Open access peer-reviewed chapter

Toxicogenomics of Bisphenol A and Neurodevelopmental Disorders

Written By

Bingling Wang, Ruqin Gao and Da‐Hong Wang

Submitted: October 19th, 2016 Reviewed: March 8th, 2017 Published: June 7th, 2017

DOI: 10.5772/intechopen.68415

From the Edited Volume

Bisphenol A

Edited by Pinar Erkekoglu and Belma Kocer-Gumusel

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Abstract

Bisphenol A (BPA) has been widely used in many industrial and consumer products and is known as an endocrine‐disrupting chemical. To find the underlying genetic basis and molecular mechanisms of BPA‐associated neurodevelopmental disorders (NDs), this chapter addressed the toxicogenomics of BPA with publicly accessed Comparative Toxicogenomics Database. The present results indicated that the key cellular components (CC) of the nervous system such as neuron, synapse, dendrite and axon are common in CC annotation; the commonly found molecular functions are neurotransmitter receptor or transducer binding or activity; and the main common biological processes include synaptic signalling, cognition, learning or memory, behaviour, the development of nervous system and brain. Neuroactive ligand‐receptor interaction, dopaminergic, glutamatergic and serotonergic synapses, monoamine transport and synaptic vesicle pathway were the common pathways. Simultaneously, the BPA-disease may share the common pathways with drug addictions such as cocaine addiction. Unique pathways might also contribute to the BPA action in different NDs such as one carbon metabolism and detoxification of oxidative stress in Down syndrome. Although GO and pathway results indicate some common annotations, the predicted PPI molecular function clusters are quite different for each ND. In addition, some of the NDs share the same transcription factors (TFs) and miRNAs, which indicate these disorders have the similar expression profiles. Finally, chemicals having comparable interacting genes to BPA should be considered.

Keywords

  • bisphenol A
  • toxicogenomics
  • neurodevelopmental disorders

1. Introduction

The critical windows of vulnerability during human brain development are mainly from the third trimester to at least 2–3 years after birth [1]. Any developmental neurotoxicant exposure during this critical window has the possibility to cause various clinical neurodevelopmental disorders (NDs) in humans (e.g. autism, anxiety disorder, schizophrenia, dyslexia and epilepsy). Bisphenol A (BPA), as a proved endocrine‐disrupting chemical, has been widely used as the plasticizer in many consumer products made of polycarbonate plastic such as baby bottles, tableware, food containers and water bottles. BPA can also be found in breast milk [2, 3]. Infants and children were found to have the highest estimated daily intake of BPA per body weight [4, 5]. A review by Healy et al. [6] affirmed that the potential for non‐dietary sources make a substantial contribution to the total daily BPA exposure in young children and recommended risk‐assessment models implement new frameworks, which specifically address exposure and hazard in early childhood. Pinson et al. [7] reviewed the human and rodent data on the neurodevelopmental alterations of BPA, and found that mostly reported effects were social and sexual behaviour and cognition that were unique to humans. The related mechanisms reported included the disruption of thyroid function, alterations of neurotransmitters levels, calcium signalling and neurotoxicity. Given the extensive BPA exposure during the critical windows of the brain development and the possible neurodevelopmental alterations, here we explore the possible genetic basis and the molecular mechanisms of BPA‐associated NDs.

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2. BPA‐gene interactions and neurodevelopmental disorders

Comparative toxicogenomics database (CTD, http://ctdbase.org) is a robust, publicly available database that aims to advance understanding about how environmental exposures affect human health with manually curated information about chemical‐gene/protein interactions, chemical‐disease and gene‐disease relationships, with functional and pathway data to aid in the development of hypotheses about the mechanisms underlying environmentally influenced diseases [8]. In this work, all BPA‐gene/protein interactions were downloaded from CTD, in which BPA‐gene/protein interactions associated to the following 17 NDs were selected as our targeted NDs for further analysis according to MESH ID used in CTD—anxiety disorders (AD), attention deficit and disruptive behaviour disorders (ADDBD), autism spectrum disorder (ASD), bipolar disorder (BD), developmental disabilities (DD), Down syndrome (DS), foetal alcohol spectrum disorders (FASD), intellectual disability (ID), language development disorders (LDD), learning disorders (LD), motor skills disorders (MSD), obsessive‐compulsive disorder (OCD), pervasive child development disorders (PCDD), schizophrenia (Sch), speech disorders (SD), stereotypic movement disorder (SMD) and Tourette syndrome (TS). Thus, BPA‐gene/protein interactions associated to these 17 NDs were collected for further analysis.

According to the reference score on relationships between chemicals‐genes, genes‐diseases and chemicals‐diseases [9], we found that ID was most likely having the atypical connectivity with BPA (Table 1). Inference BPA interacted genes were up to 119. Inference score of more than 20 was found for LD, Sch, ASD and AD, whereas it was less than 10 for DS, TS, MSD, OCD, ADDBD, LDD, DD, FASD and PCDD. The results showed that it was only two inference BPA interacted genes for TS, ADDBD and FASD, and in total, 403 BPA bi‐interacted genes were curated. A total of 563 BPA‐mRNA bi‐interactions were found, in which 240 expressions were down‐regulated, 169 up‐regulated and 153 were altered (not mentioned up or down) regulation. Simultaneously, eighty‐one BPA‐protein bi‐interactions, two protein‐BPA bi‐interactions and eight BPA‐DNA methylation interactions were reported.

Disease name Inference BPA‐interacted genes (n) Inference score Reference count
ID ACBD6, ADK, ADRA2B, AHI1, ALDH5A1, AP4E1, AP4M1, APC, ARL14EP, ASCC3, ASCL1, BBS7, BDNF, CA8, CACNA1G, CALCA, CAPN10, CASP2, CCBE1, CCNA2, CIC, CNDP1, CNKSR1, COL18A1, DEAF1, DISC1, DNMT3A, DOCK8, DYNC1H1, EEF1B2, ELP2, ENTPD1, ERLIN2, FAM126A, FASN, FGFR2, FMR1, FOLR1, FRY, GAMT, GNAS, GON4L, GRIN2B, HDAC4, HEXA, HIST3H3, INPP4A, INPP5E, KCNA2, KDM5A, KDM5C, KDM6B, KIF1BP, KIF7, L2HGDH, LAMA1, LARP7, LETM1, LINS1, MAN1B1, MCC, MECP2, MED13L, MEF2C, METTL23, MFSD2A, NAGLU, NDST1, NF1, NRXN1, NSD1, PARP1, PAX6, PDHX, PECR, PEX6, PMM2, POLR3B, PRKCG, PRKRA, PTCHD1, PTEN, RAB39B, RABL6, RALGDS, RGS7, SC5D, SCAPER, SCN8A, SETBP1, SHANK2, SHANK3, SIN3A, SLC2A1, SLC31A1, SLC4A10, SNX14, SRD5A3, SRGAP3, STRA6, SURF1, SYNGAP1, TAF2, TH, TMCO1, TMEM135, TRMT1, TSEN2, TSEN34, TSEN54, TTI2, UBR7, UROC1, VIP, VRK1, WDR45B, WDR62, ZBTB40, ZCCHC8 (119) 86.31 51
LD ACHE, APOD, APP, BCL2, CAMKMT, GRIA1, HMOX1, HTR1A, HTR7, IL1B, IL1RN, KL, MAPT, MECP2, MICU1, MT1, NF1, PARK2, PDE1B, PNOC, POR, PSEN1, RNF135, SIGMAR1, SLC17A6, SLC17A7, SYP, TH, TRH, VEGFA (30) 30.96 39
Sch ACOT6, ADAMTS3, ADCY7, ADGRF4, AHI1, AKT1, ALS2CL, APOE, AVP, BDNF, BTG1, CAMK2B, CASP4, CCDC137, CCL2, CELF2, CFAP65, CHD4, CHI3L1, CLINT1, CNR1, COL3A1, COMT, CP, CPLX1, CPLX2, DAO, DGCR2, DISC1, DIXDC1, DLG1, DPYD, DRD1, DRD2, DRD3, DRD4, DTNBP1, EDEM2, EIF5, ESAM, FAM3D, FASTKD5, FGFR1, GABRA6, GABRB2, GABRD, GAD1, GAD2, GIF, GPR153, GRIK2, GRIK5, GRIN2B, GRIN2D, GRM2, GRM3, GSK3A, GSK3B, HCAR2, HLA‐DRB1, HNRNPA3, HP, HRH1, HTR2A, HTR6, HTR7, IL1B, IL2RA, IL6, IL6R, INPP5A, KDM2B, KDR, KLF12, KPNA1, LAMA1, LAMA2, LGR4, LRP1, MAGI2, MAOB, MET, MTHFR, MTOR, ND4, NDUFV2, NKAPL, NOS1, NPRL2, NR3C1, NRG1, NRG3, NRGN, NRIP1, NRXN1, NTF3, NTNG1, NTNG2, NTRK1, NTSR1, OXTR, PAK2, PCM1, PDE4B, PHB, PIK3CB, PITPNM1, PLCB1, PLCL2, PLXNA2, PML, PRODH, PVALB, RB1CC1, RELN, RGS12, RGS4, RGS9, RTN4, RTN4R, SAP30BP, SBNO1, SDF4, SELENBP1, SLC26A7, SLC6A1, SLC6A3, SLC6A4, SP4, SPATA5, SRSF1, SYN2, SYP, TAAR6, TAC1, TEKT5, THBS1, TNF, TP53, TPH1, TRAK1, TRRAP, TSPAN18, UGT1A3, VIPR2, VPS35, VPS39, WDR11, ZKSCAN4, ZNF565 (150) 30.91 86
ASD AVPR1A, BDNF, C3ORF58, CEP41, CHD8, CIRBP, CXORF36, DHCR24, DIO2, DIO3, DLG4, DLX1, DNMT3A, DNMT3B, DPP6, DPYD, EN2, FOXP1, GABRB3, GRIN2B, GTF2I, HEY1, HFE, IL1RAPL1, ITGB3, JARID2, LAMC3, LRRN3, LRRTM3, MEF2C, MTNR1A, NRXN1, NRXN2, NTSR1, OXTR, PCDH9, PTCHD1, RELN, RYR2, SCN1A, SFSWAP, SHANK3, SIN3A, SNTG2, SOX5, SOX9, TBL1X, TET1, TET3, TSHZ3, UPP2 (51) 24.05 29
AD ADORA2A, APP, CARTPT, CHRNA5, CHRNB2, CNR1, CRH, CRHR2, CRP, DIXDC1, DNMT1, DRD2, EOMES, FOS, GABRA2, GLO1, GNB1, GRM8, HTR7, MAGI2, MDK, MECP2, MIF, NPS, NPY, NPY1R, OXT, PAM, SERPINA1, SHANK1, SLC6A3, SLC6A4, TNF, UCN (34) 21.95 52
SMD CRH, MEF2C, TRH (3) 13.04 3
BD AKR1C4, ANK3, BDNF, BHLHE40, CACNA1C, COMT, CPLX1, CPLX2, DIXDC1, DRD1, DRD5, GRIK2, GRK3, GSK3A, GSK3B, HTR2A, INS, MTHFR, NDUFV2, NR3C1, NTNG1, NTNG2, NTRK1, NTRK2, PDE4B, POMC, PVALB, RELN, S100B, SERPINA1, SLC5A3, SLC6A4, SNAP25, SP4, TAC1, TACR1, TENM4, TRPC3, TSHB (39) 12.32 31
SD GRIN2A, MFSD2A, TTPA (3) 12.24 3
DS CALCA, CXCL8, GATA1, GSTM2, MTHFR, MTR, NTF3, PRDX2, PRDX6, RCAN1, S100B, SLC19A1, SOD1, VIP (14) 9.35 10
TS DRD3, SLITRK1 (2) 8.31 2
MSD AKAP5, CAMKMT, FGFR2, OGG1, PTEN, SHANK1 (6) 7.05 6
OCD BDNF, CCKBR, HOXB8, HTR1D, HTR2A, SLC6A4, SLITRK5 (7) 5.95 7
ADDBD DRD4, S100B (2) 4.03 2
LDD BCL11A, DPYD, ERF, FOXP2, GRIN2A, KCNA2, NRXN1, PTEN, SETBP1, SHANK3 (10) 3.52 10
DD ARFGAP1, CAMKMT, CBL, CHRNA4, CNTN4, DOCK8, DRD2, KCNQ2, KCNT1, LRP2, MECP2, NANS, NTRK2, PMP22, PNKP, PTEN, SHANK3, SLC2A1, SLC33A1, SLC4A4, SLC6A8, STAMBP (22) 2.99 24
FASD CAT, NOS1 (2) 2.49 2
PCDD DRD4, MECP2, MKL2 (3) 2.47 3

Table 1.

Selected neurodevelopmental diseases and related BPA‐interacted genes.

ID: intellectual disability; LD: learning disorders; Sch: schizophrenia; ASD: autism spectrum disorder; AD: anxiety disorders; SMD: stereotypic movement disorder; BD: bipolar disorder; SD: speech disorders; DS: Down syndrome; TS: Tourette syndrome; MSD: motor skills disorders; OCD: obsessive‐compulsive disorder; ADDBD: attention deficit and disruptive behavior disorders; LDD: language development disorders; DD: developmental disabilities; FASD: foetal alcohol spectrum disorders; PCDD: pervasive child development disorders.


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3. Microarray data and differently expressed gene screening

To explore the possible clinical application of the genes curated, we used Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) and ArrayExpress (http://www.ebi.ac.uk/arrayexpress) to find the microarray data for peripheral blood, and special tissue gene expression profiling in NDs. The differently expressed genes (DEGs) in each ND samples were identified. If more than one microarray dataset is found, all the datasets are integrated to perform the meta‐analysis for the DEGs. Based on the inference scores and the counts of inference BPA‐interacted genes, we only selected ID, LD, Sch, ASD, AD and BD as our target diseases for the possible microarray data.

We only found some common genes for BD between CTD and the microarray data. It was in the GSE46449 [10] and only four common genes (BDNF, CACNA1C, CPLX2, HTR2A, SP4) were found. Therefore, the existing microarray data is not enough for further annotation.

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4. Gene function enrichment analysis

The curated genes in CTD for each ND were uploaded to DAVID 6.8 Beta (https://david-d.ncifcrf.gov/tools.jsp). Homo sapiens were used as the background population. The gene ontology (GO) and pathway were analysed [11, 12]. Simultaneously, WikiPathways and Reactome of EnrichR [13, 14] were used for duplicated pathway prediction. STRING (http://string-db.org) is a database of known and predicted protein-protein interactions (PPI), and can be used to predict the functional associations between proteins [15]. Based on the information provided by the STRING database, all genes related to each neurodevelopmental disorder are used to construct a PPI network. The functional molecules in the PPI network are subsequently identified by the molecular complex detection (MCODE) plugin [16] of Cytoscape [17]. The MCODE is a well-known automated method to find highly interconnected subgraphs as molecular complexes or clusters in a PPI network. The proteins in each module will be transferred in Genemania app [18] to predict the possible target proteins or biomarkers.

4.1. Intellectual disability

Of the 119 interacted genes, 117 were bi-interacted. GO analysis with these 117 genes indicated that BPA bi-interacted genes are involved in the biological processes (BP) such as cognition, the development of nervous system, head, brain, forebrain, pallium, telencephalon and embryonic organ (Table 2). Other BPs included learning or memory, behaviour (social, single- or multi-organism), intraspecies interaction between organisms, embryonic organ morphogenesis, regulation of synapse structure or activity and neuron apoptotic process. Of the BPs, nervous system development was also reported in a recent study on systematic phenomics analysis for the genes muted in ID by Kochinke et al. [19]. Some genes possibly involved in the cellular component (CC) of somatodendritic compartment and the molecular functions (MF) of chromatic binding. Pathway analysis only found MECP2 and associated Rett Syndrome in WikiPathways, in which six BPA bi-interacted genes were involved. This might suggest that ID and Rett syndrome possess the same pathway.

Term Count P value FDR Genes
BP
Cognition 16 2.49E−10 4.53E−07 DEAF1, VIP, MEF2C, PTCHD1, TH, NF1, MECP2, PRKCG, NRXN1, PTEN, SHANK2, SHANK3, GRIN2B, GNAS, STRA6, SYNGAP1
Learning or memory 14 4.79E−09 8.72E−06 DEAF1, VIP, MEF2C, TH, NF1, MECP2, PRKCG, NRXN1, PTEN, SHANK2, SHANK3, GRIN2B, STRA6, SYNGAP1
Nervous system development 39 1.56E−08 2.85E−05 FGFR2, MEF2C, DEAF1, NAGLU, BBS7, NDST1, PTCHD1, KCNA2, TH, PAX6, MFSD2A, PTEN, BDNF, FOLR1, INPP5E, ADRA2B, CASP2, KIF1BP, DISC1, APC, DNMT3A, ALDH5A1, NF1, FMR1, MECP2, AHI1, PRKCG, NRXN1, SHANK2, SHANK3, FRY, ASCL1, HDAC4, SLC4A10, WDR62, SCN8A, SYNGAP1, KDM6B, FAM126A
Head development 22 2.28E−08 4.14E−05 MEF2C, FGFR2, NAGLU, BBS7, NDST1, PTCHD1, NF1, TH, PAX6, MECP2, AHI1, MFSD2A, NRXN1, PTEN, SHANK3, ASCL1, SLC4A10, WDR62, STRA6, CASP2, DISC1, KDM6B
Brain development 21 4.94E−08 0.0001 MEF2C, FGFR2, NAGLU, BBS7, NDST1, PTCHD1, NF1, TH, PAX6, MECP2, AHI1, MFSD2A, NRXN1, PTEN, SHANK3, ASCL1, SLC4A10, WDR62, CASP2, DISC1, KDM6B
Single-organism behaviour 16 9.96E−08 0.0002 DEAF1, VIP, MEF2C, KCNA2, TH, NF1, MECP2, PRKCG, NRXN1, PTEN, SHANK2, SHANK3, SLC4A10, GRIN2B, STRA6, SYNGAP1
Forebrain development 15 2.10E−07 0.0004 FGFR2, MEF2C, NDST1, PTCHD1, NF1, TH, PAX6, MFSD2A, PTEN, SHANK3, ASCL1, SLC4A10, WDR62, DISC1, KDM6B
Behaviour 18 2.56E−07 0.0005 DEAF1, VIP, MEF2C, NAGLU, PTCHD1, KCNA2, TH, NF1, MECP2, PRKCG, NRXN1, PTEN, SHANK2, SHANK3, SLC4A10, GRIN2B, STRA6, SYNGAP1
Central nervous system development 22 9.19E−07 0.0017 MEF2C, FGFR2, NAGLU, BBS7, NDST1, PTCHD1, ALDH5A1, NF1, TH, PAX6, MECP2, AHI1, MFSD2A, NRXN1, PTEN, SHANK3, ASCL1, SLC4A10, WDR62, CASP2, DISC1, KDM6B
Social behaviour 7 9.59E−07 0.0017 PTCHD1, TH, MECP2, NRXN1, PTEN, SHANK2, SHANK3
Intraspecies interaction between organisms 7 9.59E−07 0.0017 PTCHD1, TH, MECP2, NRXN1, PTEN, SHANK2, SHANK3
Pallium development 10 1.74E−06 0.0032 MEF2C, ASCL1, WDR62, NF1, TH, PAX6, MFSD2A, PTEN, KDM6B, DISC1
Embryonic organ morphogenesis 12 3.27E−06 0.0060 FGFR2, MEF2C, NAGLU, NDST1, BBS7, FOLR1, PRKRA, TH, PAX6, AHI1, STRA6, GNAS
Learning 9 4.59E−06 0.0084 DEAF1, NF1, TH, MECP2, STRA6, NRXN1, SYNGAP1, SHANK2, SHANK3
Regulation of synapse structure or activity 11 4.63E−06 0.0084 MEF2C, BDNF, FMR1, NF1, MECP2, NRXN1, SYNGAP1, PTEN, SHANK2, SHANK3, DISC1
Multi-organism behaviour 7 5.03E−06 0.0092 PTCHD1, TH, MECP2, NRXN1, PTEN, SHANK2, SHANK3
Telencephalon development 11 5.17E−06 0.0094 MEF2C, ASCL1, WDR62, NF1, TH, PAX6, MFSD2A, PTEN, KDM6B, SHANK3, DISC1
Regulation of neuron apoptotic process 10 8.61E−06 0.0157 MEF2C, ASCL1, HDAC4, BDNF, NF1, MECP2, PRKCG, SYNGAP1, PARP1, CASP2
Neuron apoptotic process 10 1.27E−05 0.0231 MEF2C, ASCL1, HDAC4, BDNF, NF1, MECP2, PRKCG, SYNGAP1, PARP1, CASP2
Observational learning 4 1.58E−05 0.0287 NF1, STRA6, NRXN1, SHANK3
Embryonic organ development 13 2.24E−05 0.0408 MEF2C, FGFR2, NAGLU, BBS7, NDST1, FOLR1, PRKRA, TH, PAX6, AHI1, GAMT, STRA6, GNAS
CC
Somatodendritic compartment 18 1.10E−05 0.0152 VIP, SNX14, KCNA2, FMR1, TH, NF1, PRKCG, NRXN1, PMM2, PTEN, SHANK2, SHANK3, ASCL1, SLC4A10, GNAS, SYNGAP1, SLC31A1, APC
MF
Chromatin binding 15 1.23E−05 0.0180 TAF2, MEF2C, DNMT3A, FMR1, PAX6, MECP2, CIC, HDAC4, ASCL1, VRK1, SIN3A, KDM5A, HIST3H3, NSD1, KDM6B

Table 2.

GO analysis for the genes related to intellectual disability.

PPI analysis found four molecular modules (Figure 1). TSEN2, TSEN34, TSEN54 and VRK1 were involved in module 1. TSEN2, TSEN34 and TSEN54 are tRNA splicing endonuclease subunits and can interact through physical interaction or co-expression. VRK1 might interact with TSEN2, TSEN34 and TSEN54 through the same pathway, physical interaction or co-expression. CLP1 and TSEN15 can physically interact with TSEN2, TSEN34 and TSEN54 [2022], therefore, BPA has the potential to interact with these two genes. BPA might also interact with WARS and WARS2 because of their predicted interaction with TSEN34 [23, 24]. WARS and WARS2 are involved in the tryptophan metabolic pathway, which have been reported to appear to provide a unifying biochemical basis for ASDs [25]. Tryptophan is a precursor of important compounds, such as serotonin, quinolinic acid and kynurenic acid, which are involved in neurodevelopment and synaptogenesis. Decreased tryptophan metabolism may alter brain development, neuroimmune activity and mitochondrial function. In module 2, ASCL1, HDAC4, BDNF, KDM6B, TH, HIST3H3, PAX6 and SIN3A interacted through co-localization, co-expression and physical interactions. TH and KDM6B linked other six node proteins through CALCOCO1 [26]. In module 3, LARP7, GAMT and TRMT1 were interacted by physical interactions, co-expression and predicted, pathway or genetic interaction. In this module, CDK9 plays an import role to link the three genes mainly by physical interactions [2729], although there was no direct evidence for BPA-CDK9 interaction. CDK9 might associate with ID by JUN binding [30] or by AFF family of RNA-binding proteins [31]. In module 4, PARP1, FASN and PTEN interact through physical interaction, co-expression, predicted, pathway, genetic interaction and shared protein domains. Recent findings have proven that the mTOR pathway is altered in cells with defective DNA repair. PARP1 is related to the accumulation of irreparable DNA damage [32], while PTEN is a phosphatase to mediate switching off the PI3K/Akt/mTOR signalling pathway, which has been reportedly associated with ID [3335]. FASN (expression of fatty acid synthase) is found negatively correlated with PTEN [36], but the in-between genes were not explored. FASN may co-express with MAST2 [26], PRKDC [26, 37] or BMI1 to physically interact with PTEN.

Figure 1.

Networks for the genes in PPI MCODE molecular modules for ID.

4.2. Learning disorders

A total of 29 BPA bi-interacted genes related to LD were found. Some of these genes are involved in the BPs such as behaviour, learning or memory, cognition, synaptic-signalling related, cell-cell signalling related, secretion, neuron death or apoptotic-related processes (Table 3). Simultaneously, some of these genes may participate in the CCs such as synapse, presynapse, dendrite, somatodendritic compartment, axon or secretory vesicle. Five KEGG pathways might be influenced by BPA (Table 4). Retrograde endocannabinoid signalling, serotonergic synapse and glutamatergic synapse pathways may be influenced by BPA and involve in LD. Nicotine addiction and Alzheimer’s disease may share the same pathway with LD. WikiPathways indicated monoamine transport, synaptic vesicle pathway, MECP2 and associated Rett syndrome pathway might also be influenced. Interestingly, some genes involved in LD are also found in sudden infant death syndrome (SIDS) susceptibility pathways. Reactome pathway confirmed the serotonergic synapse pathway found in KEGG, and additionally suggested that organic anion transporters pathway may be influenced by BPA.

Term Count P value FDR Genes
BP
Single-organism behaviour 14 2.98E−14 5.29E−11 SLC17A7, APP, HTR1A, PSEN1, PDE1B, GRIA1, BCL2, MAPT, NF1, TH, MECP2, IL1B, PARK2, TRH
Behaviour 14 2.07E−12 3.67E−09 SLC17A7, APP, HTR1A, PSEN1, PDE1B, GRIA1, BCL2, MAPT, NF1, TH, MECP2, IL1B, PARK2, TRH
Learning or memory 10 9.30E−11 1.65E−07 SLC17A7, APP, PDE1B, PSEN1, GRIA1, NF1, TH, MECP2, IL1B, PARK2
Cognition 10 3.03E−10 5.39E−07 SLC17A7, APP, PDE1B, PSEN1, GRIA1, NF1, TH, MECP2, IL1B, PARK2
Chemical synaptic transmission 12 2.11E−09 3.75E−06 SYP, SLC17A7, ACHE, HTR1A, PNOC, PSEN1, GRIA1, HTR7, NF1, TH, MECP2, PARK2
Trans-synaptic signalling 12 2.11E−09 3.75E−06 SYP, SLC17A7, ACHE, HTR1A, PNOC, PSEN1, GRIA1, HTR7, NF1, TH, MECP2, PARK2
Synaptic signalling 12 2.11E−09 3.75E−06 SYP, SLC17A7, ACHE, HTR1A, PNOC, PSEN1, GRIA1, HTR7, NF1, TH, MECP2, PARK2
Anterograde trans-synaptic signalling 12 2.11E−09 3.75E−06 SYP, SLC17A7, ACHE, HTR1A, PNOC, PSEN1, GRIA1, HTR7, NF1, TH, MECP2, PARK2
Secretion by cell 13 2.26E−08 4.02E−05 SLC17A7, ACHE, APP, HTR1A, PSEN1, HMOX1, NF1, VEGFA, IL1RN, MECP2, IL1B, PARK2, TRH
Cell-cell signalling 15 3.65E−08 6.49E−05 ACHE, TH, IL1RN, NF1, MECP2, PARK2, TRH, SYP, SLC17A7, HTR1A, PNOC, PSEN1, GRIA1, HTR7, IL1B
Secretion 13 9.70E−08 1.73E−04 SLC17A7, ACHE, APP, HTR1A, PSEN1, HMOX1, NF1, VEGFA, IL1RN, MECP2, IL1B, PARK2, TRH
Regulation of cell communication 19 1.13E−07 2.01E−04 ACHE, KL, NF1, IL1RN, MECP2, PARK2, TRH, POR, SYP, APP, CAMKMT, HTR1A, APOD, PSEN1, GRIA1, BCL2, HMOX1, VEGFA, IL1B
Regulation of signalling 19 1.46E−07 2.60E−04 ACHE, KL, NF1, IL1RN, MECP2, PARK2, TRH, POR, SYP, APP, CAMKMT, HTR1A, APOD, PSEN1, GRIA1, BCL2, HMOX1, VEGFA, IL1B
System process 16 1.56E−07 2.78E−04 TH, NF1, MECP2, PARK2, SLC17A7, APP, HTR1A, PNOC, PSEN1, PDE1B, GRIA1, HTR7, BCL2, HMOX1, VEGFA, IL1B
Dicarboxylic acid transport 6 1.68E−07 2.98E−04 SLC17A7, SLC17A6, PSEN1, NF1, IL1B, TRH
Organic hydroxy compound metabolic process 9 2.69E−07 4.79E−04 APP, HTR1A, PDE1B, BCL2, TH, MECP2, IL1B, PARK2, POR
Neuron death 8 4.39E−07 7.81E−04 APP, PSEN1, HMOX1, BCL2, NF1, MECP2, PARK2, SIGMAR1
Locomotory behaviour 7 6.43E−07 1.14E−03 APP, PDE1B, MAPT, TH, MECP2, PARK2, TRH
Response to hypoxia 8 7.59E−07 1.35E−03 HMOX1, BCL2, VEGFA, NF1, TH, MECP2, IL1B, TRH
Memory 6 7.93E−07 1.41E−03 SLC17A7, PSEN1, GRIA1, TH, MECP2, IL1B
Regulation of neurotransmitter levels 7 8.92E−07 1.59E−03 SLC17A7, ACHE, PDE1B, PSEN1, NF1, TH, PARK2
Regulation of neuron apoptotic process 7 9.19E−07 1.63E−03 PSEN1, HMOX1, BCL2, NF1, MECP2, PARK2, SIGMAR1
Response to decreased oxygen levels 8 9.52E−07 1.69E−03 HMOX1, BCL2, VEGFA, NF1, TH, MECP2, IL1B, TRH
Neuron apoptotic process 7 1.22E−06 2.16E−03 APP, PSEN1, HMOX1, BCL2, NF1, MECP2, PARK2
Response to oxygen levels 8 1.41E−06 2.51E−03 HMOX1, BCL2, VEGFA, NF1, TH, MECP2, IL1B, TRH
Central nervous system development 11 1.65E−06 2.93E−03 SLC17A7, APP, APOD, PSEN1, MAPT, BCL2, NF1, TH, MECP2, IL1B, PARK2
Nitrogen compound transport 10 2.10E−06 3.74E−03 SLC17A7, SLC17A6, PSEN1, NF1, IL1RN, TH, MECP2, IL1B, PARK2, TRH
Learning 6 3.41E−06 6.06E−03 APP, PDE1B, NF1, TH, MECP2, PARK2
Response to oxidative stress 8 4.34E−06 7.72E−03 APP, APOD, PSEN1, MAPT, HMOX1, BCL2, IL1B, PARK2
Regulation of neuron death 7 5.01E−06 8.91E−03 PSEN1, HMOX1, BCL2, NF1, MECP2, PARK2, SIGMAR1
Chemical homeostasis 11 5.20E−06 9.25E−03 SLC17A7, MICU1, APP, PSEN1, KL, HMOX1, BCL2, VEGFA, TH, IL1B, PARK2
CC
Synapse part 13 4.60E−10 5.87E−07 ACHE, TH, NF1, MECP2, PARK2, SIGMAR1, SYP, SLC17A7, APP, SLC17A6, PSEN1, GRIA1, MAPT
Neuron projection 15 1.09E−09 1.39E−06 TH, NF1, PARK2, SIGMAR1, SYP, SLC17A7, APP, HTR1A, SLC17A6, PNOC, APOD, PSEN1, GRIA1, MAPT, HTR7
Neuron part 16 4.99E−09 6.37E−06 TH, NF1, PARK2, SIGMAR1, SYP, SLC17A7, APP, HTR1A, SLC17A6, PNOC, PDE1B, APOD, PSEN1, GRIA1, MAPT, HTR7
Synapse 13 6.19E−09 7.90E−06 ACHE, TH, NF1, MECP2, PARK2, SIGMAR1, SYP, SLC17A7, APP, SLC17A6, PSEN1, GRIA1, MAPT
Presynapse 9 5.66E−08 7.23E−05 SYP, SLC17A7, APP, SLC17A6, PSEN1, GRIA1, NF1, TH, PARK2
Dendrite 10 2.30E−07 2.94E−04 APP, HTR1A, PNOC, APOD, PSEN1, GRIA1, HTR7, MAPT, NF1, TH
Somatodendritic compartment 11 4.77E−07 6.09E−04 APP, HTR1A, PNOC, APOD, PDE1B, PSEN1, GRIA1, HTR7, MAPT, NF1, TH
Axon 9 1.38E−06 1.76E−03 SYP, SLC17A7, APP, PNOC, PSEN1, GRIA1, MAPT, NF1, TH
Secretory vesicle 9 2.35E−06 3.00E−03 SYP, SLC17A7, APP, SLC17A6, GRIA1, VEGFA, TH, IL1B, TRH
MF
Protein domain specific binding 10 7.72E−07 1.04E−03 SYP, APP, PSEN1, GRIA1, MAPT, BCL2, TH, MECP2, IL1B, PARK2

Table 3.

GO analysis for the genes related to learning disorders.

Terms Count P value Genes
KEGG
Nicotine addiction 3 0.0047 SLC17A7, SLC17A6, GRIA1
Alzheimer’s disease 4 0.0088 APP, PSEN1, MAPT, IL1B
Retrograde endocannabinoid signalling 3 0.0278 SLC17A7, SLC17A6, GRIA1
Serotonergic synapse 3 0.0331 APP, HTR1A, HTR7
Glutamatergic synapse 3 0.0348 SLC17A7, SLC17A6, GRIA1
WikiPathways
SIDS susceptibility pathways 6 2.83E−05 MECP2, IL1RN, TH, IL1B, HTR1A, VEGFA
Integrated pancreatic cancer pathway 5 0.0008 APP, ACHE, BCL2, MAPT, VEGFA
Monoamine transport 3 0.0003 ACHE, TH, IL1B
Synaptic vesicle pathway 3 0.0011 SLC17A6, SLC17A7, SYP
Alzheimer’s disease 4 0.0011 APP, IL1B, PSEN1, MAPT
Mecp2 and associated Rett syndrome 3 0.0009 GRIA1, MECP2, NF1
Overview of nanoparticle effects 2 0.0028 BCL2, HMOX1
Reactome
Organic anion transporters 2 0.0215 SLC17A7, SLC17A6
Serotonin receptors 2 0.0321 HTR1A, HTR7
TRAF6-mediated NF-kB activation 2 0.0631 APP, RNF135
Interleukin-1 signalling 2 0.0932 IL1RN, IL1B
Biocart
Generation of amyloid b-peptide by PS1 2 0.0427 APP, PSEN1
Deregulation of CDK5 in Alzheimer’s Disease 2 0.0427 APP, MAPT

Table 4.

Pathway analysis for the genes related to learning disorders.

Only one module was found for LD (Figure 2: LD). In this module, HTR1A, MAPT, TH, PARK2 and TRH were interacted by physical interactions, co-expression, predicted, pathway, co-localization, genetic interactions and shared protein domains. PARK2 is known to play a role in neurological development or function and when disturbed can account for LD [38, 39]. TH links PARK2 by sharing the same pathway [40], in which HOXA4 could co-express with TRHR [41], which could co-express with MAPT [42]. Serotonin gene (HTR1A) is also involved in this module, which is consistent with the serotonergic synapse and serotonin receptors pathway in KEGG and Reactome, respectively.

Figure 2.

Networks for the genes in the PPI MCODE molecular modules for LD, ASD, AD and BD.

4.3. Schizophrenia

A total of 149 genes related to Sch were found to be BPA bi-interacted. Significant BPs included those found in LD such as behaviour, learning or memory, cognition, synaptic signalling related and cell-cell signalling related. Synaptic transmission-related, cell communication-related and phosphorus metabolic processes were also found (Table 5). Like LD, the genes participate in synapse, presynapse, dendrite, somatodendritic compartment and axon cellular components. Other CCs include cell body, intrinsic or integral component of plasma membrane, synaptic membrane and plasma membrane region. Unlike LD with little significant MFs found, Sch showed many significant MFs including the activity of signal transducer, neurotransmitter receptor, transmembrane-signalling receptor, molecular transducer, glutamate receptor and dopamine neurotransmitter receptor, dopamine or catecholamine binding. The same as LD, WikiPathways found that BPA could be linked to Sch through Alzheimer’s disease, monoamine transport and SIDS susceptibility pathways (Table 6). The KEGG pathways such as neuroactive ligand-receptor interaction, cocaine addiction, dopaminergic synapse, cAMP signalling pathway and calcium-signalling pathway were also found to be significant. Reactome pathways included transmission across chemical synapse, amine ligand-binding receptors, neuronal system and signalling by GPCR, PDGF, FGFR4, FGFR3, FGFR1 or EGFR.

Term Count P value FDR Genes
BP
Synaptic signalling 44 2.29E−27 4.33E−24 DRD1, CPLX2, CCL2, CPLX1, SLC6A1, DRD3, GABRB2, GRIK2, DRD2, SLC6A3, SLC6A4, DRD4, GRIK5, OXTR, TAC1, DTNBP1, AKT1, SYP, PLCL2, GAD2, HRH1, GRIN2B, APOE, GRIN2D, CNR1, SYN2, CAMK2B, GAD1, DLG1, GABRD, NOS1, NRXN1, NTSR1, LAMA2, GRM3, GRM2, GSK3A, HTR7, GSK3B, NTRK1, HTR6, RELN, NRGN, HTR2A
Anterograde Trans-synaptic signalling 44 2.29E−27 4.33E−24 DRD1, CPLX2, CCL2, CPLX1, SLC6A1, DRD3, GABRB2, GRIK2, DRD2, SLC6A3, SLC6A4, DRD4, GRIK5, OXTR, TAC1, DTNBP1, AKT1, SYP, PLCL2, GAD2, HRH1, GRIN2B, APOE, GRIN2D, CNR1, SYN2, CAMK2B, GAD1, DLG1, GABRD, NOS1, NRXN1, NTSR1, LAMA2, GRM3, GRM2, GSK3A, HTR7, GSK3B, NTRK1, HTR6, RELN, NRGN, HTR2A
Trans-synaptic signalling 44 2.29E−27 4.33E−24 DRD1, CPLX2, CCL2, CPLX1, SLC6A1, DRD3, GABRB2, GRIK2, DRD2, SLC6A3, SLC6A4, DRD4, GRIK5, OXTR, TAC1, DTNBP1, AKT1, SYP, PLCL2, GAD2, HRH1, GRIN2B, APOE, GRIN2D, CNR1, SYN2, CAMK2B, GAD1, DLG1, GABRD, NOS1, NRXN1, NTSR1, LAMA2, GRM3, GRM2, GSK3A, HTR7, GSK3B, NTRK1, HTR6, RELN, NRGN, HTR2A
Chemical synaptic transmission 44 2.29E−27 4.33E−24 DRD1, CPLX2, CCL2, CPLX1, SLC6A1, DRD3, GABRB2, GRIK2, DRD2, SLC6A3, SLC6A4, DRD4, GRIK5, OXTR, TAC1, DTNBP1, AKT1, SYP, PLCL2, GAD2, HRH1, GRIN2B, APOE, GRIN2D, CNR1, SYN2, CAMK2B, GAD1, DLG1, GABRD, NOS1, NRXN1, NTSR1, LAMA2, GRM3, GRM2, GSK3A, HTR7, GSK3B, NTRK1, HTR6, RELN, NRGN, HTR2A
Cell-cell signalling 62 3.34E−26 6.31E−23 SLC6A1, FAM3D, GRIK2, GABRB2, SLC6A3, SLC6A4, GRIK5, VIPR2, LGR4, AKT1, SYP, BDNF, GRIN2B, APOE, GRIN2D, IL1B, PLCB1, HCAR2, DISC1, DLG1, AVP, MAGI2, NRXN1, NTSR1, GRM3, GRM2, HTR7, HTR6, RELN, NRGN, FGFR1, DRD1, CPLX2, CCL2, CPLX1, TNF, DRD3, HLA-DRB1, DRD2, DRD4, OXTR, TAC1, DTNBP1, PLCL2, HRH1, GAD2, CNR1, SYN2, CAMK2B, VPS35, GAD1, GABRD, DIXDC1, IL6, NOS1, NTF3, LAMA2, LRP1, GSK3A, NTRK1, GSK3B, HTR2A
Modulation of synaptic transmission 31 6.10E−24 1.15E−20 CPLX2, DRD1, CCL2, DRD3, SLC6A1, GRIK2, DRD2, DRD4, SLC6A4, GRIK5, TAC1, OXTR, DTNBP1, SYP, PLCL2, HRH1, APOE, CNR1, CAMK2B, NOS1, NTF3, NRXN1, NTSR1, LAMA2, GRM3, GRM2, GSK3B, NTRK1, RELN, NRGN, HTR2A
Regulation of cell communication 72 2.46E−17 4.64E−14 SLC6A1, FAM3D, GRIK2, SLC6A4, GRIK5, LGR4, SYP, AKT1, BDNF, PAK2, APOE, IL1B, PLCB1, NRG1, HCAR2, DISC1, ALS2CL, DLG1, AVP, MAGI2, PIK3CB, TP53, NRXN1, IL6R, NTSR1, GRM3, GRM2, HTR6, RELN, NRGN, ADAMTS3, FGFR1, DRD1, CPLX2, CCL2, TNF, DRD3, HLA-DRB1, DRD2, DRD4, COL3A1, PML, TAC1, OXTR, NPRL2, DTNBP1, PLCL2, HRH1, RGS12, RB1CC1, CNR1, CAMK2B, VPS35, THBS1, CHD4, DIXDC1, IL6, NOS1, NTF3, PHB, RTN4R, CHI3L1, KDR, LAMA2, LRP1, GSK3A, NTRK1, RGS4, GSK3B, MTOR, RGS9, HTR2A
Regulation of signalling 72 5.99E−17 2.11E−13 SLC6A1, FAM3D, GRIK2, SLC6A4, GRIK5, LGR4, SYP, AKT1, BDNF, PAK2, APOE, IL1B, PLCB1, NRG1, HCAR2, DISC1, ALS2CL, DLG1, AVP, MAGI2, PIK3CB, TP53, NRXN1, IL6R, NTSR1, GRM3, GRM2, HTR6, RELN, NRGN, ADAMTS3, FGFR1, DRD1, CPLX2, CCL2, TNF, DRD3, HLA-DRB1, DRD2, DRD4, COL3A1, PML, TAC1, OXTR, NPRL2, DTNBP1, PLCL2, HRH1, RGS12, RB1CC1, CNR1, CAMK2B, VPS35, THBS1, CHD4, DIXDC1, IL6, NOS1, NTF3, PHB, RTN4R, CHI3L1, KDR, LAMA2, LRP1, GSK3A, NTRK1, RGS4, GSK3B, MTOR, RGS9, HTR2A
Single-organism behaviour 27 1.71E−15 3.14E−12 DRD1, DRD3, SLC6A1, DRD2, GRIK2, DRD4, SLC6A4, TAC1, OXTR, COMT, HRH1, GRIN2B, GRIN2D, CNR1, IL1B, THBS1, PLCB1, AVP, IL6, NOS1, NRXN1, NTSR1, NTRK1, RELN, MTOR, NRGN, HTR2A
Positive regulation of cell communication 48 9.61E−15 1.82E−11 FGFR1, DRD1, CCL2, TNF, DRD3, HLA-DRB1, GRIK2, DRD2, DRD4, COL3A1, PML, OXTR, TAC1, DTNBP1, LGR4, AKT1, BDNF, PAK2, RB1CC1, IL1B, VPS35, NRG1, PLCB1, THBS1, HCAR2, DISC1, DIXDC1, IL6, NOS1, NTF3, PIK3CB, PHB, TP53, CHI3L1, IL6R, NRXN1, NTSR1, KDR, LAMA2, GSK3A, NTRK1, GSK3B, HTR6, RELN, NRGN, MTOR, ADAMTS3, HTR2A
Positive regulation of signalling 48 1.10E−14 2.08E−11 FGFR1, DRD1, CCL2, TNF, DRD3, HLA-DRB1, GRIK2, DRD2, DRD4, COL3A1, PML, OXTR, TAC1, DTNBP1, LGR4, AKT1, BDNF, PAK2, RB1CC1, IL1B, VPS35, NRG1, PLCB1, THBS1, HCAR2, DISC1, DIXDC1, IL6, NOS1, NTF3, PIK3CB, PHB, TP53, CHI3L1, IL6R, NRXN1, NTSR1, KDR, LAMA2, GSK3A, NTRK1, GSK3B, HTR6, RELN, NRGN, MTOR, ADAMTS3, HTR2A
Learning or memory 21 1.10E−14 2.08E−11 DRD1, DRD3, SLC6A1, DRD2, DRD4, SLC6A4, TAC1, OXTR, COMT, NRXN1, NTSR1, HRH1, GRIN2B, CNR1, NTRK1, IL1B, RELN, NRGN, MTOR, PLCB1, HTR2A
Behaviour 30 1.11E−14 2.10E−11 DRD1, DRD3, SLC6A1, DRD2, GRIK2, SLC6A3, DRD4, SLC6A4, TAC1, OXTR, COMT, HRH1, GRIN2B, GRIN2D, CNR1, IL1B, THBS1, PLCB1, NRG1, IL6, AVP, NOS1, TP53, NRXN1, NTSR1, NTRK1, RELN, MTOR, NRGN, HTR2A
Cognition 22 1.22E−14 2.31E−11 DRD1, DRD3, SLC6A1, DRD2, DRD4, SLC6A4, TAC1, OXTR, COMT, NRXN1, NTSR1, DGCR2, HRH1, GRIN2B, CNR1, NTRK1, IL1B, RELN, NRGN, MTOR, PLCB1, HTR2A
Neuron-neuron synaptic transmission 16 1.33E−14 2.52E−11 DRD1, DRD3, SLC6A1, DRD2, GRIK2, GABRB2, SLC6A3, DRD4, SLC6A4, GRIK5, TAC1, OXTR, NRXN1, NTRK1, RELN, HTR2A
Response to alkaloid 18 1.48E−14 2.79E−11 IL6, AVP, DRD1, TNF, NOS1, SLC6A1, ND4, DRD3, DRD2, SLC6A3, DRD4, TAC1, OXTR, CNR1, NTRK1, IL1B, MTOR, HTR2A
Positive regulation of synaptic transmission 16 8.02E−14 1.52E−10 DRD1, CCL2, NOS1, DRD2, GRIK2, DRD4, TAC1, OXTR, NRXN1, NTSR1, DTNBP1, LAMA2, NTRK1, GSK3B, RELN, NRGN
Regulation of phosphate metabolic process 47 2.16E−13 4.07E−10 FGFR1, DRD1, CCL2, NRG3, TNF, ADCY7, DRD3, GRIK2, DRD2, DRD4, PML, NPRL2, VIPR2, DTNBP1, PLCL2, AKT1, HRH1, PAK2, APOE, RB1CC1, IL1B, NRG1, PLCB1, THBS1, DLG1, IL6, AVP, MAGI2, NOS1, NTF3, PIK3CB, PHB, TP53, RTN4R, CHI3L1, IL6R, NTSR1, KDR, GRM3, GRM2, GSK3A, RGS4, NTRK1, GSK3B, RELN, MTOR, HTR2A
Regulation of phosphorus metabolic process 47 2.20E−13 4.16E−10 FGFR1, DRD1, CCL2, NRG3, TNF, ADCY7, DRD3, GRIK2, DRD2, DRD4, PML, NPRL2, VIPR2, DTNBP1, PLCL2, AKT1, HRH1, PAK2, APOE, RB1CC1, IL1B, NRG1, PLCB1, THBS1, DLG1, IL6, AVP, MAGI2, NOS1, NTF3, PIK3CB, PHB, TP53, RTN4R, CHI3L1, IL6R, NTSR1, KDR, GRM3, GRM2, GSK3A, RGS4, NTRK1, GSK3B, RELN, MTOR, HTR2A
Regulation of transport 49 8.08E−13 1.53E−09 FGFR1, DRD1, CPLX2, CCL2, CPLX1, TNF, SLC6A1, DRD3, HLA-DRB1, FAM3D, DRD2, DRD4, GRIK5, PML, OXTR, TAC1, COMT, EDEM2, DTNBP1, LGR4, AKT1, APOE, CNR1, PDE4B, IL1B, CAMK2B, VPS35, NRG1, THBS1, HCAR2, DLG1, IL6, AVP, MAGI2, NOS1, NTF3, PIK3CB, MAOB, TP53, AHI1, NRXN1, NTSR1, PCM1, LRP1, GSK3A, GSK3B, RELN, MTOR, HTR2A
CC
Neuron projection 48 3.23E−21 4.54E−18 DRD1, CPLX2, CCL2, CPLX1, SLC6A1, GRIK2, DRD2, SLC6A3, SLC6A4, DRD4, GRIK5, TAC1, COMT, DTNBP1, HNRNPA3, SYP, GAD2, MTHFR, RGS12, GRIN2B, PVALB, APOE, CNR1, PDE4B, CAMK2B, NRG1, DISC1, DLG1, AVP, NOS1, MAGI2, RTN4R, NRXN1, NTSR1, LAMA2, GRM3, GRM2, LRP1, HTR7, NTRK1, GSK3B, HTR6, RELN, NRGN, MTOR, TPH1, KPNA1, HTR2A
Synapse 40 6.12E−19 8.61E−16 CPLX2, DRD1, CCL2, CPLX1, GABRB2, GRIK2, DRD2, SLC6A3, DRD4, SLC6A4, GRIK5, COMT, DTNBP1, AKT1, SYP, GAD2, MTHFR, RGS12, GRIN2B, PVALB, GRIN2D, PDE4B, SYN2, CAMK2B, NRG1, GAD1, DISC1, DLG1, GABRD, NOS1, MAGI2, GABRA6, NRXN1, NTSR1, LAMA2, GRM3, GRM2, GSK3A, GSK3B, NRGN
Synapse part 36 1.32E−18 1.86E−15 CPLX2, DRD1, CPLX1, GABRB2, DRD2, GRIK2, SLC6A3, DRD4, SLC6A4, GRIK5, COMT, DTNBP1, SYP, AKT1, GAD2, GRIN2B, PVALB, GRIN2D, PDE4B, SYN2, CAMK2B, GAD1, DISC1, DLG1, GABRD, NOS1, MAGI2, GABRA6, NRXN1, NTSR1, LAMA2, GRM3, GRM2, GSK3A, GSK3B, NRGN
Neuron part 51 3.07E−18 4.33E−15 SLC6A1, GRIK2, SLC6A3, SLC6A4, GRIK5, SYP, GRIN2B, PVALB, APOE, PDE4B, NRG1, DISC1, DLG1, AVP, MAGI2, NRXN1, NTSR1, GRM3, GRM2, HTR7, HTR6, RELN, NRGN, TPH1, KPNA1, CPLX2, DRD1, CPLX1, CCL2, DRD2, DRD4, TAC1, COMT, DTNBP1, HNRNPA3, GAD2, MTHFR, RGS12, CNR1, SYN2, CAMK2B, GAD1, NOS1, RTN4R, LAMA2, LRP1, NTRK1, GSK3B, RGS9, MTOR, HTR2A
Dendrite 32 1.49E−17 2.10E−14 CPLX2, DRD1, CCL2, CPLX1, GRIK2, DRD2, DRD4, GRIK5, COMT, DTNBP1, RGS12, APOE, PDE4B, CAMK2B, NRG1, AVP, NOS1, MAGI2, NTSR1, LAMA2, GRM3, GRM2, LRP1, GSK3B, NTRK1, HTR7, HTR6, RELN, NRGN, MTOR, KPNA1, HTR2A
Somatodendritic compartment 37 2.66E−17 3.74E−14 DRD1, CPLX2, CCL2, CPLX1, GRIK2, DRD2, SLC6A3, DRD4, GRIK5, TAC1, COMT, DTNBP1, RGS12, PVALB, APOE, PDE4B, CAMK2B, NRG1, AVP, NOS1, MAGI2, RTN4R, NRXN1, NTSR1, LAMA2, GRM3, GRM2, LRP1, HTR7, GSK3B, NTRK1, HTR6, RELN, NRGN, MTOR, KPNA1, HTR2A
Axon 29 7.56E−16 1.10E−12 CPLX2, DRD1, CCL2, CPLX1, SLC6A1, DRD2, GRIK2, SLC6A3, DRD4, GRIK5, TAC1, COMT, DTNBP1, SYP, GAD2, PVALB, CNR1, NRG1, DISC1, DLG1, RTN4R, NRXN1, NTSR1, GRM3, GRM2, GSK3B, NTRK1, NRGN, HTR2A
Postsynapse 25 4.28E−14 6.02E−11 GABRD, DRD1, NOS1, MAGI2, GABRB2, GRIK2, DRD2, GABRA6, DRD4, GRIK5, COMT, NTSR1, DTNBP1, AKT1, LAMA2, GRM3, GRIN2B, GSK3A, GRIN2D, GSK3B, PDE4B, CAMK2B, NRGN, DISC1, DLG1
Cell body 26 2.58E−11 3.63E−08 CPLX2, DRD1, CPLX1, CCL2, DRD2, GRIK2, SLC6A3, DRD4, GRIK5, TAC1, COMT, RGS12, PVALB, APOE, CAMK2B, NRG1, DISC1, RTN4R, NRXN1, NTSR1, LRP1, NTRK1, GSK3B, MTOR, NRGN, HTR2A
Presynapse 20 2.97E−11 4.19E−08 CPLX2, CPLX1, DRD2, GRIK2, SLC6A3, DRD4, SLC6A4, GRIK5, NRXN1, NTSR1, DTNBP1, SYP, GAD2, GRM3, GRM2, PVALB, PDE4B, SYN2, GAD1, DISC1
Intrinsic component of plasma membrane 45 1.08E−10 1.52E−07 FGFR1, DRD1, NRG3, TNF, SLC6A1, DRD3, HLA-DRB1, GABRB2, GRIK2, DRD2, PLXNA2, SLC6A3, SLC6A4, DRD4, GRIK5, OXTR, VIPR2, LGR4, HRH1, GRIN2B, GRIN2D, CNR1, NRG1, DLG1, GABRD, IL6, GABRA6, PHB, MET, NTNG1, RTN4R, IL6R, NRXN1, NTSR1, TSPAN18, KDR, GRM3, GRM2, LRP1, SLC26A7, HTR7, NTRK1, HTR6, CP, HTR2A
Integral component of plasma membrane 43 4.17E−10 5.87E−07 FGFR1, DRD1, TNF, NRG3, SLC6A1, HLA-DRB1, DRD3, GABRB2, GRIK2, DRD2, PLXNA2, SLC6A3, SLC6A4, DRD4, GRIK5, OXTR, VIPR2, LGR4, HRH1, GRIN2B, GRIN2D, CNR1, NRG1, DLG1, GABRD, IL6, GABRA6, PHB, MET, RTN4R, IL6R, NRXN1, NTSR1, TSPAN18, KDR, GRM3, GRM2, LRP1, SLC26A7, HTR7, NTRK1, HTR6, HTR2A
Neuronal cell body 23 4.45E−10 6.27E−07 DRD1, CPLX2, CCL2, CPLX1, GRIK2, DRD2, SLC6A3, DRD4, GRIK5, RTN4R, TAC1, NRXN1, NTSR1, LRP1, RGS12, PVALB, APOE, GSK3B, NTRK1, CAMK2B, NRGN, MTOR, HTR2A
Axon part 16 4.61E−09 6.49E−06 DRD1, CPLX2, CCL2, CPLX1, DRD2, GRIK2, DRD4, RTN4R, GRIK5, NRXN1, NTSR1, DTNBP1, SYP, PVALB, NRG1, DLG1
Dendritic spine 12 2.08E−08 2.93E−05 LAMA2, DRD1, GRM3, NOS1, DRD2, GSK3B, PDE4B, DRD4, COMT, NRGN, NTSR1, DTNBP1
Neuron spine 12 2.46E−08 3.47E−05 LAMA2, DRD1, GRM3, NOS1, DRD2, GSK3B, PDE4B, DRD4, COMT, NRGN, NTSR1, DTNBP1
Synaptic membrane 16 4.23E−08 5.96E−05 GABRD, GRIK2, GABRB2, GABRA6, GRIK5, NRXN1, COMT, DTNBP1, SYP, GRM3, GAD2, GRM2, GRIN2B, GRIN2D, DISC1, DLG1
Excitatory synapse 13 8.32E−08 1.17E−04 SYP, GRM3, MAGI2, NOS1, DRD2, GRIK2, PDE4B, GRIK5, CAMK2B, NRGN, DTNBP1, DISC1, DLG1
Plasma membrane region 28 1.94E−07 2.73E−04 DRD1, DRD2, GRIK2, GABRB2, SLC6A3, GRIK5, OXTR, COMT, DTNBP1, SYP, GAD2, GRIN2B, GRIN2D, NRG1, DISC1, DLG1, GABRD, NOS1, GABRA6, MET, GIF, NRXN1, IL6R, GRM3, GRM2, SLC26A7, RGS9, HTR2A
Axon terminus 11 2.90E−07 4.08E−04 SYP, DRD1, CPLX2, CPLX1, CCL2, PVALB, DRD2, GRIK2, DRD4, GRIK5, NTSR1
MF
Signal transducer activity 46 2.55E−11 3.79E−08 FGFR1, DRD1, NRG3, DRD3, HLA-DRB1, GABRB2, GRIK2, DRD2, PLXNA2, ADGRF4, DRD4, GRIK5, OXTR, NR3C1, VIPR2, LGR4, PLCL2, TAAR6, HRH1, RGS12, GRIN2B, PAK2, GRIN2D, CNR1, PLCB1, NRG1, HCAR2, GABRD, AVP, MAGI2, IL2RA, GABRA6, MET, RTN4R, IL6R, NRXN1, NTSR1, KDR, GPR153, GRM3, GRM2, HTR7, NTRK1, HTR6, RGS9, HTR2A
Neurotransmitter receptor activity 12 8.07E−10 1.20E−06 DRD1, GRIN2B, DRD3, DRD2, GRIK2, HTR7, GRIN2D, GABRA6, HTR6, DRD4, GRIK5, HTR2A
Transmembrane receptor activity 37 2.01E−09 2.98E−06 FGFR1, DRD1, HLA-DRB1, DRD3, GABRB2, GRIK2, PLXNA2, DRD2, ADGRF4, DRD4, GRIK5, OXTR, VIPR2, LGR4, TAAR6, HRH1, GRIN2B, GRIN2D, CNR1, HCAR2, DLG1, GABRD, IL2RA, GABRA6, MET, RTN4R, IL6R, NRXN1, NTSR1, KDR, GPR153, GRM3, GRM2, NTRK1, HTR7, HTR6, HTR2A
Transmembrane signalling receptor activity 36 2.61E−09 3.87E−06 FGFR1, DRD1, HLA-DRB1, DRD3, GABRB2, GRIK2, PLXNA2, DRD2, ADGRF4, DRD4, GRIK5, OXTR, VIPR2, LGR4, HRH1, TAAR6, GRIN2B, GRIN2D, CNR1, HCAR2, GABRD, IL2RA, GABRA6, MET, RTN4R, IL6R, NRXN1, NTSR1, KDR, GPR153, GRM3, GRM2, NTRK1, HTR7, HTR6, HTR2A
Signalling receptor activity 37 5.46E−09 8.09E−06 FGFR1, DRD1, HLA-DRB1, DRD3, GABRB2, GRIK2, PLXNA2, DRD2, ADGRF4, DRD4, GRIK5, OXTR, NR3C1, VIPR2, LGR4, HRH1, TAAR6, GRIN2B, GRIN2D, CNR1, HCAR2, GABRD, IL2RA, GABRA6, MET, RTN4R, IL6R, NRXN1, NTSR1, KDR, GPR153, GRM3, GRM2, NTRK1, HTR7, HTR6, HTR2A
Molecular transducer activity 39 4.31E−08 6.38E−05 FGFR1, DRD1, HLA-DRB1, DRD3, GABRB2, GRIK2, PLXNA2, DRD2, ADGRF4, DRD4, GRIK5, OXTR, NR3C1, VIPR2, LGR4, TAAR6, HRH1, GRIN2B, GRIN2D, CNR1, HCAR2, DLG1, GABRD, IL2RA, GABRA6, MET, RTN4R, IL6R, NRXN1, NTSR1, KDR, GPR153, GRM3, LRP1, GRM2, NTRK1, HTR7, HTR6, HTR2A
Receptor activity 39 4.31E−08 6.38E−05 FGFR1, DRD1, HLA-DRB1, DRD3, GABRB2, GRIK2, PLXNA2, DRD2, ADGRF4, DRD4, GRIK5, OXTR, NR3C1, VIPR2, LGR4, TAAR6, HRH1, GRIN2B, GRIN2D, CNR1, HCAR2, DLG1, GABRD, IL2RA, GABRA6, MET, RTN4R, IL6R, NRXN1, NTSR1, KDR, GPR153, GRM3, LRP1, GRM2, NTRK1, HTR7, HTR6, HTR2A
Receptor binding 34 4.69E−07 6.95E−04 CCL2, NRG3, TNF, FAM3D, DRD3, DRD2, SLC6A3, COL3A1, TAC1, PLCL2, BDNF, APOE, TRAK1, IL1B, VPS35, DAO, NRG1, THBS1, DLG1, IL6, AVP, MAGI2, NTF3, PHB, TP53, IL6R, NRXN1, KDR, NRIP1, LAMA2, LAMA1, LRP1, NTRK1, RELN
Dopamine binding 5 1.93E−06 2.85E−03 DRD1, DRD3, DRD2, SLC6A3, DRD4
Glutamate receptor activity 6 3.67E−06 5.44E−03 GRM3, GRM2, GRIN2B, GRIK2, GRIN2D, GRIK5
Drug binding 9 8.84E−06 1.31E−02 DRD1, IL2RA, DRD3, DRD2, SLC6A3, CNR1, SLC6A4, DRD4, HTR2A
Catecholamine binding 5 1.03E−05 1.52E−02 DRD1, DRD3, DRD2, SLC6A3, DRD4
Dopamine neurotransmitter receptor activity 4 2.39E−05 3.54E−02 DRD1, DRD3, DRD2, DRD4

Table 5.

GO analysis for the genes related to schizophrenia.

Term Count P value Genes
KEGG
Neuroactive ligand-receptor interaction 23 2.33E−08 GABRD, DRD1, DRD3, GABRB2, GRIK2, DRD2, GABRA6, DRD4, GRIK5, OXTR, NR3C1, NTSR1, VIPR2, HRH1, GRM3, TAAR6, GRM2, GRIN2B, GRIN2D, CNR1, HTR7, HTR6, HTR2A
Cocaine addiction 10 2.35E−05 DRD1, GRM3, BDNF, GRM2, GRIN2B, DRD2, SLC6A3, GRIN2D, MAOB, RGS9
Dopaminergic synapse 13 2.28E−04 DRD1, DRD3, DRD2, SLC6A3, MAOB, DRD4, COMT, AKT1, GRIN2B, GSK3A, GSK3B, CAMK2B, PLCB1
cAMP signalling pathway 14 4.17E−03 DRD1, ADCY7, PIK3CB, DRD2, OXTR, VIPR2, AKT1, BDNF, GRIN2B, GRIN2D, PDE4B, HTR6, CAMK2B, HCAR2
Calcium signalling pathway 12 4.66E−02 DRD1, HRH1, NOS1, ADCY7, HTR7, GRIN2D, HTR6, OXTR, CAMK2B, NTSR1, PLCB1, HTR2A
WikiPathways
Monoamine GPCRs 8 3.30E−05 HTR6, HRH1, HTR7, HTR2A, DRD1, DRD2, DRD3, DRD4
Circadian rhythm-related genes 15 9.90E−05 NTRK1, GSK3B, TPH1, PML, SLC6A4, IL6, HTR7, NRIP1, AVP, DRD1, DRD2, TP53, DRD3, LGR4, DRD4
SIDS susceptibility pathways 12 8.30E−04 IL6, TPH1, VIPR2, BDNF, IL1B, HTR2A, AVP, TAC1, NR3C1, TNF, IL6R, SLC6A4
Spinal cord injury 10 9.54E−04 RTN4R, IL6, BDNF, IL1B, PLXNA2, CCL2, NOS1, TP53, TNF, RTN4
Alzheimer’s disease 10 9.54E−04 GSK3B, LRP1, IL1B, APOE, NOS1, PLCB1, TP53, TNF, GRIN2B, GRIN2D
Vitamin B12 metabolism 7 9.54E−04 IL6, GIF, IL1B, MTHFR, CCL2, APOE, TNF
Monoamine transport 6 8.30E−04 IL1B, NOS1, SLC6A1, TNF, SLC6A3, SLC6A4
Hypothetical network for drug addiction 6 8.30E−04 CAMK2B, DRD1, DRD2, GRIN2B, DRD4, GRIN2D
Reactome
Transmission across chemical synapses 17 7.71E−07 CAMK2B, GABRB2, GABRA6, GRIK5, GAD1, GAD2, GRIK2, SLC6A1, COMT, ADCY7, GRIN2B, SYN2, CPLX1, SLC6A3, GRIN2D, DLG1, PLCB1
Amine ligand-binding receptors 9 2.36E−06 HTR6, HRH1, HTR7, TAAR6, HTR2A, DRD1, DRD2, DRD3, DRD4
Neuronal system 17 3.63E−05 CAMK2B, GABRB2, GABRA6, GRIK5, GAD1, GAD2, GRIK2, SLC6A1, COMT, ADCY7, GRIN2B, SYN2, CPLX1, SLC6A3, GRIN2D, DLG1, PLCB1
Signalling by GPCR 35 2.07E−04 CAMK2B, OXTR, VIPR2, PIK3CB, HTR2A, PHB, ADCY7, HCAR2, RGS4, GRM3, GRM2, HTR6, HRH1, HTR7, CNR1, PDE4B, AKT1, CCL2, DRD1, TAC1, DRD2, RGS9, DRD3, DRD4, NTSR1, TAAR6, NRG1, GRIN2B, GRIN2D, NRG3, IL2RA, RGS12, AVP, PLCB1, FGFR1
Signal Transduction 53 2.07E−04 GSK3B, GSK3A, OXTR, VIPR2, TRRAP, HTR2A, PIK3CB, NR3C1, TNF, GRM3, RGS4, GRM2, HTR6, HTR7, KDR, PDE4B, AKT1, VPS35, IL6R, RGS9, TAAR6, NRG1, NRG3, AVP, PLCB1, TP53, CAMK2B, LRP1, PHB, ADCY7, THBS1, RTN4, HCAR2, HRH1, CNR1, CCL2, APOE, DRD1, DRD2, TAC1, DRD3, PAK2, DRD4, NTSR1, NTRK1, GRIN2B, MTOR, GRIN2D, IL6, IL2RA, RGS12, LGR4, FGFR1
Class A/1 (Rhodopsin-like receptors) 16 2.07E−04 OXTR, TAAR6, HTR2A, HCAR2, HTR6, HRH1, HTR7, CNR1, CCL2, AVP, DRD1, DRD2, TAC1, DRD3, NTSR1, DRD4
GPCR ligand binding 18 6.14E−04 OXTR, TAAR6, HTR2A, HCAR2, GRM3, GRM2, HTR6, HRH1, HTR7, CNR1, CCL2, DRD1, AVP, DRD2, TAC1, DRD3, DRD4, NTSR1
Signalling by PDGF 15 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7, GRIN2B, THBS1, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1
Downstream signalling of activated FGFR4 14 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7, GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1
Downstream signalling of activated FGFR3 14 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7, GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1
Signalling by FGFR4 14 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7, GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1
Downstream signalling of activated FGFR2 14 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7, GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1
Signalling by FGFR3 14 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7, GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1
Downstream signalling of activated FGFR1 14 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7, GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1
NGF signalling via TRKA from the plasma membrane 15 1.72E−03 NTRK1, CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7, GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1
Signalling by FGFR1 14 1.80E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7, GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1
DAP12 signalling 14 2.09E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7, GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1
Downstream signal transduction 14 2.00E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7, GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1
Neurotransmitter receptor ainding and downstream transmission in the postsynaptic cell 10 7.83E−04 CAMK2B, GABRB2, DLG1, GABRA6, GRIK5, GRIK2, PLCB1, ADCY7, GRIN2B, GRIN2D
Signalling by EGFR 14 2.51E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7, GRIN2B, MTOR, GRIN2D, NRG3, IL2RA,AKT1,FGFR1

Table 6.

Pathway analysis for the genes related to schizophrenia.

Five molecular modules were found for Sch (Figure 3). In module 1, 24 genes were connected by predicted, co-expression, physical interaction, co-localization, shared protein domains and pathway and genetic interactions. Almost all these genes showed co-expression [43, 44] and genetic interactions [45]. Except these 24 genes, GRID2, GRIK3 and GRIK4 might also be influenced by BPA because of their shared protein domains with GRIK2, GRIK5, GRIN2D, GRM2 and GRM3 and genetic interactions. KCNJ12 might also be interacted by BPA because of predicted, co-expression, genetic interactions and physical interactions. KCNJ12 has been reported may involve in the candidate pathway of Sch [46]. IL6, HP, AKT1, GSK3B, TNF, PIK3CB, and TP53 are composites of module 2. AKT/GSK3 pathway in which AKT1 and GSK3B has been reportedly associated in Sch [47]. TP53, as a key element in maintaining genomic stability and cell apoptosis and having been evidently proved a Sch susceptibility gene, linked TNF, AKT1 and GSK3B by direct co-expression, physical interactions and genetic interactions. Other genes such as AKT2 and DVL1 in this module might also interact with BPA because of the co-expression of AKT2 and PIK3CB [37], and DVL1 and AKT1 [48]. In module 3, SLC6A3, GAD1, COMT and RELN were involved through physical interaction, co-expression, predicted, pathway, co-localization and shared protein domains. LRPAP1, ITGB1, DAB1, PAFAH1B3, PAFAH1B2, VLDLR, MAP1B and SNCA might interact with BPA because of their involvement in the same pathway with RELN [40]. LRTOMT and COMTD1 might also be the candidate interacted genes with BPA because of their shared protein domains. In module 4, 10 genes are involved. Co-expression and physical interactions are the main interaction modes for these genes. HCRTR1, ZDHHC23, CLIC6 and MUC20 are the possible candidate genes influenced by BPA mainly because of their physical and genetic interactions. In module 5, TSPAN18, NKAPL and ZKSCAN4 were connected by physical interactions, co-expression, co-localization and shared protein domains. NKAP, ZSCAN9, ZSCAN16-related genes could also be the candidate interacted genes of BPA because of the shared protein domains or co-expression.

Figure 3.

Networks for the genes in the PPI MCODE molecular modules for Sch.

4.4. Autism spectrum disorders

We found 51 ASD genes that could biinteract with BPA. These genes are partly involved in the BPs such as organism development, system development, synapse organization, behaviour, learning or memory, regulation of synapse structure or activity, multicellular organismal process, nervous system development, membrane potential, cellular process and cell-cell signalling-related processes. Involved CC was synaptic membrane, and MFs included neuroligin family protein binding and chromatin binding. The KEGG pathways such as neuroactive ligand-receptor interaction and cocaine addiction were found as Sch. Like ID and LD, MECP2 and associated Rett syndrome (WikiPathways) was also found in ASD. PRC2 methylates histones and DNA, non-integrin membrane-ECM interactions, and gastrin-CREB-signalling pathway via PKC and MAPK were the main pathways found in Reactome.

Two molecular modules were found for ASD (Figure 2: ASD-1, ASD-2). In module 1, TET3, SIN3A, DNMT3A and DNMT3B were connected to each other by physical interactions, co-expression, predicted, pathway, co-localization, genetic interactions and shared protein domains. HDAC2 and MORF4L1 might be the candidate genes interacted with BPA because of their predicted interaction with SIN3A [24]. DNMT3L and MYB are another two main genes in this module because of their direct or indirect interactions with other genes. AVPR1A, OXTR and NTSR1 composite the module 2 through physical interactions, co-expression, pathway, co-localization and shared protein domains. OXT and NTS are another two main genes in this module; they share the same pathway with OXTR, NTSR1, AVPR1A and some other genes [40] and, thus, might be influenced by BPA.

4.5. Anxiety disorders

A total of 34 genes associated with AD were found bi-interacted with BPA. GO analysis for these genes indicated that behaviour, learning or memory, cognition, monoamine transport, chemical synaptic transmission, cell-cell signalling, anterograde trans-synaptic signalling and neurological system process were all significant BPs such as LD, Sch and ASD. Interestingly, blood circulation, circulatory system process and regulation of blood pressure were found significant for AD. Like ID, LD, Sch and ASD, significant CCs included neuron part, neuron projection, somatodendritic compartment, synapse part, axon, synapse, dendrite, cell body, presynapse and neuronal cell body. Significant MFs included receptor binding, neuropeptide hormone activity and G-protein–coupled receptor binding. The significant KEGG pathways were as those found in LD. Neuroactive ligand-receptor interaction, alcoholism, cAMP signalling pathway, serotonergic and dopaminergic synapse, Rap1 signalling pathway and retrograde endocannabinoid signalling are the potential KEGG pathways that might be influenced by BPA in AD. For WikiPathways, monoamine transport was again found related to BPA bi-interacted genes in AD. Other significant pathways included circadian rhythm-related genes, nicotine activity on dopaminergic neurons, corticotropin-releasing, GPCRs, cytosine methylation, myometrial relaxation and contraction pathways and estrogen-signalling pathway. In Reactome pathways, GPCR related, Class A/1, Class B/2, G alpha–related signalling events and peptide ligand-binding receptors were found possibly involved in the BPA-AD interactions.

Only one molecular module was found for AD, in which UCN, ADORA2A, CRH, NPS, CRHR2, NPY, NPY1R, APP, HTR7, CNR1, GRM8, SLC6A3, DRD2 and CARTPT were involved (Figure 2: AD). The interaction modes for these genes included predicted, physical interactions, shared protein domains, co-expression and co-localization. The genes in this module are all involved in neuroactive ligand-receptor interaction (KEGG pathway) which is consistent with the Reactome pathways of GPCR signalling and G alpha signalling events.

4.6. Bipolar disorder

A total of 39 genes were found bi-interacted with BPA for BD. The BPs, CCs and MFs were quite the same as AD. Neuroactive ligand-receptor interaction, dopaminergic synapse, calcium-signalling pathway, neurotrophin-signalling pathway, synaptic vesicle cycle, insulin secretion, morphine signalling pathway, MAPK signalling pathway, glutamatergic synapse and serotonergic synapse were found in KEGG pathways. Like LD and Sch, SIDS susceptibility pathways was also found significant for BD. GPCR-related pathways such as monoamine GPCRs in WikiPathways and GPCR ligand binding in Reactome were found to be involved in BPA-BD as in BPA-AD.

One molecular module was found for BD (Figure 2: BD), in which D1, NTRK1, DRD5, PVALB, NTRK2, HTR2A, COMT and INS were involved. Shared protein domains, co-localization and co-expression were the main interactions in this module. COMTD1 and LRTOMT might also be influenced by BPA because of their shared protein domains with COMT.

4.7. Other neurodevelopmental disorders

A total of 14 genes were found for bi-interacted BPA in DS. GO analysis indicated cellular oxidant detoxification-related BPs significant for these genes, and the MF of antioxidant activity was found significant consistently. The pathway analysis showed that KEGG pathway like one carbon pool by folate, and some pathways related to folate, one carbon or water-soluble vitamins metabolism in WikiPathways or Reactome pathways. Detoxification of reactive oxygen species and cellular responses to stress were also found significant in Reactome pathways. Consistent with the results of GO and pathway analyses, PPI interaction showed two different molecular modules, one with SLC19A1, MTR and MTHFR, and the other with SOD1, PRDX2 and PRDX6. It is clear that the module 1 is related to the clustering function of folate and other water-soluble vitamins metabolism, and the module 2 is for the detoxification of reactive oxygen species. Folate pathway has been regarded as involved in the pathogenesis of DS. Simultaneously, BPA exposure has the potential effects on the human phenotypes and altering DNA methylation [49, 50], which could be counteracted by the supplementation of methyl donors such as folate, choline, betaine and vitamin B12 [50]. Detoxification of reactive oxygen species and cellular responses to stress are important to maintain the mitochondrial function, which has been associated with the aetiology of early-onset dementia in patients with DS [51, 52].

For other NDs, less reference count or low inference score was found. But the limited results of GO and pathway analyses showed similar BPs, CCs, MFs and pathways with the above mentioned NDs in some extent.

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5. Gene regulation

Transcription factors (TFs) and microRNAs (miRNAs), the largest families of transacting, share a common regulatory logic and represent the most numerous gene regulatory factors in multicellular genomes [53, 54]. The library of ENCODE and ChEA Consensus TFs from ChIP-X in EnrichR (http://amp.pharm.mssm.edu/Enrichr/ [13, 14]) were used for the possible TFs and related networks. The TargetScan library in EnrichR was used for the possible miRNA interaction. Here we only analysed the genes of ID, LD, Sch, ASD, LD, SMD, BD and SD whose inference score all over 10.

For the TFs, it was only ID, ASD, AD and BD that were found significant TFs (Table 7). USF2, MAX, SPI1, SMAD4, POU5F1, PPARD, MYC and RUNX1 were found significant for ID. The regulated genes for each of these TFs are shown in Table 7. The direct evidences for the USF2 linked to ID were the regulating role of USF2 on FMR1 of Fragile X mental retardation [55, 56]. SUZ12 was found common in ASD, AD and BD, and REST was found in both ASD and BD. SUZ12, as a component of the polycomb repressive complex, was shown to interact with some of long non-coding RNAs like AK055040 to involve in neural development and brain function [57]. REST is a key TF that represses expression of genes involved in neurogenesis and neuronal function in non-neural and immature neural cell types [58].

Term Overlap Adjusted P-value Combined score Genes
ID
USF2 16/965 0.0050 9.01 PECR, FMR1, PMM2, HEXA, PTEN, TRMT1, WDR62, ZBTB40, MED13L, AP4M1, NAGLU, CAPN10, FASN, SC5D, MAN1B1, RALGDS
MAX 27/2073 0.0049 8.74 HDAC4, KDM5A, HEXA, PTEN, ADK, WDR62, TSEN2, ZBTB40, AP4M1, EEF1B2, NAGLU, CASP2, SC5D, RALGDS, PARP1, PMM2, SRD5A3, ELP2, VRK1, TRMT1, TTI2, METTL23, AHI1, POLR3B, FASN, L2HGDH, MAN1B1
SPI1 17/1056 0.0050 8.46 KDM5A, KDM6B, TSEN34, DOCK8, DNMT3A, AP4E1, ELP2, VRK1, ERLIN2, TSEN54, TMCO1, EEF1B2, METTL23, AHI1, POLR3B, CAPN10, PEX6
SMAD4 11/584 0.0152 6.85 INPP4A, PDHX, SETBP1, DOCK8, PAX6, SRGAP3, FRY, MCC, GRIN2B, FGFR2, SHANK2
POU5F1 7/261 0.0167 6.31 EEF1B2, ENTPD1, UBR7, FASN, PAX6, FGFR2, ZBTB40
PPARD 7/285 0.0232 5.83 TMEM135, POLR3B, SLC31A1, PMM2, NF1, TSEN2, TTI2
MYC 18/1515 0.0416 4.47 ACBD6, PARP1, PMM2, SRD5A3, PTEN, ADK, SLC2A1, ELP2, TRMT1, TSEN2, AP4M1, EEF1B2, METTL23, POLR3B, NAGLU, FASN, MAN1B1, RALGDS
RUNX1 16/1294 0.0426 4.46 DOCK8, PTEN, SLC2A1, ELP2, FRY, KIF7, TSEN54, TMCO1, LETM1, NAGLU, DEAF1, CAPN10, NSD1, GNAS, SC5D, RALGDS
ASD
SUZ12 15/1684 0.0009 10.75 DLX1, RYR2, OXTR, TSHZ3, BDNF, EN2, DIO3, NRXN2, AVPR1A, GRIN2B, DPP6, RELN, LRRTM3, SOX9, NTSR1
TCF3 9/1006 0.0323 5.60 LRRTM3, ITGB3, DNMT3A, DNMT3B, NRXN2, TBL1X, JARID2, FOXP1, SCN1A
REST 10/1280 0.0323 5.38 GABRB3, RYR2, DPP6, RELN, LRRN3, BDNF, NRXN1, DNMT3A, NRXN2, C3ORF58
AD
SUZ12 13/1684 0.0001 14.64 GABRA2, EOMES, UCN, APP, CHRNA5, OXT, SLC6A4, HTR7, ADORA2A, CNR1, NPY, GRM8, DRD2
BD
REST 10/1280 0.0073 8.07 POMC, SNAP25, NTRK2, RELN, TRPC3, BDNF, GRIK2, DRD1, CPLX2, DRD5
SUZ12 10/1684 0.0331 5.13 NTNG1, NTRK2, RELN, TENM4, BDNF, GRIK2, TAC1, CPLX2, DRD5, SLC6A4

Table 7.

Transcription factors for the BPA-interacted genes involved in the neurodevelopmental disorders.

Some miRNAs were found in Sch, ASD, AD and BD (Table 8). MIR-218 and MIR-485-3p were significant in both Sch and AD. It has been reported that miR-218 is involved in Sch [59], and miR-485-3p is associated with obsessive-compulsive disorder, a type of AD [60]. MIR-380-3p was found significant in both ASD and BD, but no direct evidence in human studies.

Term Overlap Adjusted P-value Combined score Genes
Sch
MIR-485-3P 7/155 0.0171 7.68 ADAMTS3, CNR1, NRXN1, MAGI2, GAD2, CPLX2, NR3C1
MIR-218 11/402 0.0171 7.60 KLF12, RELN, HTR7, NRXN1, MAGI2, GRIK2, TAC1, NR3C1, SLC6A1, RTN4, LGR4
ASD
MIR-380-3P 5/103 0.0008 13.50 MEF2C, LRRTM3, BDNF, NRXN1, IL1RAPL1
MIR-524 8/437 0.0009 12.82 DLX1, MEF2C, LRRTM3, PCDH9, IL1RAPL1, TBL1X, SOX9, FOXP1
MIR-368 3/40 0.0061 9.16 DLX1, MEF2C, BDNF
MIR-302C 5/243 0.0120 7.57 GABRB3, DLX1, PCDH9, TBL1X, FOXP1
MIR-518C 4/149 0.0143 7.07 PCDH9, ITGB3, DNMT3A, NRXN2
MIR-373 4/227 0.0483 5.01 GABRB3, DLG4, EN2, SOX9
MIR-191 2/29 0.0483 4.45 BDNF, FOXP1
AD
MIR-218 5/402 0.0232 7.15 MECP2, HTR7, MAGI2, GNB1, NPY1R
MIR-498 3/114 0.0232 6.98 MECP2, CRH, PAM
MIR-101 4/257 0.0232 6.83 APP, MAGI2, GNB1, FOS
MIR-141, MIR-200A 4/310 0.0325 6.07 MECP2, CNR1, DIXDC1, DRD2
MIR-485-3P 3/155 0.0336 5.97 CNR1, MAGI2, GNB1
BD
MIR-494 4/164 0.0251 6.71 SP4, GRIK2, CACNA1C, TAC1
MIR-410 3/93 0.0317 6.41 NTRK2, SP4, NR3C1
MIR-380-3P 3/103 0.0317 6.27 SNAP25, BDNF, SP4

Table 8.

miRNA for the BPA bi-interacted genes in neurodevelopmental disorders.

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6. Comparable chemicals

The CTD provides a way to group chemicals based upon their biological effects, instead of their physical or structural properties, which provides a novel way to view and classify genes and chemicals and will help advance testable hypotheses about environmental chemical-gene disease networks [61]. Comparable chemicals were curated for the possible sharing with many of the networks common to BPA in neurodevelopmental disorders (Table 9). Tetrachlorodibenzodioxin, benzo(a)pyrene, vehicle emissions and dibutyle phthalate, as the common environmental pollutants, were found interacting with 312, 269, 204 and 159 of the 403 BPA bi-interacted genes in the NDs, respectively. Drugs such as valproic acid, acetaminophen, cyclosporine, pirinixic acid, tretinoin and tetradecanoylphorbol Acetate were found interacted with 316, 269, 247, 187, 201, 193 and 146 of the 403 BPA bi-interacted genes, respectively. Dietary pollutant aflatoxin B1, pesticide atrazine, and occupational exposure like copper sulphate, ammonium chloride and silicon dioxide and even estrogen estradiol could interact with the genes of those BPA bi-interacted within the NDs.

Chemical CAS RN Similarity index CIGs CIGs for NDs
Tetrachlorodibenzodioxin 1746-01-6 0.5582 12,047 312
Valproic acid 99-66-1 0.5035 10,936 316
Benzo(a)pyrene 50-32-8 0.4511 9511 269
Acetaminophen 103-90-2 0.4093 8435 247
Aflatoxin B1 1162-65-8 0.3851 8140 252
Cyclosporine 59865-13-3 0.3566 7234 187
Nanotubes, carbon 0.3498 7134 199
Vehicle emissions 0.3458 7156 204
Pirinixic acid 50892-23-4 0.3305 6663 201
Estradiol 50-28-2 0.2930 5864 202
Copper Sulfate 7758-98-7 0.2785 5598 145
(6-(4-(2-Piperidin-1-ylethoxy)phenyl))-3-pyridin-4-ylpyrazolo(1,5-a)pyrimidine 0.2583 5186 186
4-(5-Benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide 0.2582 5185 183
Ethinyl estradiol 57-63-6 0.2535 5101 153
Tretinoin 302-79-4 0.2428 4835 193
Tetradecanoylphorbol acetate 16561-29-8 0.2315 4530 146
Atrazine 1912-24-9 0.2293 4559 175
Ammonium chloride 12125-02-9 0.2273 4509 215
Dibutyl phthalate 84-74-2 0.2262 4427 159
Silicon dioxide 7631-86-9 0.2224 4441 157

Table 9.

Chemicals having comparable sets of interacting genes to bisphenol A.

CIGs: common interacting genes; NDs: neurodevelopmental disorders.


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7. Future trends and conclusion

With the existed data libraries (mainly CTD, GO, pathway, TFs and miRNA relate databases), bioinformatics softwares (Cytoscape, MCODE and Genemania) or web-based tools (STRING, GEO, ArrayExpress, David and EnrichR), BPs, CCs, MFs, signal pathways and gene regulation in the BPA-gene-disease networks were presented. These data integration and curation yielded insight into the actions of BPA and provide a basis for developing hypotheses about the molecular mechanisms underlying the aetiology of the neurodevelopmental disorder ID, LD, Sch, ASD, AD and BD, although most of the other neurodevelopmental disorders showed no enough information to make a conclusion. The nervous system–related CCs such as neuron related, synapse related, dendrite and axon related are common in CC annotation; the commonly found MFs are neurotransmitter receptor binding or activity, signal transducer or receptor binding or activity; and the main commonly involved BPs include synaptic signalling, cognition, learning or memory, behaviour, the development of nervous system and brain, and the regulation of the related BPs. Neuroactive ligand-receptor interaction, dopaminergic, glutamatergic and serotonergic synapse, monoamine transport, synaptic vesicle pathway may involve in the action of BPA in the neurodevelopmental disorders. Simultaneously, the BPA disease may share the common pathways with drug addictions (cocaine addiction, nicotine addiction and alcoholism), or other types of neurological diseases (Alzheimer’s disease, Rett syndrome and sudden infant death syndrome). Unique pathways might also contribute to the BPA action in different NDs like one carbon metabolism and detoxification of oxidative stress–related pathways in Down syndrome. Although GO and pathway results indicate some common characteristics, the predicted PPI molecular function clusters are quite different for each ND. In addition, some of the NDs share the same TFs and miRNAs, which indicate these disorders have the similar expression profiles. What needs to be emphasized that the BPA-gene-disease networks might be influenced by some of the comparable chemicals such as environmental pollutants, drugs, dietary pollutants or occupational exposure, which share the same interacted genes with BPA.

The integrated and curated biological processes and pathways shall shed light on the future studies to find the possible BPA interacted or influenced genes. This will contribute to complete the BPA-disease networks, which surely help to screen the potential biomarker of BPA-induced neurodevelopmental diseases. However, it should be noted that most of the evidences were from curation of the cell or animal experiments. Simultaneously, the biinteraction mode for BPA-gene interaction was adopted for the precise network. Therefore, the future study design should consider the human subjects. Given the sample shortage, the peripheral blood instead of the brain tissue should be preferred in the future. This will contribute to the clinical diagnosis or intervention. Finally, our results should be carefully interpreted because the results might be changed with the increasing abundance of the enrichment of BPA bi-interacted genes.

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Written By

Bingling Wang, Ruqin Gao and Da‐Hong Wang

Submitted: October 19th, 2016 Reviewed: March 8th, 2017 Published: June 7th, 2017