**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 epi‐ lepsy). 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 neu‐ rodevelopmental 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.

## **2. BPA‐gene interactions and neurodevelopmental disorders**

Comparative toxicogenomics database (CTD, http://ctdbase.org) is a robust, publicly avail‐ able 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 dis‐ order (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‐compul‐ sive 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


**1. Introduction**

92 Bisphenol A Exposure and Health Risks

analysis.

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 epi‐ lepsy). 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 neu‐ rodevelopmental 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.

**2. BPA‐gene interactions and neurodevelopmental disorders**

Comparative toxicogenomics database (CTD, http://ctdbase.org) is a robust, publicly avail‐ able 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 dis‐ order (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‐compul‐ sive 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

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


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.

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

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