**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 pos‐ sible 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 neuro‐ nal function in non‐neural and immature neural cell types [58].

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.


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

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

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 pos‐ sible 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

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 neuro‐

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.

with DS [51, 52].

114 Bisphenol A Exposure and Health Risks

mentioned NDs in some extent.

SD whose inference score all over 10.

nal function in non‐neural and immature neural cell types [58].

**5. Gene regulation**

**Table 7.** Transcription factors for the BPA‐interacted genes involved in the neurodevelopmental disorders.


**Table 8.** miRNA for the BPA bi‐interacted genes in neurodevelopmental disorders.

## **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 chemi‐ cal‐gene disease networks [61]. Comparable chemicals were curated for the possible shar‐ ing 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,


CIGs: common interacting genes; NDs: neurodevelopmental disorders.

**Table 9.** Chemicals having comparable sets of interacting genes to bisphenol A.

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.
