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REVIEW article

Front. Endocrinol., 29 August 2025

Sec. Experimental Endocrinology

Volume 16 - 2025 | https://doi.org/10.3389/fendo.2025.1645540

This article is part of the Research TopicEndocrine Disruptors Affecting Human and Companion Animal Endocrine Function: Similarities and Indicators in the One Health Concept – Volume IIView all articles

Prenatal exposure to Bisphenol-A as a risk factor for infant neurodevelopment

Ivan Hazel Bello-CortesIvan Hazel Bello-Cortes1Jose Antonio García-GarcíaJose Antonio García-García2Manuel Gutirrez-AguilarManuel Gutiérrez-Aguilar3Daniela Araiza-OliveraDaniela Araiza-Olivera4Celia Snchez-PrezCelia Sánchez-Pérez5Gabriela García-Cern,Gabriela García-Cerón1,6Sofia Morn-Ramos,Sofia Morán-Ramos1,7Hugo TovarHugo Tovar7Andrea Bonilla-BrunnerAndrea Bonilla-Brunner8Roeb García-Arrazola*Roeb García-Arrazola1*
  • 1Department of Food Science and Biotechnology, Faculty of Chemistry, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
  • 2Department of Education, Hospital General de México, Mexico City, Mexico
  • 3Department of Biochemistry, Faculty of Chemistry, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
  • 4Fox Chase Cancer Center, Temple Health, Philadelphia, PA, United States
  • 5Institute of Applied Sciences and Technology, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
  • 6Postgraduate Degree in Biological Sciences, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
  • 7Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
  • 8R&D Department, Bioplaster Research Inc., Dover, DE, United States

It has been established a chronic human exposure to a particular class of chemicals known as endocrine-disrupting compounds (EDCs). Studies conducted in vitro, in vivo, and in silico have demonstrated that EDCs can disrupt the endocrine system through epigenetic mechanisms. These changes can be heritable and are associated with a wide range of diseases. Since exposure concentrations of these compounds are measured in parts per million (ppm) or even parts per billion (ppb), a critical question arises: does this pose a significant risk to humankind and future generations? We conducted a comprehensive review of human epidemiological data to provide an assessment of the risk of neurodevelopmental disorders in children associated with maternal exposure to Bisphenol A (BPA). BPA is one of the most studied and relevant EDC’s related to food exposure. Our analysis reveals a correlation between BPA exposure during pregnancy and behavioral issues in offspring on 80% of the reviewed articles. Notably, male infants exposed to BPA during the third trimester exhibited a heightened risk. Our findings highlight the importance of considering potential new health regulations aimed at safeguarding the fetal environment and reducing the risk of neurodevelopmental disorders in children.

1 Introduction

The globalization and commercialization of the food industry have significantly promoted the widespread adoption of plastic packaging for the purposes of transportation and preservation. For example, extensive use of polycarbonate packages and containers, as well as cans with an inner coating of epoxy resins, have been shown to exude Bisphenol A (BPA) (1). BPA is a monomer used to produce polycarbonate polymers and has the potential to leach into food items upon contact and be ingested by humans (2).

1.1 Health effects of Bisphenol A

Exposure to BPA has been consistently linked to a broad spectrum of adverse health outcomes. These include, but are not limited to, reproductive toxicity, manifesting as infertility, menstrual irregularities, and dysfunction of the testicular and ovarian systems (35). Metabolic disorders such as obesity, insulin resistance, and type 2 diabetes (3, 6). Furthermore, immunological disturbances, including immunosuppression and chronic inflammation (7, 8), along with neurotoxicity, characterized by altered brain development and behavior (3, 9). Besides, an elevated risk of hormone-dependent cancers has also been observed in relation to BPA exposure (3, 10). Significantly, these detrimental effects can emerge even at low doses and during critical developmental windows, notably gestation and infancy (11).

The understanding of BPA’s long-term effects is further informed by the Developmental Origins of Health and Disease (DOHaD) hypothesis. This paradigm posits that early developmental environmental factors, encompassing nutrition, stress, and toxicant exposure like BPA, possess the capacity to “program” an individual’s susceptibility to chronic diseases and neurobehavioral disorders later in life (12). Current research endeavors are focused on identifying critical windows of susceptibility and elucidating the underlying molecular mechanisms, with a particular emphasis on epigenetic processes (13).

1.2 BPA exposure, metabolism, and regulatory landscape

Most daily human exposure to BPA comes from its presence in food and beverages (14). For instance, the World Health Organization & Food and Agriculture Organization of the United Nations reported in 2011 that canned food for adults contains BPA concentrations from 10 to 70 μg/l and canned beverages from 10 to 23 μg/l (15). The highest concentrations of BPA levels were found in vegetables (0.149 μg/g in green beans) followed by meat (0.0057 μg/g in chicken breast) (14). A study by the Food and Drug Administration (FDA) estimated an average daily intake of 0.2 μg/kg-bw for a population 2 years and older in the United States, with 90% of the population consuming up to 0.5 μg/kg-bw (16).

Once BPA enters the body along with food, it is absorbed by the gastrointestinal system and transported to the liver to be rapidly metabolized into BPA glucuronide and, to a very small proportion, into BPA sulfate (17). BPA is almost completely bio-transformed by glucuronidation (99.9%) before reaching the bloodstream and subsequently eliminated via urine (18) (Figure 1). However, BPA does not remain in its conjugated form in certain tissues, including the placenta in pregnant women (Figure 2), where glucuronidases can deconjugate BPA and return it to its free form, leading to a likely fetal exposure (19). According to Bolognesi et al. (20), the fetus cannot eliminate free BPA through glucuronidation due to its low metabolic maturity. There is also evidence that sulfation of BPA may be transformed to its free state by arylsulfatase C, which is found in estrogen responsive (ER) tissues (19) (Figure 3). While traditionally BPA metabolites were considered inactive, recent studies indicate that conjugated metabolites can indeed alter cellular functions, including the modulation of energy metabolism and immune responses in neutrophils and urothelial cells (21). Active metabolites such as 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) has been demonstrated to act as a potent estrogenic agonist, capable of promoting breast cancer cell proliferation and disrupting cardiovascular function (22). Glucuronidated and sulfated metabolites may additionally impact adipogenesis, favoring white fat accumulation and impeding brown fat formation (23). The regulatory landscape surrounding BPA focuses on establishing safe exposure doses for humans. The No Observed Adverse Effect Level (NOAEL) is defined as the dose at which no detectable adverse effects are observed. Adverse effects may manifest as biochemical, anatomical changes, or functional failures within the organism under defined experimental conditions. The Tolerable Daily Intake (TDI) is an empirically derived value obtained by dividing the NOAEL by a protection factor for humans. This factor accounts for the possibility that humans may exhibit a ten-fold greater susceptibility to a toxic effect than animals, owing to increased sensitivity, enhanced bioactivation, and a slower elimination rate in humans (24). In the United States, the equivalent of the TDI is termed the Reference Dose (RfD), which is determined through a similar methodology (25).

Figure 1
Flowchart depicting the metabolic pathway of BPA through oral ingestion. BPA (in red) moves from the intestine to the liver, with conversion to BPA-G (in blue) via UDP-glucuronosyltransferase/sulfotransferase (A), then to the kidneys for excretion.

Figure 1. BPA metabolism. BPA, introduced into the body orally, is rapidly metabolized in the intestines and liver, converting it into its inactive state, BPA glucuronide.

Figure 2
Diagram illustrating the metabolic pathway of bisphenol A (BPA). BPA is ingested orally, processed in the intestine, liver, and kidneys, and excreted. BPA metabolites, labeled as BPA-G, can cross the placenta, affecting the fetus. Enzymes involved include UDP-glucuronosyltransferase, sulfotranferase, β-glucuronidase, and arylsulfatase C. Red arrows indicate BPA, and blue arrows indicate BPA-G.

Figure 2. BPA metabolism during pregnancy, BPA is activated again in the placenta to free BPA by means of the enzyme β-glucuronidase. The fetus could inactivate BPA by sulfation, but not by glucuronidation; however, arylsulfatase C activates it again.

Figure 3
Diagram illustrating the metabolic pathways of Bisphenol A (BPA) involving its conversion to BPA Glucuronide and BPA Sulfate. It shows the use of UDP-glucuronosyltransferase and sulfotransferase enzymes. The process involves substrates such as uridine diphosphate glucuronic acid and PAPS, and produces compounds like D-glucuronic acid and hydrogen sulfate, releasing water in some steps. Chemical structures are depicted for each compound.

Figure 3. Activation and metabolic deactivation of BPA. Process of deactivation of BPA through glucuronidation and sulfation, and its reactivation through β-glucuronidase and Arylsulfatase C. 3′-phosphoadenosine-5′-phosphosulfate (PAPS), 3′-phosphoadenosine-5′-phosphate (PAP).

In 2008 the FDA generated its first draft risk assessment and established a NOAEL of 5,000 μg/kg bw/day for systemic toxicity (26), a limit confirmed in 2009, 2011 (27) and in 2014 (16). Although the United States Environmental Protection Agency (EPA) established in 1988 a Reference Dose (RfD) of 50µg/kg bw/day based on a reduced body weight in a Rat Chronic Oral Bioassay (28), the FDA did not establish a formal acceptable daily intake (ADI) since BPA monomers are not an additive and dictated that the intake in humans is over 27,000 times lower than lethal doses in animals (26).

BPA has garnered attention as an endocrine disrupting compound (EDC) from various food safety institutions globally which, in turn, have conducted diverse risk analyses regarding BPA ingestion within their populations. Countries like Canada and Australia have stated that the levels of BPA consumption among their residents do not pose a health risk. Nevertheless, in 2010, both nations discontinued the use of this material in baby bottles (29, 30). In 2012, the United States banned the material from baby bottles (31) and a year later it made an amendment withdrawing the use of epoxy resins from cans of infant milk formula (32). In the European Union, the use of BPA in food contact materials was allowed in 2011 (33) and banned in baby bottles and training cups (34). In 2018, the European Union amended its regulations, reducing the specific migration limit for polycarbonate and epoxy resins in food contact materials from 0.6 to 0.05mg/kg and extending this standard to encompass varnishes and coatings used in contact with food (35). In 2023, EFSA pointed out a temporary tolerable daily intake (t-TDI) of 0.2ng/kg bw/day (36).

1.3 Mechanisms of BPA toxicity

Exogenous compounds that interfere with the synthesis, secretion, and elimination of hormones responsible for reproduction, development, homeostasis, and behavior are collectively termed endocrine disruptors (EDs) (37). Disruption mechanisms can occur via both genomic and non-genomic pathways. The genomic pathway involves EDs binding to hormonal receptors of gene promoters and target cells, leading to conformational changes in protein production and influencing the function and regulation of gene expression. Conversely, the non-genomic pathway manifests when EDs bind to plasma membrane hormone receptors, triggering signal cascades that activate protein second messengers, ultimately leading to alterations in hormonal signaling and synthesis (38). Therefore, EDs perturb the endocrine system, which in turn alters the synthesis of regulatory hormones within the human body, resulting in endocrine-related cancers, reproductive problems, and neurodevelopmental alterations. These alterations may manifest even decades following exposure to EDs (3, 39).

Unconjugated BPA induces its deleterious effects by binding estrogen and antagonizing androgen receptors, making them unresponsive to its natural ligand, the hormone estradiol-17β and dihydrotestosterone (Figure 4). Consequently, BPA is classified as an endocrine disruptor or a xenoestrogen as it prevents proper binding of the hormone to its receptors (41). In more detail, Bisphenol A acts as a ligand for nuclear ER receptors ERα and ERβ, which are found in the cell nucleus with a lower affinity for BPA than for estradiol. Nevertheless, BPA has an 80-fold higher affinity for the ERRγ receptor, which is found in the nucleus of placental and brain cells (42, 43). The receptor-ligand complex is characterized by its dynamic nature, allowing for dissociation and reversibility (44). BPA can also bind, as an agonist, the GPR30 receptor on the cell membrane and the hormone-binding globulin, leading to rapid activation of downstream signaling pathways contributing to testosterone-estrogen imbalances and interfering with neuroendocrine regulation; however, these effects are transient and contingent upon the sustained presence of BPA (42, 43, 45).

Figure 4
Chemical structure diagrams of three compounds. A: Bisphenol-A features two benzene rings linked by a carbon bridge with hydroxyl groups. B: 17β-Estradiol shows a steroid structure with hydroxyl groups. C: Dihydrotestosterone is depicted with its steroid framework, including a ketone and hydroxyl group.

Figure 4. Structural features of bisphenol A, estradiol-17β and dihydrotestosterone, modified from (40).

Exposure to low doses of BPA, even below established safety limits, has been shown to cause significant adverse, some studies even suggest a non-monotonic dose-response curve, where lower exposure levels may be associated with different ailments (46). The existence of a non-monotonic dose response, where lower exposures may be linked to worse outcomes, challenges traditional toxicological assumptions of a linear dose-response relationship (47). This implies that a simple reduction in BPA levels might not eliminate the risk, and in some cases, chronic very low exposures could be more problematic than acute higher ones.

1.4 Neurodevelopmental implications of BPA exposure

Neurodevelopmental deficits can be identified through the symptoms of common mental disorders, which are divided into internalizing and externalizing behaviors. Internalizing behaviors are non-visible attitudes which affect the individual’s mental health, such as depression, anxiety, learning difficulties and lack of attention. Externalizing behaviors are noticeable attitudes in the person, such as hyperactivity, aggressiveness, or defiance of rules (48). Although clinical research in humans is still limited, results are inconsistent as reported in a recent review of the effects of EDCs on child neurodevelopment (49). In different studies, urinary BPA concentrations during pregnancy were associated with externalizing traits (e.g., inattention, hyperactivity) in 2-year-old girls (50), and with lower Intelligence Quotient (IQ) in boys at age 7 (51). In addition, Stacy et al. (52) found that BPA exposure during pregnancy acted as a possible environmental contributor to increased risks of neurobehavioral problems in children. Casas et al. (53) reported an increase in externalizing and internalizing (e.g., depression and anxiety) traits in children upon exposure to BPA during gestation, where mothers presented urine concentrations around 2.29 μg/l. Consequently, the mean value reported by Casas et al. (53) of the estimated prenatal exposure of BPA associated with neurodevelopment in children is 0.057 μg/kg bw/day. This value is 3.5 times lower than the exposure estimated by FDA in 2014.

This compelling set of evidence asserts the need to propose a new risk analysis by the corresponding health authorities. There is already a precedent in 2015 where EFSA determined to reduce the TDI from 50 to 4μg/kg bw (54) and then from 4μg/kg-bw to 0.2ng/kg-bw in 2023 (36). Moreover, we acknowledge the FDA’s perspective that average BPA exposure values estimated probabilistically, in conjunction with international policies aiming for a global reduction in BPA use in food containers, are likely to result in reduced risks to the population. Nevertheless, it’s crucial to note that these assumptions are rooted in BPA exposure beginning at 2 years of age. In contrast, the evidence presented in this paper primarily focuses on human exposure during pregnancy and its effects on children. Based on the above, the main aim of the present work is to make a comprehensive review of the existing scientific literature in humans in which prenatal exposure to BPA and its association with infant neurodevelopment is studied. To our knowledge, this is the first systematic review focusing solely on humans and the effects of BPA exposure on neurodevelopment during the prenatal period in the mother-child pair.

2 Materials and methods

2.1 Systematic review

The documentary search was conducted using Science Direct and Pubmed, employing the following keywords: BPA, Bisphenol A, neurodevelopment, prenatal, and endocrine disruptor. Inclusion criteria included articles were in English and published between January 2009 and March 2025.

From all the obtained texts, we identified those that specifically examined the impact of prenatal BPA exposure on children’s neurodevelopment where exposure levels were determined through urine samples collected from mothers at various trimesters during gestation (Figure 5). The following exclusion parameters were used for that purpose:

● Duplication.

● The evaluation of BPA effect on any other health condition besides neurodevelopment.

● The inclusion of postnatal exposure to BPA.

● The text was a review.

● The text involved animal studies.

● The sample used to obtain BPA concentrations was other than urine from pregnant women.

● The methodology to evaluate neurodevelopment in children was other than observational techniques.

Figure 5
Flowchart titled “Identification of studies via databases” with three phases: Identification, Screening, and Included. Identification: 119 studies found, 69 removed before screening. Screening: 50 screened, 15 excluded for criteria like reviews and postnatal BPA. 35 assessed for eligibility. Included: 20 studies in the review.

Figure 5. PRISMA flowchart illustrating the study identification process in this review. The diagram depicts the selection of articles from databases, the number of studies excluded, and the screening process for eligibility.

2.2 Calculation of daily intake

The calculation of Daily Intake (DI) (µg/kg body weight) of BPA in pregnant women based on urine concentration (UC) was conducted using Equation 1, following the methodology outlined by Huang et al. (55). A urine volume (UV) of 1.5 L averaged over 24 hours and an average weight (W) of 60 kg were employed according to (56).

DI= (UC)(UV)W(1)

Magnitude analysis.

The reviewed studies referred to the BPA effect magnitude on neurodevelopment as the significant difference (β) that existed between the results in population exposed to the different BPA doses included in their paper. β, or the BPA magnitude effect, was obtained as the estimate produced by a multiple linear regression model. As shown in Equation 2, Y is the neurodevelopment test’s result and X1 corresponds to the urine BPA concentration. β is in score/dose units, which shows the interaction effect of both variables.

Y=(β0+β1X1+β2X2++βnXn)+e(2)

As different variables were introduced in the model such as BPA concentration, sex and/or age, the authors only took the β value that corresponded to concentration and stablish a 95% confidence interval, where a p<0.05 value points out a significant effect.

To assess the consistency of results across the various tests employed in these studies, a comprehensive analysis was conducted. Utilizing the Review Manager 5.4 software, we generated a forest plot, based on fixed effects model, for both behavioral and cognitive ability tests along with the study weight and heterogeneity across studies. This plot illustrates the effect (β) and their associated confidence intervals. A greater distance of both the effect (β) and the confidence interval from zero indicates increased significance of the result, as the effect (β) signifies the slope of a linear estimate. This visualization allows for a nuanced understanding of the magnitude and significance of the outcomes from each evaluation.

3 Results and discussion

3.1 Prenatal exposure to Bisphenol A and its association with childhood neurodevelopment

As shown in Figure 5, the documentary search led us to initially identify 119 texts, of which 26 were eliminated because of duplication. Subsequently, 43 articles were excluded because, although discussing prenatal exposure, they primarily addressed the effects on conditions such as obesity, respiratory allergies, or cancer.

Following this initial screening, 50 articles remained. From these, 35 were chosen for further analysis. The remaining 15 were excluded as they either constituted reviews of prenatal BPA exposure’s impact on overall human health, involved animal studies, or concentrated on the effects of postnatal exposure on the neurodevelopment of children.

To standardize the data, we excluded studies assessing neurodevelopmental effects based on BPA concentration in placenta or blood (n = 8) and those employing methodologies like imaging or oxidative stress analysis rather than systematic evaluations with observational techniques (n = 7). The final data set consisted of the results of 20 articles (Table 1).

Table 1
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Table 1. Human clinical studies studying prenatal exposure to Bisphenol A (BPA) as a risk factor in infant neurodevelopment.

From these selected studies, 50% percent were done in the United States, 25% in Asia, 20% in Europe and 5% in Africa. Eighty percent of the studies (n = 16), associated BPA consumption with neurodevelopmental deficits including internalizing and externalizing behaviors, such as poor mental, social, adaptive and language development, and lower IQ.

The children neurodevelopment was evaluated at a different human growth and development period. One during infancy (< one year old), nine during early childhood (one- to three-year-olds), and 10 at the childhood. Two were between three and five years old, and eight were between six and ten years old.

3.1.1 Infancy

During the first months of life, Yolton et al. (73) found no significant trends with respect to BPA levels (p>0.10). Samples were collected during the first and second trimester of pregnancy (N=350), with detectable concentrations of BPA in 90% of cases, and infants were given the NCIU Network Neurobehavioral Scale (NNNS) at 5 weeks after birth.

3.1.2 Early childhood

Casas et al. (53), took urine samples from mothers (N=622) during the third trimester and detected BPA in 479 of them, with 382 undergoing neurodevelopmental testing in the first year. They found that BPA is related to a decrease in psychomotor development (β=-4.28, 95% CI: -8.15, -0.41, p<0.05) in one-year old children participating in the study “Childhood and the Environment of the city of Sabadell Spain” (INMA-Sabadell) using the Bayley Scales of Infant Development (BSID). In another study, Pan et al. (71) found BPA in the urine samples of 86.9% of the mothers (N=368) admitted to the hospital for delivery and assessed the potential relationship between BPA levels and neurodevelopment using the Gesell Development Schedules (GSD). The GSD test assesses four areas of neurodevelopment (motor, adaptive, language, and social) through a Development Coefficient score. An inverse relationship was found between BPA and total neurodevelopment with a 1.43-point decrease in the assessment each time the urine concentration increased 10-fold (β= -1.43, 95% CI: -2.30, -0.56, p=0.001) in both sexes.

In 2-year-old girls, Braun et al. (58) found a significant relationship between maternal urinary BPA concentration measured in the second and third trimesters (n= 249) and an increase in externalizing behaviors (β=6.0, 95% CI: 0.1, 12.0) in girls. They found that high BPA concentrations before 16 weeks were more associated with these behaviors in all children (β= 2.9, 95% CI: 0.2, 5.7), whereas the greatest effect prevailed in girls. Behavioral assessment was performed with the Behavioral Assessment System for Children (BASC-2).

Jensen et al. (66) Assessed BPA concentrations on average at week 28 in pregnant women (N=2217) belonging to the Odense Child Cohort (OCC). 796 participants had presence of the compound, of which 535 and 398 completed the vocabulary and complexity questionnaires, respectively. They compared it with language development between 18 and 36 months of age of children using the McArthur-Bates Communicative Development Inventories in its Danish adaptation (MC-CDI). They noted that high concentrations were associated with low language development in vocabulary (OR= 4.63 95% CI 1.74, 12.30) and complexity (OR= 2.43 95% CI 1.02, 5.77) in male children.

Jiang et al. (61) collected urine samples in each trimester of pregnancy from 856 women to obtain BPA concentrations and related the date to children’s neurodevelopment at 23–26 months of age using the BSID-I. They found a lower mental development at two years when BPA was observed in the second trimester (β= -2.87 95% CI: -4.98, -0.75; with a p value for trimester interaction= 0.04).

Kim et al. (68) took the urine sample of mothers (N=140) belonging to the Children’s Health and Environmental Chemicals in Korea (CHECK), of which the presence of BPA was detected in 85% when they were admitted for labor and assessed the neurodevelopment of children using the BSID-II. They found that a high concentration of BPA was related to low mental development only in girls (β= -4.07 95% CI: -7.61, -0.53, p<0.05). In turn, Pan et al. (71) found an inverse relationship between concentration and language development (β= -1.69, 95% CI: -3.23, -0.15, p = 0.032), (N=296) with the presence of BPA in 86.9% of the samples).

Braun et al. (72) analyzed urinary BPA concentrations in women in the second and third trimester of pregnancy (present in more than 97% of samples) using BASC-2. They found that all of them presented greater anxiety (β= 7, 95% CI: 1.7, 12, p<0.5) and depression (β= 4.9, 95% CI: 0.0, 9.9) at 3 years. In boys they observed a significant decrease in hyperactivity (β= -6.3, 95% CI: -12, -0.6) with respect to the values ​​of the BASC-2 study of a neurotypical person.

Zhou et al. (67) published a study using data from the South African Drakenstein Child Health Study, where they found that data of children (n=545) whose mothers urine BPA concentration was analyzed during the second trimester of pregnancy (1.95μg/l), showed a significant decrease on cognitive development in 2 years old males (β= -1.39; 95% CI: -2.54, -0.23) while there was no significant effect on girls (β= 0.56; 95% CI: -0.46, 1.56) based on BSID III test.

Barkoski et al. (74), conducted a study involving 207 mother-child pairs from the Markers of Autism Risk in Babies Learning Early Signs (MARBLES) cohort, where BPA was detected in 58.3% urine samples during the second and third trimester of pregnancy. A neurodevelopmental assessment of the children was performed when the children were already 3 years old using the Autism Diagnostic Observation Scale (ADOS) and the Mullen Scales of Early Learning (MSEL) and found no relationship between BPA concentration and autism spectrum disorder (ASD) while establishing that high concentrations of BPA during the second trimester have a borderline association with a low risk of non-neurotypical development (OR = 0.67, 95% CI: 0.43, 1.06).

However, in 2024 Oskar et al. (69) found a significant effect on girls cognitive and motor development (β= -0.63, 95% CI: -1-11, -0.15) according to MSEL test, whose mothers urine samples were collected during 3rd trimester of pregnancy and analyzed to obtain BPA concentration (0.8μg/l). Data used in this study was also from MARBLES cohort.

3.1.3 Three-to-five-year period

Perera et al. (64) found a significant effect on neurodevelopment when assessing BPA concentrations in urine of 34-week pregnant women and when evaluating their children when they were between 3 and 5 years old using the Child Behavior Check List (CBCL); however, they found that BPA (present in more than 90% of samples) had a significant effect on behaviors such as reactivity (β= 1.62, 95% CI: 1.12, 2.32, p=0.008) and aggressive behavior (β= 1.29, 95% CI: 1.09, 1.53 p=0.003) in boys.

3.1.4 Six-to-ten-year period

Another study examined urinary BPA concentrations of pregnant women (only women with BPA present in urine were included) at a mean of 27 weeks and its effects on the behavior of their offspring (n= 125) between 6 and 10 years (62). Behavioral assessment was performed with CBCL, and Diagnostic and Statistical Manual of Mental Disorders (DSM) IV scales found a relationship in somatic symptoms in boys (CBCL β= 0.28, p=0.03; DSM-IV β= 0.3, p=0.01) and an increase in shyness/depression, rule breaking, externalizing behaviors in addition to challenging behaviors and conduct disorder only in boys.

Conversely, Guo et al. (75) obtained urine samples (with a detection of BPA in 100% of the samples), from pregnant women (n=386) on the day of delivery using the Sheyang Mini Birth Cohort Study (SMBCS). Then, a neurodevelopment assessment using the Strengths and Difficulties Questionnaire (SDQ) of 10-year-old children found a significant relationship between BPA concentration and an elevated risk of total difficulties (emotional symptoms, conduct problems, prosocial behavior, hyperactivity/inattention) (OR = 1.57, 95% CI: 1.08, 2.28, P = 0.018) in boys.

Guo et al. (51), evaluated in the SMBCS the effect of prenatal BPA exposure and children’s IQ at age of 7 years using the Chinese version of the Weschler Intelligence Scale for Children (C-WISC). They found a significant relationship between the decrease in Full Intelligence Quotient (FIQ) of boys and the high concentration of BPA in their mothers (β=-1.18, 95% CI: -2.21, -0.15, p=0.025); with a p-value for the sex interaction = 0.296.

Harley et al. (60) took urine (with the presence of BPA in 100% of the samples) samples at approximately 13 and 26 weeks to subsequently assess children’s neurocognitive development at 7 years using the BASC-2 and Conner’s ADHD/DSM-IV Scales (CADS) and at 9 years old with the CADS alone. They found a significant relationship between BPA concentrations and internalizing behaviors in male children that increased (β= 1.8 95% CI: 0.3, 3.3, p<0.5) in the mother’s report and (β= 2.5 95% CI: 0.7, 4.4, p<0.01) in the teacher’s report, each time the BPA concentration doubled. In contrast, no Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms were found.

The effect of BPA (present in 100% of samples) on the IQ of 7-year-old children from the WISC IV was evaluated by Tanner et al. (57) through the Swedish Environmental Longitudinal, Mother and child, Asthma and Allergy Study (SELMA) cohort. They found a decrease of the IQ only in male children (β= -1.9, 95% CI: -3.6, -0.2, p<0.05) who were exposed to a mixture of endocrine disruptors where BPF was associated 14% and BPA 4% with a negative effect.

Roen et al. (65) obtained the sample during the third semester (with the presence of BPA in 98% of the samples) and compared it with behavior in 7 - 9-year-old children using CBCL and found that girls presented lower internalizing (β= -0.17, p=0.04) while boys presented higher internalizing (β= 0.41, p<0.0001) and externalizing (β= 0.40, p<0.0001) symptoms as BPA concentration increased.

Miodovnik et al. (70) assessed BPA concentrations, present in 90% of the samples, in pregnant women (N=407) during the third trimester and ASD-related social disability of their children between 7 and 9 years old (N=137) using the Social Responsiveness Scale (SRS). No significant association was observed (β= 1.18, 95% CI -0.75, 3.11, p>0.05). Furthermore, Bornehag et al. (59) found no significant relationship between IQ and BPA (present in 90% of samples) (β= -0.51 95% CI: -3.14, 2.13 P = 0.705) in the SELMA cohort study using the WISC IV test.

3.2 Risk for infant neurodevelopment

The estimated daily intake of Bisphenol A at which a negative effect on neurodevelopment and neurobehavior was observed between 0.01 and 0.08μg/kg body weight per day. On average, the studies show an adverse effect with intake values ​​that are below the safe levels set forth by international institutions.

A sex-dependent effect was found. Among girls, there was an increase in externalizing behaviors (58), a decrease in internalizing behaviors (65), and a deficit in mental development (68, 69). In boys, there was an increase in externalizing and internalizing behaviors (53, 60, 62, 63, 65, 76)decreased IQ (51, 57), and low mental (61, 67), verbal (66) and social (71) development.

According to the articles consulted, the deficit was more likely to be identified when high concentrations of BPA were detected in the third trimester of gestation (61% of the results). Biologically, the earliest the exposure to contaminants during the development of the gestational product, the greatest negative impact is expected. This finding should be further researched and confirmed through more clinical studies. At doses lower than those established by international authorities, the authors that evaluated a sex dependent effect, found that it is more probable for males (65% of the results) to show affectation associated with the brain.

BPA’s endocrine disruption is mediated by activation of ERRγ and GPR30 eliciting a diverse range of physiological effects. For example, within adipose tissue, BPA-GPR30 signaling augments pro-inflammatory cytokine levels, modifies adipokine expression, and promotes cell proliferation, potentially contributing to the development of obesity and metabolic syndrome (77, 78). In reproductive tissues, BPA’s binding to GPR30 induces apoptosis in spermatocytes and disrupts both placental and testicular function, thereby implicating it in infertility and developmental abnormalities (7880). In various cancer models, BPA promotes the proliferation of breast, thyroid, and testicular tumor cells via ERRγ and GPR30 (8083).

At a molecular and cellular level, BPA induces oxidative stress, inflammation, apoptosis, and disruptions in key signaling pathways such as Wnt, PI3K/Akt, and MAPK (83). Furthermore, it can modify Deoxyribonucleic Acid (DNA) methylation, histone structure, and micro Ribonucleic acid (RNA) expression, contributing to persistent epigenetic and transgenerational effects (84). The disruption of redox homeostasis and the alteration of mitochondrial function also represent crucial mechanisms in BPA’s toxicity (85). Additionally, BPA exposure compromises immune cell function by inhibiting telomerase activity, inducing DNA damage, and reducing proliferation in T cells and peripheral blood mononuclear cells (PBMCs), primarily through ER/GPR30-ERK signaling. These effects are observed at low, environmentally relevant concentrations and are reversible upon the removal of BPA (86).

Numerous studies demonstrate that BPA alters DNA methylation, histone modification, and microRNA expression, thereby impacting key genes essential for proper brain development. These epigenetic modifications can be heritable and contribute to enduring changes in neuronal function and behavior, including an increased susceptibility to neuropsychiatric disorders (87). BPA functions as an agonist/antagonist of both estrogenic and androgenic receptors, thereby interfering with the hormonal signaling pathways critical for neuronal differentiation and maturation (88). This disruption can consequently alter neurogenesis, neuronal migration, and the formation of cerebral circuits, with potential effects that are both sex-specific and transgenerational (89). BPA adversely affects the proliferation and differentiation of neural stem cells, the formation and maturation of synapses, and the overall morphology of neurons and glia, particularly within crucial regions such as the hippocampus and cerebral cortex (90). Observable outcomes include a reduction in neurogenesis, alterations in neuronal migration, decreased spine density, and changes in synaptic plasticity (91). It also affects the expression of vital neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1), and perturbs the homeostasis of key neurotransmitters like gamma-aminobutyric acid (GABA), glutamate, dopamine, and monoamines (9296). Additionally, BPA can induce oxidative stress, neuroinflammation, and mitochondrial dysfunction, all contributing to its neurotoxic effects (9).

The initiation of neurodevelopment takes place during gestation, involving the maturation of the nervous system between the 3rd and 4th weeks of pregnancy and the development of the brain from the 9th week onward. These processes are closely linked to the regulation of body coordination and behavior. A network of precursor cells of neurons is generated during pregnancy, where the interconnectivity is of vital importance for neurodevelopment after birth (97). For example, the hippocampus regulates recognition and spatial memory, and both these cognitive processes undergo major developmental changes between 32 weeks of pregnancy and 18 months of age. Similarly, the prefrontal cortex, which is the region regulating executive functions, such as attention and multitasking, reaches a developmental milestone at around 6 months of age. Finally, the histaminergic, catecholaminergic (dopamine, epinephrine, and norepinephrine), and serotonergic signaling neurotransmitter systems develop from pregnancy to 3 years of age and regulate the reward pathway, mood, and affection (98).

Estrin and Bhavnani (99) have reported that the gray matter of the fetus increased 10 times from week 29 to the day of delivery, together with several brain connections leading to the fact that brain maturation occurs mainly during the 3rd trimester. This agrees with our findings where BPA exposure during this period shows the highest neurodevelopment risk for children.

Mhaouty-Kodja et al. (100) conducted a review on neurodevelopment and BPA in animals, noting that males exhibited more significant impacts on spatial memory following exposure compared to females. Similarly, our findings indicate that males face a higher risk of deficits in neurodevelopmental memory.

It’s crucial to emphasize that the concept of “safe levels of intake” for BPA is somewhat arbitrary, given the biological variability among individuals, making some more susceptible to its deleterious effects than others. International food safety agencies typically estimate safe intake levels of environmental contaminants through diet, relying on parameters such as the no-observed-effect-level (NOEL) and the no-observed-adverse-effect-level (NOAEL). The NOEL is defined as the dose at which no detectable effects occur in an organism under specified experimental conditions (101).

In addition, according to the exposome theory, exposure to BPA can be added to exposure to other EDCs. The exposome encompasses all environmental exposures from conception to death, such as, chemical, physical, biological, and social, integrating both external and internal exposures (102). Its application in evaluating endocrine disruptors allows for the analysis of multiple and chronic exposures, as well as the effects of mixtures. This is essential for understanding the actual impact of compounds such as BPA and its substitutes (103). BPA substitutes, such as Bisphenol S (BPS), Bisphenol F (BPF), and Bisphenol AF (BPAF), have demonstrated in in vitro, in vivo, and epidemiological studies, similar or even superior hormonal potencies to BPA, affecting processes such as adipogenesis, cell differentiation, thyroid function, and neurodevelopment (104, 105). The exposome approach has revealed that simultaneous exposure to BPA and its analogs can lead to additive or synergistic effects, particularly in the activation or inhibition of hormone receptors and in the alteration of effect biomarkers (e.g., sex hormones, oxidative stress markers, inflammation). Recent studies indicate that mixtures of bisphenols can induce endocrine effects at lower concentrations than individual compounds (106). Despite these advances, significant challenges persist. These include the precise measurement of exposures, the interpretation of low-dose effects, the evaluation of mixtures, and the extrapolation of animal model results to humans. Furthermore, there are gaps in the toxicological characterization of many BPA substitutes and in the identification of specific effect biomarkers (107).

3.3 Effect’s magnitude analysis

A variety of tests, including BASC-2, BSID, CBCL, and WISC, were extensively employed in the studies under review, with the majority indicating a notable impact on neurodevelopment.

Figure 6
Forest plot presenting odds ratios with confidence intervals for various studies on cognitive and developmental outcomes. Studies are grouped into categories including BSID, GSD, MSEL, and WISC. Each study shows an odds ratio with horizontal lines indicating confidence intervals, and red squares representing effect sizes. Diamonds indicate pooled results for each subgroup. Statistical measures for heterogeneity and overall effects are included. A significant association with reduced development and cognitive outcomes is depicted across various studies. Confidence intervals and effect sizes vary, with some indicating strong negative associations.

Figure 6. Magnitudes of the effect of BPA on cognitive abilities in neurodevelopment. The effects reported in terms of the odds ratio for each of the tests used in the studies were compared and it was found that the BSID test obtains more conclusive results.

Figure 7 shows the magnitudes of the effect of BPA on cognitive abilities in neurodevelopment. We can see that the BSID evaluation is the one that obtains the greatest effect of the included studies when evaluating a deficit in the mental and psychomotor development of infants. On the other hand, the GSD, WISC and MC-CDI evaluations show significant effects on language development, IQ, and mental development. The graph shows the statistical weight of each result when estimating the sample size by means of the standard error, therefore, although Bornehag et al. (59) did not find significance in his study, its statistical weight is less than that of the results of Guo et al (51) and Tanner et al. (57), who performed the same evaluation and obtained the opposite. The diamonds situated within the intervals of each test depict the average effect of that evaluation. Interestingly, even studies yielding non-significant results, the average effect across all evaluations remains significant.

Figure 7
Forest plot illustrating odds ratios for various psychological studies, each represented by a red square with horizontal lines indicating confidence intervals. Subgroups include BASC, CBCL, DSM, SRS, and SDQ, with subtotal summaries for each. The overall test for subgroup differences shows significant heterogeneity. The x-axis is logarithmic, ranging from 0.001 to 1000, with a vertical line at 1 indicating no effect. Results for each study are detailed in a table on the left.

Figure 7. Magnitudes of the effect of BPA on behavior in neurodevelopment. A comparison of the odds ratio of each test reported in the reviewed studies is shown and it was found that the BASC test obtains more conclusive results.

Looking into behavioral evaluations in Figure 7, the BASC shows the greatest effect, scrutinizing both internalizing and externalizing behaviors. It’s crucial to note that while Braun contributes significantly to this category, having the highest number of published papers and large effects, the statistical weight of his results is relatively low compared to other authors. Hence, the significance of the average effect in this test cannot be solely attributed to Braun’s contributions.

Despite some weak effects observed in assessments by Roen et al. (65) and the unreported non-significant effects by Evans et al. (62), the cumulative average effect across all tests reveals a statistically significant impact on behavior, except for the SRS, exclusively used by Miodovnik et al. (70).

Further, it’s important to clarify that the negative effects identified by Braun et al. (72) and Roen et al. (65) indicate a decrease in certain behaviors compared to the average and aren’t tied to the statistical significance of the result.

To sum up, 16% of the studies didn’t found a significative relation between BPA exposure and neurodevelopment. Specifically (74) and (59) found no significant relation when analizing the same SELMA cohort study data that other authors revised.

Finally, it is important to consider that many neurodevelopmental consequences of unintended exposure to BPA or other emerging contaminants in pregnant mothers are clearly observable until the child’s school age. This means a period of at least 4 years in which there could be a therapeutic intervention to maximize the integral health in the neurodevelopment of an infant and improve its perspective of quality of life in adulthood. In this regard, it is worth assessing whether the neurodegenerative disorders associated with advanced age could have their origin in infant neurodevelopment.

The quality of life of neurodivergent individuals depends significantly on their ability to interact with their environment and their ability to read and write (108). This could lead to the importance of developing prenatal screens for the collection of information and design of strategies to mitigate neurodevelopmental disorders during early childhood (0 to 12 years).

4 Limitations

Cross-sectional studies simultaneously assess BPA exposure and health outcomes, which limit their interpretability, especially for results that have long latency periods. Given the short half-life of BPA, the use of a single urine sample to categorize exposure is another limitation in most human studies. BPA data was based on urine concentration only. Use of urine is a non-invasive determination method which might be best suitable towards a public health policy for the mother-child pair. Furthermore, no BPA metabolites were considered in our analysis [eg. BPA glucoronide, sulfonated BPA and more recelty MBP-4-Methyl-2,4-bis (4-hydroxyphenil) pent-1-ene].

5 Conclusions

We performed a comprehensive assessment of available literature on prenatal exposure to bisphenol A as a risk factor for childhood neurodevelopment. Evidence collected from various authors at different geographic locations indicates a potential risk towards neurodevelopmental deficits for male offspring in women ingesting at least 0.01μg/kg bw/day of BPA, particularly during the third trimester of pregnancy.

We also found that the tests that provide a greater magnitude of effect, and therefore a more conclusive result, are the Behavioral Assessment System for Children (BASC) for behavior and the Bayley Scales of Infant Development (BSID) for cognitive abilities.

The maximum doses of BPA established by FDA, are above the doses at which neurodevelopmental effects of BPA were found in this study. Consequently, we consider that international regulations should be reassessed considering these scientific findings to further quantify the prevalence and incidence of BPA and its association with neurodevelopmental disorders for the design of new public health policies.

Finally, negative neurodevelopmental outcome in children has been reported from 0.01 to 0.08μg/kg bw/day. Recent EFSA proposal to reduce t-TDI from 4μg/kg bw/day to 0.00002μg/kg bw/day could be adequate to protect neurodevelopmental deficits due to prenatal exposure to BPA. However, the non-monotonic behavior of BPA, still in debate, rethinks the use of resources such as the NOAEL and the TDI to generate strategies that protect the population from adverse health effects, at least due to BPA.

Author contributions

IB-C: Investigation, Validation, Writing – original draft, Formal Analysis, Methodology, Data curation, Writing – review & editing. JG-C: Writing – review & editing. MG-A: Writing – review & editing. DA-O: Writing – review & editing. CS-P: Writing – review & editing. GG-C: Writing – review & editing. SM-R: Writing – review & editing. HT: Writing – review & editing, Data curation. AB-B: Writing – review & editing, Visualization. RG-A: Supervision, Writing – review & editing, Writing – original draft, Funding acquisition, Conceptualization, Project administration, Resources.

Funding

The author(s) declare financial support was received for the research and/or publication of this article. We thank the Secretaría de Ciencia, Humanidades, Tecnología e Innovación (Secihti) for funding and supporting this research through a postgraduate grant to IHBC (CVU 1099898) and GGC (CVU 1103731). And the support of FQ-UNAM and DGAPA-UNAM for the financing of the project PAIP 5000-9154 and PAPIIT IT200824, respectively.

Acknowledgments

We thank LDM. Alejandro Rodriguez Corral for the graphic design in our figures. This article is part of the requirements to obtain the degree of Doctor of Science of IHBC, in the Programa de Maestría y Doctorado en Ciencias Químicas, UNAM; and is part of the research to obtain the degree of Doctor in Sciences by GGC, in the Programa de Posgrado en Ciencias Biológicas, UNAM.

Conflict of interest

Author AB-B was employed by the company Bioplaster Research Inc.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Glossary

MBP: 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene

ADHD: Attention-deficit/hyperactivity disorder

ADOS: Autism Diagnostic Observation Scale

ASD: autism spectrum disorder

W: average weight

BSID: Bayley Scales of Infant Development

BASC: Behavioral Assessment System for Children

BPA: Bisphenol A

BPA-G: Bisphenol A glucoronide

BPAF: Bisphenol AF

BPF: Bisphenol F

BPS: Bisphenol S

BDNF: brain-derived neurotrophic factor

CBCL: Child Behavior Check List

INMA-Sabadell: Childhood and the Environment of the city of Sabadell Spain

CHECK: Children&rsquo;s Health and Environmental Chemicals in Korea

CADS: Conner&rsquo;s ADHD/DSM-IV Scale

DI: daily intake

DNA: Deoxyribonucleic Acid

DOHaD: Developmental Origins of Health and Disease

DSM: Diagnostic and Statistical Manual of Mental Disorders

EDC: endocrine disrupting compound

ER: estrogen responsive

EDs: endocrine disruptors

EFSA: European Food Safety Authority

FDA: Food and Drug Administration

GABA: gamma-aminobutyric acid

GSD: Gessel Development Schedules

IGF-1: insulin-like growth factor 1

IQ: intelligence quotient

MARBLES: Markers of Autism Risk in Babies Learning Early Signs

MC-CDI: Mc Arthur-Bates Communicative Development

MSEL: Mullen Scales of Early Learning

NNNS: NCIU Network Neurobehavioural Scale

NOAEL: non-observed-adverse- effect-level

NOEL: non-observed-effect-level

OR: odds ratio

OCC: Odense Child Cohort

PBMCs: peripheral blood mononuclear cells

RfD: Reference dose

RNA: Ribonucleic acid

SMBCS: Sheyang Mini Birth Cohort Study

SRS: Social Responsiveness Scale

SDQ: Strengths and Difficulties Questionnaire

SELMA: Swedish Environmental Longitudinal, Mother and child, Asthma and Allergy Study

t-TDI: temporary tolerable daily intake

TDI: tolerable daily intake

FIQ: total intelligence quotient

EPA: United States Environmental Protection Agency

UDP: uridine diphosphate

UC: urine concentration

UV: urine volume

WISC: Weschler Intelligence Scale for Children

References

1. Khan MR, Ouladsmane M, Alammari AM, and Azam M. Bisphenol A leaches from packaging to fruit juice commercially available in markets. Food Packaging Shelf Life. (2021) 28:100678. doi: 10.1016/j.fpsl.2021.100678

Crossref Full Text | Google Scholar

2. Fan AM, Chou WC, and Lin P. Toxicity and risk assessment of bisphenol A. In: Reproductive and developmental toxicology. Elsevier (2017). p. 765–95. doi: 10.1016/B978-0-12-804239-7.00041-X

Crossref Full Text | Google Scholar

3. Beausoleil C, Emond C, Cravedi J-P, Antignac J-P, Applanat M, Appenzeller BR, et al. Regulatory identification of BPA as an endocrine disruptor: Context and methodology. Mol Cell Endocrinol. (2018) 475:4–9. doi: 10.1016/j.mce.2018.02.001

PubMed Abstract | Crossref Full Text | Google Scholar

4. Ma Y, Liu H, Wu J, Yuan L, Wang Y, Du X, et al. The adverse health effects of bisphenol A and related toxicity mechanisms. Environ Res. (2019) 176:108575. doi: 10.1016/j.envres.2019.108575

PubMed Abstract | Crossref Full Text | Google Scholar

5. Mukhopadhyay R, Prabhu NB, Kabekkodu SP, and Rai PS. Review on bisphenol A and the risk of polycystic ovarian syndrome: an insight from endocrine and gene expression. Environ Sci pollut Res. (2022) 29:32631–50. doi: 10.1007/s11356-022-19244-5

PubMed Abstract | Crossref Full Text | Google Scholar

6. Molina-López AM, Bujalance-Reyes F, Ayala-Soldado N, Mora-Medina R, Lora-Benítez A, and Moyano-Salvago R. An overview of the health effects of bisphenol A from a one health perspective. Animals. (2023) 13:2439. doi: 10.3390/ani13152439

PubMed Abstract | Crossref Full Text | Google Scholar

7. González-Casanova JE, Bermúdez V, Caro Fuentes NJ, Angarita LC, Caicedo NH, Rivas Muñoz J, et al. New evidence on BPA’s role in adipose tissue development of proinflammatory processes and its relationship with obesity. Int J Mol Sci. (2023) 24:8231. doi: 10.3390/ijms24098231

PubMed Abstract | Crossref Full Text | Google Scholar

8. Lin M-H, Lee C-Y, Chuang Y-S, and Shih C-L. Exposure to bisphenol A associated with multiple health-related outcomes in humans: An umbrella review of systematic reviews with meta-analyses. Environ Res. (2023) 237:116900. doi: 10.1016/j.envres.2023.116900

PubMed Abstract | Crossref Full Text | Google Scholar

9. Santoro A, Chianese R, Troisi J, Richards S, Nori SL, Fasano S, et al. Neuro-toxic and reproductive effects of BPA. Curr Neuropharmacology. (2019) 17:1109–32. doi: 10.2174/1570159X17666190726112101

PubMed Abstract | Crossref Full Text | Google Scholar

10. Manzoor MF, Tariq T, Fatima B, Sahar A, Tariq F, Munir S, et al. An insight into bisphenol A, food exposure and its adverse effects on health: A review. Front Nutr. (2022) , 9:1047827. doi: 10.3389/fnut.2022.1047827

PubMed Abstract | Crossref Full Text | Google Scholar

11. Martínez-Ibarra A, Martínez-Razo LD, MacDonald-Ramos K, Morales-Pacheco M, Vázquez-Martínez ER, López-López M, et al. Multisystemic alterations in humans induced by bisphenol A and phthalates: Experimental, epidemiological and clinical studies reveal the need to change health policies. Environ pollut. (2021) 271:116380. doi: 10.1016/j.envpol.2020.116380

PubMed Abstract | Crossref Full Text | Google Scholar

12. Grandjean P, Barouki R, Bellinger DC, Casteleyn L, Chadwick LH, Cordier S, et al. ). Life-long implications of developmental exposure to environmental stressors: new perspectives. Endocrinology. (2015) 156:3408–15. doi: 10.1210/en.2015-1350

PubMed Abstract | Crossref Full Text | Google Scholar

13. Tran NQV and Miyake K. Neurodevelopmental disorders and environmental toxicants: epigenetics as an underlying mechanism. Int J Genomics. (2017) 2017:1–23. doi: 10.1155/2017/7526592

PubMed Abstract | Crossref Full Text | Google Scholar

14. Lorber M, Schecter A, Paepke O, Shropshire W, Christensen K, and Birnbaum L. Exposure assessment of adult intake of bisphenol A (BPA) with emphasis on canned food dietary exposures. Environ Int. (2015) 77:55–62. doi: 10.1016/j.envint.2015.01.008

PubMed Abstract | Crossref Full Text | Google Scholar

15. FAO and WHO. Joint FAO/WHO expert meeting to review toxicological and health aspects of bisphenol A : final report, including report of stakeholder meeting on bisphenol A, 1–5 November 2010. Ottawa, Canada: World Health Organization (2011).

Google Scholar

16. FDA. Updated safety assessment of Bisphenol A (BPA) for use in food contact applications. Memorandum dated June 17, 2014. Maryland, United States: Public Health Service Food and Drug Administration (2014).

Google Scholar

17. Rebolledo-Solleiro D, Castillo Flores LY, and Solleiro-Villavicencio H. Impact of BPA on behavior, neurodevelopment and neurodegeneration. Front Bioscience. (2021) 26. doi: 10.2741/4898

PubMed Abstract | Crossref Full Text | Google Scholar

18. FitzGerald RE and Wilks MF. Bisphenol A-Why an adverse outcome pathway framework needs to be applied. Toxicol Lett. (2014) 230:368–74. doi: 10.1016/j.toxlet.2014.05.002

PubMed Abstract | Crossref Full Text | Google Scholar

19. Ginsberg G and Rice DC. Does rapid metabolism ensure negligible risk from bisphenol A? In Environ Health Perspect. (2009) 117:1639–43. doi: 10.1289/ehp.0901010

PubMed Abstract | Crossref Full Text | Google Scholar

20. Bolognesi C, Castle L, Cravedi J-P, Engel K-H, Fowler PAF, Franz R, et al. ). Scientific Opinion on the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs: Executive summary. Efsa J. (2015) 13:3978. doi: 10.2903/j.efsa.2015.3978

Crossref Full Text | Google Scholar

21. Pellerin È, Pellerin F-A, Chabaud S, Pouliot F, Pelletier M, and Bolduc S. Glucuronidated metabolites of bisphenols A and S alter the properties of normal urothelial and bladder cancer cells. Int J Mol Sci. (2022) 23:12859. doi: 10.3390/ijms232112859

PubMed Abstract | Crossref Full Text | Google Scholar

22. Maadurshni GB, Nagarajan M, Priyadharshini S, Singaravelu U, and Manivannan J. System-wide health risk prediction for 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene(MBP), a major active metabolite of environmental pollutant and food contaminant – Bisphenol A. Toxicology. (2023) 485:153414. doi: 10.1016/j.tox.2022.153414

PubMed Abstract | Crossref Full Text | Google Scholar

23. Chen M, Yang S, Yang D, and Guo X. Bisphenol A and its metabolites promote white adipogenesis and impair brown adipogenesis in vitro. Toxicology. (2024) 509:153995. doi: 10.1016/j.tox.2024.153995

PubMed Abstract | Crossref Full Text | Google Scholar

24. Renwick AG and Walker R. An analysis of the risk of exceeding the accepta ble or tolerable daily intake. Regul Toxicol Pharmacol. (1993) 18:463–80. doi: 10.1006/rtph.1993.1071

PubMed Abstract | Crossref Full Text | Google Scholar

25. Renwick AG. Duration of intake above the ADI/TDI in relation to toxicodynamics and toxicokinetics. Regul Toxicol Pharmacol. (1999) 30:S69–78. doi: 10.1006/rtph.1999.1329

PubMed Abstract | Crossref Full Text | Google Scholar

27. FDA. Updated Review of the ‘Low-Dose’ Literature (Data) on Bisphenol A (CAS RN 80-05- 7) and Response to Charge Questions Regarding the Risk Assessment on Bisphenol A. memorandum dated May 24, 2011. Washington, D.C., United States: Public Health Service Food and Drug Administration (2011).

Google Scholar

28. United States Environmental Protection Agency. Bisphenol A; CASRN 80-05-7 (1988). Available online at: https://iris.epa.gov/ChemicalLanding/&substance_nmbr=356 (Accessed July 19, 2025).

Google Scholar

29. Food Standards Australia & New Zealand. Bisphenol A (BPA) (2018). Available online at: https://www.foodstandards.gov.au/consumer/chemicals/bpa/Pages/default.aspx (Accessed March 17, 2022).

Google Scholar

30. Health Canada. Bisphenol A (BPA) - Canada.ca (2020). Available online at: https://www.Canada.ca/en/health-Canada/services/home-garden-safety/bisphenol-bpa.html.

Google Scholar

31. FDA. 77 FR 41899 - indirect food additives: polymers. Federal Register. (2012) 77:41899–902. Available online at: https://www.govinfo.gov/app/details/FR-2012-07-17/2012-17366.

Google Scholar

32. FDA. 78 FR 41840 - indirect food additives: adhesives and components of coatings. Federal Register. (2013) 78:41840–3. Available online at: https://www.govinfo.gov/app/details/FR-2013-07-12/2013-16684 (Accessed August 19, 2025).

Google Scholar

33. European Commission. (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into contact with food. Off J Eur Union (EU 10/2011). (2011) 12:1–89. Available online at: https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX:32011R0010 (Accessed February 24,2022).

Google Scholar

34. European Commission. COMMISSION DIRECTIVE 2011/8/EU of 28 January 2011 amending Directive 2002/72/EC as regards the restriction of use of Bisphenol A in plastic infant feeding bottles. Off J Eur Union (2011/8/EU). (2011) 26:11–4. Available online at: https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX:32011L0008 (Accessed February 24,2022).

Google Scholar

35. European Commission D-G and H. and FS. COMMISSION REGULATION (EU) 2018/213 of 12 February 2018 on the use of bisphenol A in varnishes and coatings intended to come into contact with food and amending Regulation (EU) No 10/2011 as regards the use of that substance in plastic food contact materials. Off J Eur Union (EU 2018/213). (2018) 41:6–12. Available online at: https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX:32018R0213 (Accessed February 24,2022).

Google Scholar

36. Lambré C, Barat Baviera JM, Bolognesi C, Chesson A, Cocconcelli PS, Crebelli R, et al. Re-evaluation of the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs. EFSA J. (2023) 21:6857. doi: 10.2903/j.efsa.2023.6857

PubMed Abstract | Crossref Full Text | Google Scholar

37. Vilela CLS, Bassin JP, and Peixoto RS. Water contamination by endocrine disruptors: Impacts, microbiological aspects and trends for environmental protection. Environ pollut. (2018) 235:546–59. doi: 10.1016/j.envpol.2017.12.098

PubMed Abstract | Crossref Full Text | Google Scholar

38. Annamalai J and Namasivayam V. Endocrine disrupting chemicals in the atmosphere: Their effects on humans and wildlife. Environ Int. (2015) 76:78–97. doi: 10.1016/j.envint.2014.12.006

PubMed Abstract | Crossref Full Text | Google Scholar

39. Ho V, Pelland-St-Pierre L, Gravel S, Bouchard MF, Verner MA, and Labrèche F. Endocrine disruptors: Challenges and future directions in epidemiologic research. Environ Res. (2022) 204:111969. doi: 10.1016/j.envres.2021.111969

PubMed Abstract | Crossref Full Text | Google Scholar

40. Cheng CY, Wong EWP, Lie PPY, Li MWM, Su L, Siu ER, et al. Environmental toxicants and male reproductive function. Spermatogenesis. (2011) 1:2–13. doi: 10.4161/spmg.1.1.13971

PubMed Abstract | Crossref Full Text | Google Scholar

41. Mahamuni D and Shrinithivihahshini ND. Inferring Bisphenol-A influences on estrogen-mediated signalling in estrogen and androgen receptors: an in silico approach. Biocatalysis Agric Biotechnol. (2019) 20:101178. doi: 10.1016/j.bcab.2019.101178

Crossref Full Text | Google Scholar

42. Mustieles V, Pérez-Lobato R, Olea N, and Fernández MF. Bisphenol A: Human exposure and neurobehavior. NeuroToxicology. (2015) 49:174–84. doi: 10.1016/j.neuro.2015.06.002

PubMed Abstract | Crossref Full Text | Google Scholar

43. Paulose T, Speroni L, Sonnenschein C, and Soto AM. Estrogens in the wrong place at the wrong time: Fetal BPA exposure and mammary cancer. Reprod Toxicol. (2015) 54:58–65. doi: 10.1016/j.reprotox.2014.09.012

PubMed Abstract | Crossref Full Text | Google Scholar

44. Teeguarden J, Hanson-Drury S, Fisher JW, and Doerge DR. Are typical human serum BPA concentrations measurable and sufficient to be estrogenic in the general population? Food Chem Toxicol. (2013) 62:949–63. doi: 10.1016/j.fct.2013.08.001

PubMed Abstract | Crossref Full Text | Google Scholar

45. Herz C, Tran HTT, Schlotz N, Michels K, and Lamy E. Low-dose levels of bisphenol A inhibit telomerase via ER/GPR30-ERK signalling, impair DNA integrity and reduce cell proliferation in primary PBMC. Sci Rep. (2017) 7:16631. doi: 10.1038/s41598-017-15978-2

PubMed Abstract | Crossref Full Text | Google Scholar

46. Lauby SC, Lapp HE, Salazar M, Semyrenko S, Chauhan D, Margolis AE, et al. Postnatal maternal care moderates the effects of prenatal bisphenol exposure on offspring neurodevelopmental, behavioral, and transcriptomic outcomes. PloS One. (2024) 19:e0305256. doi: 10.1371/journal.pone.0305256

PubMed Abstract | Crossref Full Text | Google Scholar

47. Mahalingaiah S, Meeker JD, Pearson KR, Calafat AM, Ye X, Petrozza J, et al. Temporal variability and predictors of urinary bisphenol A concentrations in men and women. Environ Health Perspect. (2008) 116:173–8. doi: 10.1289/ehp.10605

PubMed Abstract | Crossref Full Text | Google Scholar

48. Li F, Yang F, Li DK, Tian Y, Miao M, Zhang Y, et al. Prenatal bisphenol A exposure, fetal thyroid hormones and neurobehavioral development in children at 2 and 4 years: A prospective cohort study. Sci Total Environ. (2020) 722:137887. doi: 10.1016/j.scitotenv.2020.137887

PubMed Abstract | Crossref Full Text | Google Scholar

49. Tewar S, Auinger P, Braun JM, Lanphear B, Yolton K, Epstein JN, et al. Association of Bisphenol A exposure and Attention-Deficit/Hyperactivity Disorder in a national sample of U.S. children. Environ Res. (2016) 150:112–8. doi: 10.1016/j.envres.2016.05.040

PubMed Abstract | Crossref Full Text | Google Scholar

50. Braun JM, Kalloo G, Chen A, Dietrich KN, Liddy-Hicks S, Morgan S, et al. Cohort profile: the health outcomes and measures of the environment (HOME) study. Int J Epidemiol. (2016) 46:dyw006. doi: 10.1093/ije/dyw006

PubMed Abstract | Crossref Full Text | Google Scholar

51. Guo J, Wu C, Zhang J, Qi X, Lv S, Jiang S, et al. Prenatal exposure to mixture of heavy metals, pesticides and phenols and IQ in children at 7 years of age: The SMBCS study. Environ Int. (2020) 139:105692. doi: 10.1016/j.envint.2020.105692

PubMed Abstract | Crossref Full Text | Google Scholar

52. Stacy SL, Papandonatos GD, Calafat AM, Chen A, Yolton K, Lanphear BP, et al. Early life bisphenol A exposure and neurobehavior at 8 years of age: Identifying windows of heightened vulnerability. Environ Int. (2017) 107:258–65. doi: 10.1016/J.ENVINT.2017.07.021

PubMed Abstract | Crossref Full Text | Google Scholar

53. Casas M, Forns J, Martínez D, Avella-García C, Valvi D, Ballesteros-Gómez A, et al. Exposure to bisphenol A during pregnancy and child neuropsychological development in the INMA-Sabadell cohort. Environ Res. (2015) 142:671–9. doi: 10.1016/j.envres.2015.07.024

PubMed Abstract | Crossref Full Text | Google Scholar

54. EFSA. Scientific Opinion on the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs. EFSA J. (2015) 13:3978. doi: 10.2903/j.efsa.2015.3978

PubMed Abstract | Crossref Full Text | Google Scholar

55. Huang R, Liu Z, Yuan S, Yin H, Dang Z, and Wu P. ). Worldwide human daily intakes of bisphenol A (BPA) estimated from global urinary concentration dat–2016) and its risk analysis. Environ pollut. (2017) 230:143–52. doi: 10.1016/j.envpol.2017.06.026

PubMed Abstract | Crossref Full Text | Google Scholar

56. Völkel W, Kiranoglu M, and Fromme H. Determination of free and total bisphenol A in human urine to assess daily uptake as a basis for a valid risk assessment. Toxicol Lett. (2008) 179:155–62. doi: 10.1016/j.toxlet.2008.05.002

PubMed Abstract | Crossref Full Text | Google Scholar

57. Tanner EM, Hallerbäck MU, Wikström S, Lindh C, Kiviranta H, Gennings C, et al. Early prenatal exposure to suspected endocrine disruptor mixtures is associated with lower IQ at age seven. Environ International 134(September. (2020) 2019):105185. doi: 10.1016/j.envint.2019.105185

PubMed Abstract | Crossref Full Text | Google Scholar

58. Braun JM, Yolton K, Dietrich KN, Hornung R, Ye X, Calafat AM, et al. Prenatal bisphenol A exposure and early childhood behavior. Environ Health Perspect. (2009) 117:1945–52. doi: 10.1289/ehp.0900979

PubMed Abstract | Crossref Full Text | Google Scholar

59. Bornehag CG, Engdahl E, Unenge Hallerbäck M, Wikström S, Lindh C, Rüegg J, et al. Prenatal exposure to bisphenols and cognitive function in children at 7 years of age in the Swedish SELMA study. Environ Int. (2021) 150. doi: 10.1016/j.envint.2021.106433

PubMed Abstract | Crossref Full Text | Google Scholar

60. Harley KG, Gunier RB, Kogut K, Johnson C, Bradman A, Calafat AM, et al. Prenatal and early childhood bisphenol A concentrations and behavior in school-aged children. Environ Res. (2013) 126:43–50. doi: 10.1016/j.envres.2013.06.004

PubMed Abstract | Crossref Full Text | Google Scholar

61. Jiang Y, Li J, Xu S, Zhou Y, Zhao H, Li Y, et al. Prenatal exposure to bisphenol A and its alternatives and child neurodevelopment at 2 years. J Hazardous Materials. (2020) 388:121774. doi: 10.1016/j.jhazmat.2019.121774

PubMed Abstract | Crossref Full Text | Google Scholar

62. Evans SF, Kobrosly RW, Barrett ES, Thurston SW, Calafat AM, Weiss B, et al. Prenatal bisphenol A exposure and maternally reported behavior in boys and girls. NeuroToxicology. (2014) 45:91–9. doi: 10.1016/j.neuro.2014.10.003

PubMed Abstract | Crossref Full Text | Google Scholar

63. Guo J, Wu C, Zhang J, Li W, Lv S, Lu D, et al. Maternal and childhood urinary phenol concentrations, neonatal thyroid function, and behavioral problems at 10 years of age: The SMBCS study. Sci Total Environ. (2020) 743:140678. doi: 10.1016/j.scitotenv.2020.140678

PubMed Abstract | Crossref Full Text | Google Scholar

64. Perera F, Vishnevetsky J, Herbstman JB, Calafat AM, Xiong W, Rauh V, et al. Prenatal bisphenol a exposure and child behavior in an innerity cohort. Environ Health Perspect. (2012) 120:1190–4. doi: 10.1289/ehp.1104492

PubMed Abstract | Crossref Full Text | Google Scholar

65. Roen EL, Wang Y, Calafat AM, Wang S, Margolis A, Herbstman J, et al. Bisphenol A exposure and behavioral problems among inner city children at 7–9 years of age. Environ Res. (2015) 142:739–45. doi: 10.1016/j.envres.2015.01.014

PubMed Abstract | Crossref Full Text | Google Scholar

66. Jensen TK, Mustieles V, Bleses D, Frederiksen H, Trecca F, Schoeters G, et al. Prenatal bisphenol A exposure is associated with language development but not with ADHD-related behavior in toddlers from the Odense Child Cohort. Environ Research 170(December. (2019) 2018):398–405. doi: 10.1016/j.envres.2018.12.055

PubMed Abstract | Crossref Full Text | Google Scholar

67. Zhou T, Abrishamcar S, Christensen G, Eick SM, Barr DB, Vanker A, et al. Associations between prenatal exposure to environmental phenols and child neurodevelopment at two years of age in a South African birth cohort. Environ Res. (2025) 264:120325. doi: 10.1016/j.envres.2024.120325

PubMed Abstract | Crossref Full Text | Google Scholar

68. Kim S, Eom S, Kim H-J, Lee JJ, Choi G, Choi S, et al. Association between maternal exposure to major phthalates, heavy metals, and persistent organic pollutants, and the neurodevelopmental performances of their children at 1 to 2 years of age- CHECK cohort study. Sci Total Environ. (2018) 624:377–84. doi: 10.1016/j.scitotenv.2017.12.058

PubMed Abstract | Crossref Full Text | Google Scholar

69. Oskar S, Balalian AA, and Stingone JA. Identifying critical windows of prenatal phenol, paraben, and pesticide exposure and child neurodevelopment: Findings from a prospective cohort study. Sci Total Environ. (2024) 920:170754. doi: 10.1016/j.scitotenv.2024.170754

PubMed Abstract | Crossref Full Text | Google Scholar

70. Miodovnik A, Engel SM, Zhu C, Ye X, Soorya LV, Silva MJ, et al. Endocrine disruptors and childhood social impairment. NeuroToxicology. (2011) 32:261–7. doi: 10.1016/j.neuro.2010.12.009

PubMed Abstract | Crossref Full Text | Google Scholar

71. Pan R, Wang C, Shi R, Zhang Y, Wang Y, Cai C, et al. Prenatal Bisphenol A exposure and early childhood neurodevelopment in Shandong, China. Int J Hygiene Environ Health. (2019) 222:896–902. doi: 10.1016/j.ijheh.2019.03.002

PubMed Abstract | Crossref Full Text | Google Scholar

72. Braun JM, Kalkbrenner AE, Calafat AM, Yolton K, Ye X, Dietrich KN, et al. Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics. (2011) 128:873–82. doi: 10.1542/peds.2011-1335

PubMed Abstract | Crossref Full Text | Google Scholar

73. Yolton K, Xu Y, Strauss D, Altaye M, Calafat AM, and Khoury J. Prenatal exposure to bisphenol A and phthalates and infant neurobehavior. Neurotoxicology Teratology. (2011) 33:558–66. doi: 10.1016/j.ntt.2011.08.003

PubMed Abstract | Crossref Full Text | Google Scholar

74. Barkoski JM, Busgang SA, Bixby M, Bennett D, Schmidt RJ, Barr DB, et al. Prenatal phenol and paraben exposures in relation to child neurodevelopment including autism spectrum disorders in the MARBLES study. Environ Res. (2019) 179:108719. doi: 10.1016/j.envres.2019.108719

PubMed Abstract | Crossref Full Text | Google Scholar

75. Guo J, Wu C, Zhang J, Qi X, Lv S, Jiang S, et al. Prenatal exposure to mixture of heavy metals, pesticides and phenols and IQ in children at 7 years of age: The SMBCS study. Environ Int. (2020) 139:105692. doi: 10.1016/j.envint.2020.105692

PubMed Abstract | Crossref Full Text | Google Scholar

76. Perera F and Herbstman J. Prenatal environmental exposures, epigenetics, and disease. Reprod Toxicol. (2011) 31:363–73. doi: 10.1016/j.reprotox.2010.12.055

PubMed Abstract | Crossref Full Text | Google Scholar

77. Cimmino I, Oriente F, D’Esposito V, Liguoro D, Liguoro P, Ambrosio MR, et al. Low-dose Bisphenol-A regulates inflammatory cytokines through GPR30 in mammary adipose cells. J Mol Endocrinol. (2019) 63:273–83. doi: 10.1530/JME-18-0265

PubMed Abstract | Crossref Full Text | Google Scholar

78. de Aguiar Greca S-C, Kyrou I, Pink R, Randeva H, Grammatopoulos D, Silva E, et al. Involvement of the endocrine-disrupting chemical bisphenol A (BPA) in human placentation. J Clin Med. (2020) 9:405. doi: 10.3390/jcm9020405

PubMed Abstract | Crossref Full Text | Google Scholar

79. Amir S, Shah STA, Mamoulakis C, Docea AO, Kalantzi O-I, Zachariou A, et al. Endocrine disruptors acting on estrogen and androgen pathways cause reproductive disorders through multiple mechanisms: A review. Int J Environ Res Public Health. (2021) 18:1464. doi: 10.3390/ijerph18041464

PubMed Abstract | Crossref Full Text | Google Scholar

80. Chevalier N, Bouskine A, and Fenichel P. Bisphenol A promotes testicular seminoma cell proliferation through GPER/GPR30. Int J Cancer. (2012) 130:241–2. doi: 10.1002/ijc.25972

PubMed Abstract | Crossref Full Text | Google Scholar

81. Dong S, Terasaka S, and Kiyama R. Bisphenol A induces a rapid activation of Erk1/2 through GPR30 in human breast cancer cells. Environ pollut. (2011) 159:212–8. doi: 10.1016/j.envpol.2010.09.004

PubMed Abstract | Crossref Full Text | Google Scholar

82. Lei B, Peng W, Xu G, Wu M, Wen Y, Xu J, et al. Activation of G protein-coupled receptor 30 by thiodiphenol promotes proliferation of estrogen receptor α-positive breast cancer cells. Chemosphere. (2017) 169:204–11. doi: 10.1016/j.chemosphere.2016.11.066

PubMed Abstract | Crossref Full Text | Google Scholar

83. Zhang Y, Wei F, Zhang J, Hao L, Jiang J, Dang L, et al. Bisphenol A and estrogen induce proliferation of human thyroid tumor cells via an estrogen-receptor-dependent pathway. Arch Biochem Biophysics. (2017) 633:29–39. doi: 10.1016/j.abb.2017.09.002

PubMed Abstract | Crossref Full Text | Google Scholar

84. Akash MSH, Sabir S, and Rehman K. Bisphenol A-induced metabolic disorders: From exposure to mechanism of action. Environ Toxicol Pharmacol. (2020) 77:103373. doi: 10.1016/j.etap.2020.103373

PubMed Abstract | Crossref Full Text | Google Scholar

85. Meli R, Monnolo A, Annunziata C, Pirozzi C, and Ferrante MC. Oxidative stress and BPA toxicity: an antioxidant approach for male and female reproductive dysfunction. Antioxidants. (2020) 9:405. doi: 10.3390/antiox9050405

PubMed Abstract | Crossref Full Text | Google Scholar

86. Tran HTT, Herz C, and Lamy E. Long-term exposure to “low-dose” bisphenol A decreases mitochondrial DNA copy number, and accelerates telomere shortening in human CD8 + T cells. Sci Rep. (2020) 10:15786. doi: 10.1038/s41598-020-72546-x

PubMed Abstract | Crossref Full Text | Google Scholar

87. Nayan NM, Husin A, and Siran R. The risk of prenatal bisphenol A exposure in early life neurodevelopment: Insights from epigenetic regulation. Early Hum Dev. (2024) 198:106120. doi: 10.1016/j.earlhumdev.2024.106120

PubMed Abstract | Crossref Full Text | Google Scholar

88. Nesan D, Sewell LC, and Kurrasch DM. Opening the black box of endocrine disruption of brain development: Lessons from the characterization of Bisphenol A. Hormones Behav. (2018) 101:50–8. doi: 10.1016/j.yhbeh.2017.12.001

PubMed Abstract | Crossref Full Text | Google Scholar

89. Nesan D, Feighan KM, Antle MC, and Kurrasch DM. Gestational low-dose BPA exposure impacts suprachiasmatic nucleus neurogenesis and circadian activity with transgenerational effects. Sci Adv. (2021) 7:eabd1159. doi: 10.1126/sciadv.abd1159

PubMed Abstract | Crossref Full Text | Google Scholar

90. Singh SJ, Tandon A, Srivastava T, Singh N, Goyal S, Priya S, et al. Bisphenol-A (BPA) impairs hippocampal neurogenesis via inhibiting regulation of the ubiquitin proteasomal system. Mol Neurobiol. (2023) 60:3277–98. doi: 10.1007/s12035-023-03249-3

PubMed Abstract | Crossref Full Text | Google Scholar

91. Jiang C, Guan J, Tang X, Zhang Y, Li X, Li Y, et al. Prenatal low-dose Bisphenol A exposure impacts cortical development via cAMP-PKA-CREB pathway in offspring. Front Integr Neurosci. (2024) 18:1419607. doi: 10.3389/fnint.2024.1419607

PubMed Abstract | Crossref Full Text | Google Scholar

92. Huang B, Ning S, Zhang Q, Chen A, Jiang C, Cui Y, et al. Bisphenol A represses dopaminergic neuron differentiation from human embryonic stem cells through downregulating the expression of insulin-like growth factor 1. Mol Neurobiol. (2017) 54:3798–812. doi: 10.1007/s12035-016-9898-y

PubMed Abstract | Crossref Full Text | Google Scholar

93. Guo Y, Kang Y, Bai W, Liu Q, Zhang R, Wang Y, et al. Perinatal exposure to bisphenol A impairs cognitive function via the gamma-aminobutyric acid signaling pathway in male rat offspring. Environ Toxicol. (2024) 39:1235–44. doi: 10.1002/tox.24007

PubMed Abstract | Crossref Full Text | Google Scholar

94. Kaimal A, Hooversmith JM, Mansi MH, Holmes PV, MohanKumar PS, and MohanKumar SMJ. Prenatal exposure to bisphenol A and/or diethylhexyl phthalate impacts brain monoamine levels in rat offspring. J Xenobiotics. (2024) 14:1036–50. doi: 10.3390/jox14030058

PubMed Abstract | Crossref Full Text | Google Scholar

95. Raja GL, Lite C, Subhashree KD, Santosh W, and Barathi S. Prenatal bisphenol-A exposure altered exploratory and anxiety-like behaviour and induced non-monotonic, sex-specific changes in the cortical expression of CYP19A1, BDNF and intracellular signaling proteins in F1 rats. Food Chem Toxicol. (2020) 142:111442. doi: 10.1016/j.fct.2020.111442

PubMed Abstract | Crossref Full Text | Google Scholar

96. Suresh S, Singh S A, and Vellapandian C. Bisphenol A exposure links to exacerbation of memory and cognitive impairment: A systematic review of the literature. Neurosci Biobehav Rev. (2022) 143:104939. doi: 10.1016/j.neubiorev.2022.104939

PubMed Abstract | Crossref Full Text | Google Scholar

97. Stiles J and Jernigan TL. The basics of brain development. Neuropsychol Rev. (2010) 20:327–48. doi: 10.1007/s11065-010-9148-4

PubMed Abstract | Crossref Full Text | Google Scholar

98. Oliphant K and Lu J. Neurodevelopment and the gut microbiome. In: The developing microbiome: lessons from early life. Cambridge, United States: Elsevier (2020). p. 115–43. doi: 10.1016/B978-0-12-820602-7.00006-4

Crossref Full Text | Google Scholar

99. Estrin GL and Bhavnani S. Brain development: structureIn: Benson JB, editor. Encyclopedia of infant and early childhood development (Second edition), 2nd ed. Elsevier (2020)p. 205–14. doi: 10.1016/B978-0-12-809324-5.23776-0

Crossref Full Text | Google Scholar

100. Mhaouty-Kodja S, Belzunces LP, Canivenc M-C, Schroeder H, Chevrier C, and Pasquier E. Impairment of learning and memory performances induced by BPA: Evidences from the literature of a MoA mediated through an ED. Mol Cell Endocrinol. (2018) 475:54–73. doi: 10.1016/j.mce.2018.03.017

PubMed Abstract | Crossref Full Text | Google Scholar

101. Baird TJ, Caruso MJ, Gauvin DV, and Dalton JA. NOEL and NOAEL: A retrospective analysis of mention in a sample of recently conducted safety pharmacology studies. J Pharmacol Toxicological Methods. (2019) 99:106597. doi: 10.1016/j.vascn.2019.106597

PubMed Abstract | Crossref Full Text | Google Scholar

102. Lee D-H. Evidence of the possible harm of endocrine-disrupting chemicals in humans: ongoing debates and key issues. Endocrinol Metab. (2018) 33:44. doi: 10.3803/EnM.2018.33.1.44

PubMed Abstract | Crossref Full Text | Google Scholar

103. Catenza CJ, Farooq A, Shubear NS, and Donkor KK. A targeted review on fate, occurrence, risk and health implications of bisphenol analogues. Chemosphere. (2021) 268:129273. doi: 10.1016/j.chemosphere.2020.129273

PubMed Abstract | Crossref Full Text | Google Scholar

104. Beausoleil C, Le Magueresse-Battistoni B, Viguié C, Babajko S, Canivenc-Lavier M-C, Chevalier N, et al. Regulatory and academic studies to derive reference values for human health: The case of bisphenol S. Environ Res. (2022) 204:112233. doi: 10.1016/j.envres.2021.112233

PubMed Abstract | Crossref Full Text | Google Scholar

105. Stanojević M and Sollner Dolenc M. Mechanisms of bisphenol A and its analogs as endocrine disruptors via nuclear receptors and related signaling pathways. Arch Toxicol. (2025) 99:2397–417. doi: 10.1007/s00204-025-04025-z

PubMed Abstract | Crossref Full Text | Google Scholar

106. Park C, Song H, Choi J, Sim S, Kojima H, Park J, et al. The mixture effects of bisphenol derivatives on estrogen receptor and androgen receptor. Environ pollut. (2020) 260:114036. doi: 10.1016/j.envpol.2020.114036

PubMed Abstract | Crossref Full Text | Google Scholar

107. den Braver-Sewradj SP, van Spronsen R, and Hessel EVS. Substitution of bisphenol A: a review of the carcinogenicity, reproductive toxicity, and endocrine disruption potential of alternative substances. Crit Rev Toxicol. (2020) 50:128–47. doi: 10.1080/10408444.2019.1701986

PubMed Abstract | Crossref Full Text | Google Scholar

108. Oakley BF, Tillmann J, Ahmad J, Crawley D, San José Cáceres A, Holt R, et al. How do core autism traits and associated symptoms relate to quality of life? Findings Longitudinal Eur Autism Project. Autism. (2021) 25:389–404. doi: 10.1177/1362361320959959

PubMed Abstract | Crossref Full Text | Google Scholar

Keywords: Bisphenol A, prenatal exposure, neurodevelopment, behavioral assessment, systematic review

Citation: Bello-Cortes IH, García-García JA, Gutiérrez-Aguilar M, Araiza-Olivera D, Sánchez-Pérez C, García-Cerón G, Morán-Ramos S, Tovar H, Bonilla-Brunner A and García-Arrazola R (2025) Prenatal exposure to Bisphenol-A as a risk factor for infant neurodevelopment. Front. Endocrinol. 16:1645540. doi: 10.3389/fendo.2025.1645540

Received: 11 June 2025; Accepted: 07 August 2025;
Published: 29 August 2025.

Edited by:

Julianna Thuroczy, Gamma-VET Ltd., Hungary

Reviewed by:

Carolina Dalmasso, University of Kentucky, United States
Brigitte Le Magueresse-Battistoni, INSERM U1060 Laboratoire de Recherche en Cardiovasculaire, Métabolisme, diabétologie et Nutrition, France

Copyright © 2025 Bello-Cortes, García-García, Gutiérrez-Aguilar, Araiza-Olivera, Sánchez-Pérez, García-Cerón, Morán-Ramos, Tovar, Bonilla-Brunner and García-Arrazola. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Roeb García-Arrazola, cm9lYkB1bmFtLm14

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