**4. Gene function enrichment analysis**

The curated genes in CTD for each ND were uploaded to DAVID 6.8 Beta (https://david‐d.ncif‐ crf.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 trans‐ ferred in Genemania app [18] to predict the possible target proteins or biomarkers.

#### **4.1. Intellectual disability**

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 expres‐ sions 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

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

**Inference BPA‐interacted genes (n) Inference** 

SD GRIN2A, MFSD2A, TTPA (3) 12.24 3

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

DS CALCA, CXCL8, GATA1, GSTM2, MTHFR, MTR, NTF3, PRDX2, PRDX6,

LDD BCL11A, DPYD, ERF, FOXP2, GRIN2A, KCNA2, NRXN1, PTEN, SETBP1,

DD ARFGAP1, CAMKMT, CBL, CHRNA4, CNTN4, DOCK8, DRD2, KCNQ2,

SLC2A1, SLC33A1, SLC4A4, SLC6A8, STAMBP (22)

alcohol spectrum disorders; PCDD: pervasive child development disorders.

**Table 1.** Selected neurodevelopmental diseases and related BPA‐interacted genes.

KCNT1, LRP2, MECP2, NANS, NTRK2, PMP22, PNKP, PTEN, SHANK3,

FASD CAT, NOS1 (2) 2.49 2 PCDD DRD4, MECP2, MKL2 (3) 2.47 3

RCAN1, S100B, SLC19A1, SOD1, VIP (14)

SHANK3 (10)

94 Bisphenol A Exposure and Health Risks

**score**

9.35 10

3.52 10

2.99 24

**Reference count**

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 expres‐ sion profiling in NDs. The differently expressed genes (DEGs) in each ND samples were iden‐ tified. 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

bi‐interactions and eight BPA‐DNA methylation interactions were reported.

**3. Microarray data and differently expressed gene screening**

for the possible microarray data.

**Disease name**

> Of the 119 interacted genes, 117 were bi‐interacted. GO analysis with these 117 genes indi‐ cated that BPA bi‐interacted genes are involved in the biological processes (BP) such as cogni‐ tion, 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 morpho‐ genesis, 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.

> 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 sub‐ units 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 [20–22], 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,



**Table 2.** GO analysis for the genes related to intellectual disability.

**Term Count** *P* **value FDR Genes**

Cognition 16 2.49E−10 4.53E−07 DEAF1, VIP, MEF2C, PTCHD1, TH, NF1, MECP2,

Head development 22 2.28E−08 4.14E−05 MEF2C, FGFR2, NAGLU, BBS7, NDST1, PTCHD1,

Brain development 21 4.94E−08 0.0001 MEF2C, FGFR2, NAGLU, BBS7, NDST1, PTCHD1,

Behaviour 18 2.56E−07 0.0005 DEAF1, VIP, MEF2C, NAGLU, PTCHD1, KCNA2,

Social behaviour 7 9.59E−07 0.0017 PTCHD1, TH, MECP2, NRXN1, PTEN, SHANK2,

Learning 9 4.59E−06 0.0084 DEAF1, NF1, TH, MECP2, STRA6, NRXN1,

14 4.79E−09 8.72E−06 DEAF1, VIP, MEF2C, TH, NF1, MECP2, PRKCG,

39 1.56E−08 2.85E−05 FGFR2, MEF2C, DEAF1, NAGLU, BBS7, NDST1,

STRA6, SYNGAP1

CASP2, DISC1, KDM6B

WDR62, DISC1, KDM6B

DISC1, KDM6B

16 9.96E−08 0.0002 DEAF1, VIP, MEF2C, KCNA2, TH, NF1, MECP2,

15 2.10E−07 0.0004 FGFR2, MEF2C, NDST1, PTCHD1, NF1, TH, PAX6,

SYNGAP1

22 9.19E−07 0.0017 MEF2C, FGFR2, NAGLU, BBS7, NDST1, PTCHD1,

SHANK3

7 9.59E−07 0.0017 PTCHD1, TH, MECP2, NRXN1, PTEN, SHANK2, SHANK3

10 1.74E−06 0.0032 MEF2C, ASCL1, WDR62, NF1, TH, PAX6, MFSD2A,

12 3.27E−06 0.0060 FGFR2, MEF2C, NAGLU, NDST1, BBS7, FOLR1,

PTEN, KDM6B, DISC1

PRKCG, NRXN1, PTEN, SHANK2, SHANK3, GRIN2B, GNAS, STRA6, SYNGAP1

NRXN1, PTEN, SHANK2, SHANK3, GRIN2B,

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,

NF1, TH, PAX6, MECP2, AHI1, MFSD2A, NRXN1, PTEN, SHANK3, ASCL1, SLC4A10, WDR62, STRA6,

NF1, TH, PAX6, MECP2, AHI1, MFSD2A, NRXN1, PTEN, SHANK3, ASCL1, SLC4A10, WDR62, CASP2,

PRKCG, NRXN1, PTEN, SHANK2, SHANK3, SLC4A10, GRIN2B, STRA6, SYNGAP1

MFSD2A, PTEN, SHANK3, ASCL1, SLC4A10,

TH, NF1, MECP2, PRKCG, NRXN1, PTEN, SHANK2, SHANK3, SLC4A10, GRIN2B, STRA6,

ALDH5A1, NF1, TH, PAX6, MECP2, AHI1, MFSD2A, NRXN1, PTEN, SHANK3, ASCL1, SLC4A10, WDR62, CASP2, DISC1, KDM6B

PRKRA, TH, PAX6, AHI1, STRA6, GNAS

SYNGAP1, SHANK2, SHANK3

SCN8A, SYNGAP1, KDM6B, FAM126A

**BP**

Learning or memory

Nervous system development

96 Bisphenol A Exposure and Health Risks

Single‐organism behaviour

Forebrain development

Central nervous system development

Intraspecies interaction between organisms

Pallium development

Embryonic organ morphogenesis

such as serotonin, quinolinic acid and kynurenic acid, which are involved in neurodevelopment and synaptogenesis. Decreased tryptophan metabolism may alter brain development, neuro‐ immune 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 mod‐ ule 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 [27–29], 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 [33–35]. 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, sero‐ tonergic 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 associ‐ ated 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 sug‐ gested that organic anion transporters pathway may be influenced by BPA.


**4.2. Learning disorders**

98 Bisphenol A Exposure and Health Risks

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, sero‐ tonergic 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 associ‐ ated 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 sug‐

gested that organic anion transporters pathway may be influenced by BPA.

**Figure 1.** Networks for the genes in PPI MCODE molecular modules for ID.


#### Toxicogenomics of Bisphenol A and Neurodevelopmental Disorders http://dx.doi.org/10.5772/intechopen.68415 101


**Table 3.** GO analysis for the genes related to learning disorders.

**Term Count** *P* **value FDR Genes**

Regulation of neurotransmitter levels

Regulation of neuron apoptotic process

100 Bisphenol A Exposure and Health Risks

Response to decreased oxygen levels

Neuron apoptotic

Response to oxygen

Nitrogen compound

Response to oxidative

Regulation of neuron

Somatodendritic compartment

Central nervous system development

process

levels

transport

stress

death

**CC**

Memory 6 7.93E−07 1.41E−03 SLC17A7, PSEN1, GRIA1, TH, MECP2, IL1B

Learning 6 3.41E−06 6.06E−03 APP, PDE1B, NF1, TH, MECP2, PARK2

Chemical homeostasis 11 5.20E−06 9.25E−03 SLC17A7, MICU1, APP, PSEN1, KL, HMOX1,

Synapse part 13 4.60E−10 5.87E−07 ACHE, TH, NF1, MECP2, PARK2, SIGMAR1,

Neuron projection 15 1.09E−09 1.39E−06 TH, NF1, PARK2, SIGMAR1, SYP, SLC17A7,

Neuron part 16 4.99E−09 6.37E−06 TH, NF1, PARK2, SIGMAR1, SYP, SLC17A7,

Synapse 13 6.19E−09 7.90E−06 ACHE, TH, NF1, MECP2, PARK2, SIGMAR1,

Presynapse 9 5.66E−08 7.23E−05 SYP, SLC17A7, APP, SLC17A6, PSEN1, GRIA1,

Dendrite 10 2.30E−07 2.94E−04 APP, HTR1A, PNOC, APOD, PSEN1, GRIA1,

7 8.92E−07 1.59E−03 SLC17A7, ACHE, PDE1B, PSEN1, NF1, TH, PARK2

7 9.19E−07 1.63E−03 PSEN1, HMOX1, BCL2, NF1, MECP2, PARK2, SIGMAR1

8 9.52E−07 1.69E−03 HMOX1, BCL2, VEGFA, NF1, TH, MECP2, IL1B, TRH

8 1.41E−06 2.51E−03 HMOX1, BCL2, VEGFA, NF1, TH, MECP2, IL1B, TRH

11 1.65E−06 2.93E−03 SLC17A7, APP, APOD, PSEN1, MAPT, BCL2,

10 2.10E−06 3.74E−03 SLC17A7, SLC17A6, PSEN1, NF1, IL1RN, TH,

8 4.34E−06 7.72E−03 APP, APOD, PSEN1, MAPT, HMOX1, BCL2, IL1B, PARK2

7 5.01E−06 8.91E−03 PSEN1, HMOX1, BCL2, NF1, MECP2, PARK2, SIGMAR1

MAPT

MAPT

11 4.77E−07 6.09E−04 APP, HTR1A, PNOC, APOD, PDE1B, PSEN1,

NF1, TH, PARK2

HTR7, MAPT, NF1, TH

GRIA1, HTR7, MAPT, NF1, TH

GRIA1, MAPT, HTR7

PSEN1, GRIA1, MAPT, HTR7

NF1, TH, MECP2, IL1B, PARK2

BCL2, VEGFA, TH, IL1B, PARK2

SYP, SLC17A7, APP, SLC17A6, PSEN1, GRIA1,

APP, HTR1A, SLC17A6, PNOC, APOD, PSEN1,

APP, HTR1A, SLC17A6, PNOC, PDE1B, APOD,

SYP, SLC17A7, APP, SLC17A6, PSEN1, GRIA1,

MECP2, IL1B, PARK2, TRH

7 1.22E−06 2.16E−03 APP, PSEN1, HMOX1, BCL2, NF1, MECP2, PARK2


**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.

### **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 mem‐ brane, synaptic membrane and plasma membrane region. Unlike LD with little significant MFs found, Sch showed many significant MFs including the activity of signal transducer, neu‐ rotransmitter 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 dis‐ ease, 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.

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 influ‐ enced 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 pre‐ dicted, 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,

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

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 mem‐ brane, synaptic membrane and plasma membrane region. Unlike LD with little significant MFs found, Sch showed many significant MFs including the activity of signal transducer, neu‐ rotransmitter 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 dis‐ ease, 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. 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 influ‐ enced 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 pre‐ dicted, 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,

pathway in KEGG and Reactome, respectively.

**4.3. Schizophrenia**

102 Bisphenol A Exposure and Health Risks

**Figure 2.** Networks for the genes in the PPI MCODE molecular modules for LD, ASD, AD and BD.



**Term Count P value FDR Genes**

104 Bisphenol A Exposure and Health Risks

44 2.29E−27 4.33E−24 DRD1, CPLX2, CCL2, CPLX1, SLC6A1, DRD3, GABRB2,

44 2.29E−27 4.33E−24 DRD1, CPLX2, CCL2, CPLX1, SLC6A1, DRD3, GABRB2,

44 2.29E−27 4.33E−24 DRD1, CPLX2, CCL2, CPLX1, SLC6A1, DRD3, GABRB2,

44 2.29E−27 4.33E−24 DRD1, CPLX2, CCL2, CPLX1, SLC6A1, DRD3, GABRB2,

62 3.34E−26 6.31E−23 SLC6A1, FAM3D, GRIK2, GABRB2, SLC6A3, SLC6A4,

GSK3B, HTR2A

HTR2A

31 6.10E−24 1.15E−20 CPLX2, DRD1, CCL2, DRD3, SLC6A1, GRIK2, DRD2, DRD4,

72 2.46E−17 4.64E−14 SLC6A1, FAM3D, GRIK2, SLC6A4, GRIK5, LGR4, SYP,

RGS4, GSK3B, MTOR, RGS9, HTR2A

HTR2A

HTR2A

HTR2A

HTR2A

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,

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,

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,

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,

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,

SLC6A4, GRIK5, TAC1, OXTR, DTNBP1, SYP, PLCL2, HRH1, APOE, CNR1, CAMK2B, NOS1, NTF3, NRXN1, NTSR1, LAMA2, GRM3, GRM2, GSK3B, NTRK1, RELN, NRGN,

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,

**BP** Synaptic signalling

Anterograde Trans‐synaptic signalling

Trans‐synaptic signalling

Chemical synaptic transmission

Cell‐cell signalling

Modulation of synaptic transmission

Regulation of cell communication



**Term Count P value FDR Genes**

47 2.20E−13 4.16E−10 FGFR1, DRD1, CCL2, NRG3, TNF, ADCY7, DRD3, GRIK2,

49 8.08E−13 1.53E−09 FGFR1, DRD1, CPLX2, CCL2, CPLX1, TNF, SLC6A1, DRD3,

GSK3B, RELN, MTOR, HTR2A

MTOR, TPH1, KPNA1, HTR2A

48 3.23E−21 4.54E−18 DRD1, CPLX2, CCL2, CPLX1, SLC6A1, GRIK2, DRD2,

Synapse 40 6.12E−19 8.61E−16 CPLX2, DRD1, CCL2, CPLX1, GABRB2, GRIK2, DRD2,

Synapse part 36 1.32E−18 1.86E−15 CPLX2, DRD1, CPLX1, GABRB2, DRD2, GRIK2, SLC6A3,

NRGN Neuron part 51 3.07E−18 4.33E−15 SLC6A1, GRIK2, SLC6A3, SLC6A4, GRIK5, SYP, GRIN2B,

HTR2A Dendrite 32 1.49E−17 2.10E−14 CPLX2, DRD1, CCL2, CPLX1, GRIK2, DRD2, DRD4, GRIK5,

KPNA1, HTR2A

KPNA1, HTR2A

37 2.66E−17 3.74E−14 DRD1, CPLX2, CCL2, CPLX1, GRIK2, DRD2, SLC6A3,

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,

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,

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,

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

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,

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,

COMT, DTNBP1, RGS12, APOE, PDE4B, CAMK2B, NRG1, AVP, NOS1, MAGI2, NTSR1, LAMA2, GRM3, GRM2, LRP1, GSK3B, NTRK1, HTR7, HTR6, RELN, NRGN, MTOR,

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,

RGS4, NTRK1, GSK3B, RELN, MTOR, HTR2A

Regulation of phosphorus metabolic process

106 Bisphenol A Exposure and Health Risks

Regulation of transport

Somatodendritic compartment

**CC** Neuron projection



**Table 5.** GO analysis for the genes related to schizophrenia.

**Term Count P value FDR Genes**

**MF**

Signal transducer activity

108 Bisphenol A Exposure and Health Risks

Neurotransmitter receptor activity

Transmembrane receptor activity

Transmembrane signalling receptor activity

Signalling receptor activity

Molecular transducer activity

Dopamine binding

Glutamate receptor activity

Axon terminus 11 2.90E−07 4.08E−04 SYP, DRD1, CPLX2, CPLX1, CCL2, PVALB, DRD2, GRIK2,

DRD4, GRIK5, NTSR1

46 2.55E−11 3.79E−08 FGFR1, DRD1, NRG3, DRD3, HLA‐DRB1, GABRB2, GRIK2,

NTRK1, HTR6, RGS9, HTR2A

GABRA6, HTR6, DRD4, GRIK5, HTR2A

12 8.07E−10 1.20E−06 DRD1, GRIN2B, DRD3, DRD2, GRIK2, HTR7, GRIN2D,

37 2.01E−09 2.98E−06 FGFR1, DRD1, HLA‐DRB1, DRD3, GABRB2, GRIK2,

HTR7, HTR6, HTR2A

36 2.61E−09 3.87E−06 FGFR1, DRD1, HLA‐DRB1, DRD3, GABRB2, GRIK2,

37 5.46E−09 8.09E−06 FGFR1, DRD1, HLA‐DRB1, DRD3, GABRB2, GRIK2,

HTR7, HTR6, HTR2A

NTRK1, HTR7, HTR6, HTR2A

NTRK1, HTR7, HTR6, HTR2A

NTRK1, RELN

6 3.67E−06 5.44E−03 GRM3, GRM2, GRIN2B, GRIK2, GRIN2D, GRIK5

39 4.31E−08 6.38E−05 FGFR1, DRD1, HLA‐DRB1, DRD3, GABRB2, GRIK2,

Receptor activity 39 4.31E−08 6.38E−05 FGFR1, DRD1, HLA‐DRB1, DRD3, GABRB2, GRIK2,

Receptor binding 34 4.69E−07 6.95E−04 CCL2, NRG3, TNF, FAM3D, DRD3, DRD2, SLC6A3,

5 1.93E−06 2.85E−03 DRD1, DRD3, DRD2, SLC6A3, DRD4

HTR2A

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,

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,

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,

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,

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,

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,

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,




**Table 6.** Pathway analysis for the genes related to schizophrenia.

PAFAH1B2, VLDLR, MAP1B and SNCA might interact with BPA because of their involve‐ ment in the same pathway with RELN [40]. LRTOMT and COMTD1 might also be the candi‐ date 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‐localiza‐ tion 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.

#### **4.4. Autism spectrum disorders**

**Term Count** *P* **value Genes**

9 2.36E−06 HTR6, HRH1, HTR7, TAAR6, HTR2A, DRD1, DRD2, DRD3,

IL2RA, RGS12, AVP, PLCB1, FGFR1

GRIN2D, IL6, IL2RA, RGS12, LGR4, FGFR1

16 2.07E−04 OXTR, TAAR6, HTR2A, HCAR2, HTR6, HRH1, HTR7, CNR1,

14 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7,

14 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7,

14 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7,

14 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7,

15 1.72E−03 NTRK1, CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB,

14 2.00E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7,

GRIN2D, DLG1, PLCB1

SLC6A1, COMT, ADCY7, GRIN2B, SYN2, CPLX1, SLC6A3,

HCAR2, RGS4, GRM3, GRM2, HTR6, HRH1, HTR7, CNR1, PDE4B, AKT1, CCL2, DRD1, TAC1, DRD2, RGS9, DRD3, DRD4, NTSR1, TAAR6, NRG1, GRIN2B, GRIN2D, NRG3,

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,

CCL2, AVP, DRD1, DRD2, TAC1, DRD3, NTSR1, DRD4

GRIN2B, THBS1, MTOR, GRIN2D, NRG3, IL2RA, AKT1,

GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1

GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1

GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1

GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1

GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1

GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1

ADCY7, GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1,

GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1

GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1

GRIN2B, MTOR, GRIN2D, NRG3, IL2RA, AKT1, FGFR1

HRH1, HTR7, CNR1, CCL2, DRD1, AVP, DRD2, TAC1, DRD3,

DRD4 Neuronal system 17 3.63E−05 CAMK2B, GABRB2, GABRA6, GRIK5, GAD1, GAD2, GRIK2,

Signalling by GPCR 35 2.07E−04 CAMK2B, OXTR, VIPR2, PIK3CB, HTR2A, PHB, ADCY7,

Signal Transduction 53 2.07E−04 GSK3B, GSK3A, OXTR, VIPR2, TRRAP, HTR2A, PIK3CB,

GPCR ligand binding 18 6.14E−04 OXTR, TAAR6, HTR2A, HCAR2, GRM3, GRM2, HTR6,

Signalling by PDGF 15 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7,

Signalling by FGFR4 14 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7,

Signalling by FGFR3 14 1.72E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7,

FGFR1 Signalling by FGFR1 14 1.80E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7,

DAP12 signalling 14 2.09E−03 CAMK2B, GSK3B, GSK3A, NRG1, PHB, PIK3CB, ADCY7,

FGFR1

DRD4, NTSR1

Amine ligand‐binding

110 Bisphenol A Exposure and Health Risks

Class A/1 (Rhodopsin‐ like receptors)

Downstream signalling of activated FGFR4

Downstream signalling of activated FGFR3

Downstream signalling of activated FGFR2

Downstream signalling of activated FGFR1

NGF signalling via TRKA from the plasma

Downstream signal transduction

membrane

receptors

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, behav‐ iour, learning or memory, regulation of synapse structure or activity, multicellular organis‐ mal process, nervous system development, membrane potential, cellular process and cell‐cell signalling‐related processes. Involved CC was synaptic membrane, and MFs included neuro‐ ligin 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, path‐ way, 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.

**Figure 3.** Networks for the genes in the PPI MCODE molecular modules for Sch.

#### **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 signal‐ ling pathway, serotonergic and dopaminergic synapse, Rap1 signalling pathway and retro‐ grade 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 methyla‐ tion, 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 interac‐ tions, 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 consis‐ tent with the Reactome pathways of GPCR signalling and G alpha signalling events.

#### **4.6. Bipolar disorder**

**Figure 3.** Networks for the genes in the PPI MCODE molecular modules for Sch.

112 Bisphenol A Exposure and Health Risks

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‐signal‐ ling pathway, neurotrophin‐signalling pathway, synaptic vesicle cycle, insulin secretion, mor‐ phine 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 oxi‐ dant 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 oxy‐ gen 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 differ‐ ent 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.
