease. JAMA Neurol. 2014;71(9):1189–90. https://doi.org/10.1001/jamaneurol.2014.795.

    Article  PubMed  Google Scholar 

  27. Richardson JR, Roy A, Shalat SL, von Stein RT, Hossain MM, Buckley B, et al. Elevated serum pesticide levels and risk for Alzheimer disease. JAMA Neurol. 2014;71(3):284–90. https://doi.org/10.1001/jamaneurol.2013.6030.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bernard A. Elevated serum DDE and risk for Alzheimer disease. JAMA Neurol. 2014;71(8):1055–6. https://doi.org/10.1001/jamaneurol.2014.432.

    Article  PubMed  Google Scholar 

  29. Mostafalou S, Abdollahi M. The link of organophosphorus pesticides with neurodegenerative and neurodevelopmental diseases based on evidence and mechanisms. Toxicology. 2018;409:44–52. https://doi.org/10.1016/j.tox.2018.07.014.

    Article  PubMed  CAS  Google Scholar 

  30. Chen N, Guo Z, Luo Z, Zheng F, Shao W, Yu G, et al. Drp1-mediated mitochondrial fission contributes to mitophagy in paraquat-induced neuronal cell damage. Environ Pollut. 2021;272:116413. https://doi.org/10.1016/j.envpol.2020.116413.

    Article  PubMed  CAS  Google Scholar 

  31. van der Plaat DA, de Jong K, de Vries M, van Diemen CC, Nedeljković I, Amin N, et al. Occupational exposure to pesticides is associated with differential DNA methylation. Occup Environ Med. 2018;75(6):427–35. https://doi.org/10.1136/oemed-2017-104787.

    Article  PubMed  Google Scholar 

  32. Lee YS, Lewis JA, Ippolito DL, Hussainzada N, Lein PJ, Jackson DA, et al. Repeated exposure to neurotoxic levels of chlorpyrifos alters hippocampal expression of neurotrophins and neuropeptides. Toxicology. 2016;340:53–62. https://doi.org/10.1016/j.tox.2016.01.001.

    Article  PubMed  CAS  Google Scholar 

  33. Zhao MW, Yang P, Zhao LL. Chlorpyrifos activates cell pyroptosis and increases susceptibility on oxidative stress-induced toxicity by miR-181/SIRT1/PGC-1α/Nrf2 signaling pathway in human neuroblastoma SH-SY5Y cells: implication for association between chlorpyrifos and Parkinson's disease. Environ Toxicol. 2019;34(6):699–707. https://doi.org/10.1002/tox.22736.

    Article  PubMed  CAS  Google Scholar 

  34. Schmitt C, Peterson E, Willis A, Kumar N, McManus M, Subbiah S, et al. Transgenerational effects of developmental exposure to chlorpyrifos-oxon in zebrafish (DANIO RERIO). Toxicol Appl Pharmacol. 2020;408:115275. https://doi.org/10.1016/j.taap.2020.115275.

    Article  PubMed  CAS  Google Scholar 

  35. Kochmanski J, VanOeveren SE, Patterson JR, Bernstein AI. Developmental dieldrin exposure alters DNA methylation at genes related to dopaminergic neuron development and parkinson's disease in mouse midbrain. Toxicol Sci. 2019;169(2):593–607. https://doi.org/10.1093/toxsci/kfz069.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Song C, Kanthasamy A, Anantharam V, Sun F, Kanthasamy AG. Environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells: relevance to epigenetic mechanisms of neurodegeneration. Mol Pharmacol. 2010;77(4):621–32. https://doi.org/10.1124/mol.109.062174.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Fedeli D, Montani M, Bordoni L, Galeazzi R, Nasuti C, Correia-Sá L, et al. In vivo and in silico studies to identify mechanisms associated with Nurr1 modulation following early life exposure to permethrin in rats. Neuroscience. 2017;340:411–23. https://doi.org/10.1016/j.neuroscience.2016.10.071.

    Article  PubMed  CAS  Google Scholar 

  38. Bordoni L, Nasuti C, Fedeli D, Galeazzi R, Laudadio E, Massaccesi L, et al. Early impairment of epigenetic pattern in neurodegeneration: additional mechanisms behind pyrethroid toxicity. Exp Gerontol. 2019;124:110629. https://doi.org/10.1016/j.exger.2019.06.002.

    Article  PubMed  CAS  Google Scholar 

  39. Bordoni L, Nasuti C, Mirto M, Caradonna F, Gabbianelli R. Intergenerational effect of early life exposure to permethrin: changes in global DNA methylation and in nurr1 gene expression. Toxics. 2015;3(4):451–61. https://doi.org/10.3390/toxics3040451.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Bordoni L, Nasuti C, Di Stefano A, Marinelli L, Gabbianelli R. Epigenetic memory of early-life parental perturbation: dopamine decrease and dna methylation changes in offspring. Oxidative Med Cell Longev. 2019;2019:1472623–11. https://doi.org/10.1155/2019/1472623.

    Article  CAS  Google Scholar 

  41. Song C, Kanthasamy A, Jin H, Anantharam V, Kanthasamy AG. Paraquat induces epigenetic changes by promoting histone acetylation in cell culture models of dopaminergic degeneration. Neurotoxicology. 2011;32(5):586–95. https://doi.org/10.1016/j.neuro.2011.05.018.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Huang M, Lou D, Cai Q, Chang X, Wang X, Zhou Z. Characterization of paraquat-induced miRNA profiling response in hNPCs undergoing proliferation. Int J Mol Sci. 2014;15(10):18422–36. https://doi.org/10.3390/ijms151018422.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Yan M, Dou T, Lv W, Wang X, Zhao L, Chang X, et al. Integrated analysis of paraquat-induced microRNAs-mRNAs changes in human neural progenitor cells. Toxicol in Vitro. 2017;44:196–205. https://doi.org/10.1016/j.tiv.2017.06.010.

    Article  PubMed  CAS  Google Scholar 

  44. Huang M, Lou D, Wang YP, Cai Q, Li HH. Paraquat inhibited differentiation in human neural progenitor cells (hNPCs) and down regulated miR-200a expression by targeting CTNNB1. Environ Toxicol Pharmacol. 2016;42:205–11. https://doi.org/10.1016/j.etap.2016.01.018.

    Article  PubMed  CAS  Google Scholar 

  45. Cai Z, Zheng F, Ding Y, Zhan Y, Gong R, Li J, et al. Nrf2-regulated miR-380-3p blocks the translation of Sp3 protein and its mediation of paraquat-induced toxicity in mouse neuroblastoma N2a cells. Toxicol Sci. 2019;171(2):515–29. https://doi.org/10.1093/toxsci/kfz162.

    Article  PubMed Central  CAS  Google Scholar 

  46. Narasimhan M, Riar AK, Rathinam ML, Vedpathak D, Henderson G, Mahimainathan L. Hydrogen peroxide responsive miR153 targets Nrf2/ARE cytoprotection in paraquat induced dopaminergic neurotoxicity. Toxicol Lett. 2014;228(3):179–91. https://doi.org/10.1016/j.toxlet.2014.05.020.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Wang Q, Zhan Y, Ren N, Wang Z, Zhang Q, Wu S, et al. Paraquat and MPTP alter microRNA expression profiles, and downregulated expression of miR-17-5p contributes to PQ-induced dopaminergic neurodegeneration. J Appl Toxicol. 2018;38(5):665–77. https://doi.org/10.1002/jat.3571.

    Article  PubMed  CAS  Google Scholar 

  48. Wang L, Yang H, Wang Q, Zhang Q, Wang Z, Zhang Q, et al. Paraquat and MPTP induce alteration in the expression profile of long noncoding RNAs in the substantia nigra of mice: role of the transcription factor Nrf2. Toxicol Lett. 2018;291:11–28. https://doi.org/10.1016/j.toxlet.2018.04.002.

    Article  PubMed  CAS  Google Scholar 

  49. Zhang Y, Shao W, Wu J, Huang S, Yang H, Luo Z, et al. Inflammatory lncRNA AK039862 regulates paraquat-inhibited proliferation and migration of microglial and neuronal cells through the Pafah1b1/Foxa1 pathway in co-culture environments. Ecotoxicol Environ Saf. 2021;208:111424. https://doi.org/10.1016/j.ecoenv.2020.111424.

    Article  PubMed  CAS  Google Scholar 

  50. Yang H, Lin Q, Chen N, Luo Z, Zheng C, Li J, et al. LncRNA NR_030777 alleviates Paraquat-induced neurotoxicity by regulating Zfp326 and Cpne5. Toxicol Sci. 2020;178(1):173–88. https://doi.org/10.1093/toxsci/kfaa121.

    Article  PubMed  CAS  Google Scholar 

  51. Chen N, Tang J, Su Q, Chou WC, Zheng F, Guo Z, et al. Paraquat-induced oxidative stress regulates N6-methyladenosine (m (6) a) modification of circular RNAs. Environ Pollut. 2021;290:117816. https://doi.org/10.1016/j.envpol.2021.117816.

    Article  PubMed  CAS  Google Scholar 

  52. Cao Y, Chen LJ, Zhang ZW, Yao HD, Liu C, Li S, et al. Global DNA hypomethylation: a potential mechanism in king pigeon nerve tissue damage induced by avermectin. Chem Biol Interact. 2014;219:113–22. https://doi.org/10.1016/j.cbi.2014.05.004.

    Article  PubMed  CAS  Google Scholar 

  53. Qian Y, Ji C, Yue S, Zhao M. Exposure of low-dose fipronil enantioselectively induced anxiety-like behavior associated with DNA methylation changes in embryonic and larval zebrafish. Environ Pollut. 2019;249:362–71. https://doi.org/10.1016/j.envpol.2019.03.038.

    Article  PubMed  CAS  Google Scholar 

  54. Xing H, Wang C, Wu H, Chen D, Li S, Xu S. Effects of atrazine and chlorpyrifos on DNA methylation in the brain and gonad of the common carp. Comp Biochem Physiol C Toxicol Pharmacol. 2015;168:11–9. https://doi.org/10.1016/j.cbpc.2014.11.002.

    Article  PubMed  CAS  Google Scholar 

  55. Vester AI, Hermetz K, Burt A, Everson T, Marsit CJ, Caudle WM. Combined neurodevelopmental exposure to deltamethrin and corticosterone is associated with Nr3c1 hypermethylation in the midbrain of male mice. Neurotoxicol Teratol. 2020;80:106887. https://doi.org/10.1016/j.ntt.2020.106887.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013;38(1):23–38. https://doi.org/10.1038/npp.2012.112.

    Article  PubMed  CAS  Google Scholar 

  57. Ding X, Li Y, Lü J, Zhao Q, Guo Y, Lu Z, et al. piRNA-823 Is involved in cancer stem cell regulation through altering DNA methylation in association with luminal breast cancer. Front Cell Dev Biol. 2021;9:641052. https://doi.org/10.3389/fcell.2021.641052.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Xu TH, Liu M, Zhou XE, Liang G, Zhao G, Xu HE, et al. Structure of nucleosome-bound DNA methyltransferases DNMT3A and DNMT3B. Nature. 2020;586(7827):151–5. https://doi.org/10.1038/s41586-020-2747-1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Onodera A, González-Avalos E, Lio CJ, Georges RO, Bellacosa A, Nakayama T, et al. Roles of TET and TDG in DNA demethylation in proliferating and non-proliferating immune cells. Genome Biol. 2021;22(1):186. https://doi.org/10.1186/s13059-021-02384-1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Martin EM, Fry RC. Environmental influences on the epigenome: exposure- associated DNA methylation in human populations. Annu Rev Public Health. 2018;39(1):309–33. https://doi.org/10.1146/annurev-publhealth-040617-014629.

    Article  PubMed  Google Scholar 

  61. Yang N, Wei Y, Wang T, Guo J, Sun Q, Hu Y, et al. Genome-wide analysis of DNA methylation during antagonism of DMOG to MnCl2-induced cytotoxicity in the mouse substantia nigra. Sci Rep. 2016;6(1):28933. https://doi.org/10.1038/srep28933.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Schneider JS, Kidd SK, Anderson DW. Influence of developmental lead exposure on expression of DNA methyltransferases and methyl cytosine-binding proteins in hippocampus. Toxicol Lett. 2013;217(1):75–81. https://doi.org/10.1016/j.toxlet.2012.12.004.

    Article  PubMed  CAS  Google Scholar 

  63. Cohn WE, Volkin E. Nucleoside-5′-phosphates from ribonucleic acid. Nature. 1951;167(4247):483–4. https://doi.org/10.1038/167483a0.

    Article  CAS  Google Scholar 

  64. Chen K, Zhao BS, He C. Nucleic acid modifications in regulation of gene expression. Cell Chem Biol. 2016;23(1):74–85. https://doi.org/10.1016/j.chembiol.2015.11.007.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Duechler M, Leszczyńska G, Sochacka E, Nawrot B. Nucleoside modifications in the regulation of gene expression: focus on tRNA. Cell Mol Life Sci. 2016;73(16):3075–95. https://doi.org/10.1007/s00018-016-2217-y.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Cayir A, Barrow TM, Guo L, Byun HM. Exposure to environmental toxicants reduces global N6-methyladenosine RNA methylation and alters expression of RNA methylation modulator genes. Environ Res. 2019;175:228–34. https://doi.org/10.1016/j.envres.2019.05.011.

    Article  PubMed  CAS  Google Scholar 

  67. Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci U S A. 1974;71(10):3971–5. https://doi.org/10.1073/pnas.71.10.3971.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Reichel M, Köster T, Staiger D. Marking RNA: m6A writers, readers, and functions in Arabidopsis. J Mol Cell Biol 2019; 11 (10): 899–910. doi:https://doi.org/10.1093/jmcb/mjz085.

  69. Liu Q, Gregory RI. RNAmod: an integrated system for the annotation of mRNA modifications. Nucleic Acids Res. 2019;47(W1):W548–w555. https://doi.org/10.1093/nar/gkz479.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Liu N, Zhou KI, Parisien M, Dai Q, Diatchenko L, Pan T. N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein. Nucleic Acids Res. 2017;45(10):6051–63. https://doi.org/10.1093/nar/gkx141.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Riaz S, Niaz Z, Khan S, Liu Y, Sui Z. Detection, characterization and expression dynamics of histone proteins in the dinoflagellate Alexandrium pacificum during growth regulation. Harmful Algae. 2019;87:101630. https://doi.org/10.1016/j.hal.2019.101630.

    Article  PubMed  CAS  Google Scholar 

  72. Kimura H. Histone modifications for human epigenome analysis. J Hum Genet. 2013;58(7):439–45. https://doi.org/10.1038/jhg.2013.66.

    Article  PubMed  CAS  Google Scholar 

  73. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403(6765):41–5. https://doi.org/10.1038/47412.

    Article  CAS  Google Scholar 

  74. Lawrence M, Daujat S, Schneider R. Lateral thinking: how histone modifications regulate gene expression. Trends Genet. 2016;32(1):42–56. https://doi.org/10.1016/j.tig.2015.10.007.

    Article  PubMed  CAS  Google Scholar 

  75. Ma L, Cao J, Liu L, Du Q, Li Z, Zou D, et al. LncBook: a curated knowledgebase of human long non-coding RNAs. Nucleic Acids Res. 2019;47(D1):D128–d134. https://doi.org/10.1093/nar/gky960.

    Article  PubMed  CAS  Google Scholar 

  76. Wallace DR, Taalab YM, Heinze S, Tariba Lovaković B, Pizent A, Renieri E, et al. Toxic-metal-induced alteration in miRNA expression profile as a proposed mechanism for disease development. Cells. 2020;9(4):901. https://doi.org/10.3390/cells9040901.

    Article  PubMed Central  CAS  Google Scholar 

  77. Go RCP, Corley MJ, Ross GW, Petrovitch H, Masaki KH, Maunakea AK, et al. Genome-wide epigenetic analyses in Japanese immigrant plantation workers with Parkinson's disease and exposure to organochlorines reveal possible involvement of glial genes and pathways involved in neurotoxicity. BMC Neurosci. 2020;21(1):31. https://doi.org/10.1186/s12868-020-00582-4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Weldon BA, Shubin SP, Smith MN, Workman T, Artemenko A, Griffith WC, et al. Urinary microRNAs as potential biomarkers of pesticide exposure. Toxicol Appl Pharmacol. 2016;312:19–25. https://doi.org/10.1016/j.taap.2016.01.018.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Guo J, Zhang J, Wu C, Lv S, Lu D, Qi X, et al. Associations of prenatal and childhood chlorpyrifos exposure with neurodevelopment of 3-year-old children. Environ Pollut. 2019;251:538–46. https://doi.org/10.1016/j.envpol.2019.05.040.

    Article  PubMed  CAS  Google Scholar 

  80. Chiu KC, Sisca F, Ying JH, Tsai WJ, Hsieh WS, Chen PC, et al. Prenatal chlorpyrifos exposure in association with PPARγ H3K4me3 and DNA methylation levels and child development. Environ Pollut. 2021;274:116511. https://doi.org/10.1016/j.envpol.2021.116511.

    Article  PubMed  CAS  Google Scholar 

  81. Lind PM, Salihovic S, Lind L. High plasma organochlorine pesticide levels are related to increased biological age as calculated by DNA methylation analysis. Environ Int. 2018;113:109–13. https://doi.org/10.1016/j.envint.2018.01.019.

    Article  PubMed  CAS  Google Scholar 

  82. Yu X, Zhao B, Su Y, Zhang Y, Chen J, Wu W, et al. Association of prenatal organochlorine pesticide-dichlorodiphenyltrichloroethane exposure with fetal genome-wide DNA methylation. Life Sci. 2018;200:81–6. https://doi.org/10.1016/j.lfs.2018.03.030.

    Article  PubMed  CAS  Google Scholar 

  83. Kim S, Cho YH, Lee I, Kim W, Won S, Ku JL, et al. Prenatal exposure to persistent organic pollutants and methylation of LINE-1 and imprinted genes in placenta: a CHECK cohort study. Environ Int. 2018;119:398–406. https://doi.org/10.1016/j.envint.2018.06.039.

    Article  PubMed  CAS  Google Scholar 

  84. Allen EM, Florang VR, Davenport LL, Jinsmaa Y, Doorn JA. Cellular localization of dieldrin and structure-activity relationship of dieldrin analogues in dopaminergic cells. Chem Res Toxicol. 2013;26(7):1043–54. https://doi.org/10.1021/tx300458b.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Kanthasamy AG, Kitazawa M, Kanthasamy A, Anantharam V. Dieldrin-induced neurotoxicity: relevance to Parkinson's disease pathogenesis. Neurotoxicology. 2005;26(4):701–19. https://doi.org/10.1016/j.neuro.2004.07.010.

    Article  PubMed  CAS  Google Scholar 

  86. Moretto A, Colosio C. Biochemical and toxicological evidence of neurological effects of pesticides: the example of Parkinson's disease. Neurotoxicology. 2011;32(4):383–91. https://doi.org/10.1016/j.neuro.2011.03.004.

    Article  PubMed  CAS  Google Scholar 

  87. Matsuo N. Discovery and development of pyrethroid insecticides. Proc Jpn Acad Ser B Phys Biol Sci. 2019;95(7):378–400. https://doi.org/10.2183/pjab.95.027.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Barr DB, Olsson AO, Wong LY, Udunka S, Baker SE, Whitehead RD, et al. Urinary concentrations of metabolites of pyrethroid insecticides in the general U.S. population: National Health and nutrition examination survey 1999-2002. Environ Health Perspect. 2010;118(6):742–8. https://doi.org/10.1289/ehp.0901275.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Furlong MA, Paul KC, Cockburn M, Bronstein J, Keener A, Rosario ID, et al. Ambient pyrethroid pesticide exposures in adult life and depression in older residents of california's central valley. Environ Epidemiol. 2020;4(6):e123. https://doi.org/10.1097/ee9.0000000000000123.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Li HY, Zhong YF, Wu SY, Shi N. NF-E2 related factor 2 activation and heme oxygenase-1 induction by tert-butylhydroquinone protect against deltamethrin-mediated oxidative stress in PC12 cells. Chem Res Toxicol. 2007;20(9):1242–51. https://doi.org/10.1021/tx700076q.

    Article  PubMed  CAS  Google Scholar 

  91. Li HY, Wu SY, Shi N. Transcription factor Nrf2 activation by deltamethrin in PC12 cells: involvement of ROS. Toxicol Lett. 2007;171(1–2):87–98. https://doi.org/10.1016/j.toxlet.2007.04.007.

    Article  PubMed  CAS  Google Scholar 

  92. Li HY, Wu SY, Ma Q, Shi N. The pesticide deltamethrin increases free radical production and promotes nuclear translocation of the stress response transcription factor Nrf2 in rat brain. Toxicol Ind Health. 2011;27(7):579–90. https://doi.org/10.1177/0748233710393400.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Carloni M, Nasuti C, Fedeli D, Montani M, Vadhana MS, Amici A, et al. Early life permethrin exposure induces long-term brain changes in Nurr1, NF-kB and Nrf-2. Brain Res. 2013;1515:19–28. https://doi.org/10.1016/j.brainres.2013.03.048.

    Article  PubMed  CAS  Google Scholar 

  94. Du Y, Nomura Y, Satar G, Hu Z, Nauen R, He SY, et al. Molecular evidence for dual pyrethroid-receptor sites on a mosquito sodium channel. Proc Natl Acad Sci U S A. 2013;110(29):11785–90. https://doi.org/10.1073/pnas.1305118110.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Kubik TD, Snell TK, Saavedra-Rodriguez K, Wilusz J, Anderson JR, Lozano-Fuentes S, et al. Aedes aegypti miRNA-33 modulates permethrin induced toxicity by regulating VGSC transcripts. Sci Rep. 2021;11(1):7301. https://doi.org/10.1038/s41598-021-86665-6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Gandy MN, Corral MG, Mylne JS, Stubbs KA. An interactive database to explore herbicide physicochemical properties. Org Biomol Chem. 2015;13(20):5586–90. https://doi.org/10.1039/c5ob00469a.

    Article  PubMed  CAS  Google Scholar 

  97. Richardson JR, Fitsanakis V, Westerink RHS, Kanthasamy AG. Neurotoxicity of pesticides. Acta Neuropathol. 2019;138(3):343–62. https://doi.org/10.1007/s00401-019-02033-9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, et al. Rotenone, paraquat, and Parkinson's disease. Environ Health Perspect. 2011;119(6):866–72. https://doi.org/10.1289/ehp.1002839.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Bastías-Candia S, Zolezzi JM, Inestrosa NC. Revisiting the paraquat-induced sporadic Parkinson's disease-like model. Mol Neurobiol. 2019;56(2):1044–55. https://doi.org/10.1007/s12035-018-1148-z.

    Article  PubMed  CAS  Google Scholar 

  100. Li H, Wu S, Wang Z, Lin W, Zhang C, Huang B. Neuroprotective effects of tert-butylhydroquinone on paraquat-induced dopaminergic cell degeneration in C57BL/6 mice and in PC12 cells. Arch Toxicol. 2012;86(11):1729–40. https://doi.org/10.1007/s00204-012-0935-y.

    Article  PubMed  CAS  Google Scholar 

  101. Kong M, Ba M, Liang H, Ma L, Yu Q, Yu T, et al. 5′-Aza-dC sensitizes paraquat toxic effects on PC12 cell. Neurosci Lett. 2012;524(1):35–9. https://doi.org/10.1016/j.neulet.2012.07.001.

    Article  PubMed  CAS  Google Scholar 

  102. Wang X, Zhou S, Ding X, Zhu G, Guo J. Effect of triazophos, fipronil and their mixture on miRNA expression in adult zebrafish. J Environ Sci Health B. 2010;45(7):648–57. https://doi.org/10.1080/03601234.2010.502435.

    Article  PubMed  CAS  Google Scholar 

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Funding

The financial support from the National Natural Science Foundation of China (grant number: 81973083, 81903352, 22006019, 82173553), the Joint Funds for the innovation of science and Technology, Fujian province (grant number: 2017Y9105, 2018Y9098, 2019Y9020), the Provincial Natural Science Foundation of Fujian Province (key project) (grant number: 2020 J02021),the Provincial Natural Science Foundation of Fujian Province (grant number: 2019 J05081), Natural Science Foundation of Zhejiang Province (grant number: LQ19H260002), Ningbo Natural Science Foundation (grant number: 2018A610317).

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  1. Fujian Key Lab of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, Fujian Province, China

    Guangxia Yu, Qianqian Su, Yao Chen, Lingyan Wu, Siying Wu & Huangyuan Li

  2. Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, Fujian Province, China

    Guangxia Yu, Qianqian Su, Yao Chen, Lingyan Wu & Huangyuan Li

  3. Key Lab of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, Fujian Province, China

    Guangxia Yu & Huangyuan Li

  4. Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian Province, China

    Siying Wu

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Yu, G., Su, Q., Chen, Y. et al. Epigenetics in neurodegenerative disorders induced by pesticides. Genes and Environ 43, 55 (2021). https://doi.org/10.1186/s41021-021-00224-z

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ISSN: 1880-7062

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