Is Bisphenol A (BPA) a Threat to Children's Behavior?
Vicente Mustieles1, Carmen Messerlian2, Iris Reina1, Andrea Rodríguez-Carrillo1, Nicolás Olea1, and Mariana F. Fernández1*
*1University of Granada, Center for Biomedical Research (CIBM); Biosanitary Research Institute of Granada (ibs.GRANADA), Spain; Consortium for Biomedical Research in Epidemiology & Public Health (CIBERESP), Spain.
2Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
In 2015 we reviewed the state of knowledge regarding the potential impact of bisphenol A (BPA) exposure on child neurobehavior. At that time, we expressed concern about the effects of BPA on children’s behavior, especially when exposure takes place in utero. Since then, the number of human studies addressing the BPA-neurobehavior hypothesis has doubled, most of them reinforcing previous prenatal associations and frequently showing differences between boys and girls. An increasing number of studies have also shown an association between postnatal BPA exposure and diverse neurobehavioral impairments, including attention-deficit and hyperactivity disorder (ADHD). It may never be possible to establish a causal link between this specific endocrine disruptor and a particular neurobehavioral endpoint; however, research data on the relationship between human BPA exposure and children’s behavior has revealed a relatively consistent pattern that cannot be ignored. The mounting experimental and epidemiologic evidence on neurobehavioral effects support more than ever the need to apply the precautionary principle during development, especially in relation to pregnant women and children. It seems that the time to act has arrived.
Neurobehavioral disabilities affect millions of children worldwide, and the prevalence of some neurodevelopmental disorders appears to be increasing. Subclinical symptoms are even more frequent and also contribute to a poorer quality of life and lower academic achievement1. Epidemiologic and animal studies have demonstrated that exposure to several families of endocrine-disrupting chemicals (EDCs) contribute to the risk of neurodevelopmental impairment1,2.
Bisphenol A (BPA) is a well-known EDC that can interfere with hormonal balance, even at low doses, via multiple steroid hormone receptors that mediate a myriad of cellular effects3. The mechanistic understanding of its effects is particularly complex: BPA can bind not only to nuclear and membrane estrogen receptors but also to thyroid, glucocorticoid, and peroxisome proliferator-activated receptors, and it can also interact with steroidogenic enzymes, among other molecular targets4,5. This biological promiscuity might explain the pleiotropic effects exerted by BPA on behavior, reproduction, and metabolism6,7. The developing brain is a key target for this compound, and pre-, peri- and post-natal BPA exposure has been linked to a variety of altered behaviors, as demonstrated in multiple experimental models3.
In 2015 we reviewed the state of knowledge on the relationship between human BPA exposure and neurobehavior5. We expressed concern about the effects of BPA on children’s behavior, especially when exposure takes place in utero. Although only 12 epidemiologic studies were available at that time, their findings pointed in the same direction as experimental studies, suggesting a negative impact of prenatal BPA exposure on children’s neurobehavioral functioning in a sex-dependent manner5. The results suggested that male fetuses were more frequently affected by prenatal BPA exposure than females, in line with the current hypothesis of environmental intrauterine sex-dependent vulnerability8.
Since March 2015, the number of human studies addressing the BPA-neurobehavior hypothesis has doubled9–19, most of them reinforcing previous associations and frequently showing differences between boys and girls. For example, earlier findings by Perera et al. (2012)20 and Roen et al. (2015)21 were confirmed by Perera et al. (2016)13, showing a consistent longitudinal pattern of internalizing problems, including anxiety and depression symptoms, among boys from childhood to adolescence in a birth cohort from the U.S.. More recently, Casas et al. (2015)9 in Spain, Philippat et al. (2017)15 in France, and Braun et al. (2017)14 in Canada all supported the findings of previous studies by Harley et al. (2013)22 in California and by Evans et al. (2014)23 in a multicenter U.S. cohort. These reported more frequent behavior problems related to prenatal BPA exposure in the males than in the females. Notably, Braun and colleagues (2017)14 studied 812 mother-child pairs belonging to the Maternal–Infant Research on Environmental Chemicals (MIREC) study, finding that higher prenatal urinary BPA concentrations were significantly associated with more frequent internalizing problems among three-year-old boys and with poorer executive function and higher social impairments. In contrast, two birth cohorts observed more behavior problems24 and social impairments17 related to prenatal BPA exposure in girls than in boys. Overall, epidemiologic data support a probable negative effect of prenatal BPA exposure on children’s behavior in a sex-dependent manner.
An increasing number of studies show that postnatal BPA exposure is also associated with diverse neurobehavioral impairments among both boys and girls10,11,16,21,22. For example, some studies, including two representative national surveys, have reported associations with symptoms of attention-deficit and hyperactivity (ADHD) and with the prevalence of ADHD. Findlay and Kohen (2015)10 observed positive cross-sectional associations between urinary BPA concentrations and ADHD symptoms in 2730 Canadian children/youths aged 6-17, while Tewar et al. (2016)12 found a positive cross-sectional association between BPA concentrations and the risk of ADHD in 460 North American children/youths aged 8-15 years. A more recent case-control study in China also reported a stepwise increase in the risk of ADHD across increasing quartiles of urinary BPA concentrations19. These associations reinforce data from some previous prospective studies that found more ADHD symptoms in response to higher prenatal BPA concentrations9,15,24. These associations are also supported by experimental data25,26.
The human brain is a sexually dimorphic organ, and major morphological differences are permanently shaped during prenatal development under the influence of steroid hormones, especially estrogen and aromatizable androgens27,28. BPA has been shown to alter sex-specific structural and behavioral patterns in experimental animals, including non-human primates, increasing, decreasing, and/or eliminating sex differences29–32. It is possible that BPA induces these effects through epigenetic modifications related to the estrogen-androgen balance, given evidence that BPA affects the gene expression of several estrogen receptor subtypes (ERα, ERβ and ERγ) in a sex- and brain region-specific manner29. Hence, in utero BPA exposure could predetermine later responses of certain brain areas to steroid hormones. Moreover, a recent high-quality experimental study by the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) demonstrated that low BPA doses in utero alter the rat brain transcriptome, mainly in the hypothalamus, finding sex-specific effects on hypothalamic ERα and ERβ expression33.
More than 90% of Europeans and Americans have detectable concentrations of BPA in their urine, and diet is considered the main source of BPA exposure in humans34–37. Despite the ubiquity of BPA, its non-persistence and short biological half-life and the episodic nature of its exposure make BPA characterization very difficult, frequently producing an important degree of exposure misclassification. This results in a greater tendency to obtain null results, the so-called attenuation bias15,38. Therefore, it is possible that we have been systematically underestimating the effects of BPA, and researchers in the field should consider the potential impact of this attenuation when interpreting epidemiologic findings11,15,38. However, despite these methodological limitations, the overall picture of the relationship between human BPA exposure and behavior is relatively consistent across studies and populations. Moreover, the widespread nature of exposure to BPA means that even subtle changes in behavior at the individual level may have relevant effects at the population level, with public health repercussions39,40.
In 2008, a National Toxicology Program assessment, based on animal data, reported that BPA-related neural and behavioral endpoints were a major concern for fetuses, infants, and children41. Since then, some governments have implemented preventive measures, such as the banning of BPA in baby bottles by Canada and subsequently by the European Union42,43, and the total prohibition of BPA in France44. Additionally, regulatory organizations such as the European Food Safety Authority (EFSA) have been progressively reducing their estimation of the tolerable daily intake (TDI) in subsequent risk assessments. Thus, the TDI for BPA was lowered from 50 µg/kg bw/day to 4 µg/kg bw/day in 201545. Nevertheless, recent well-conducted experimental studies have shown that BPA can impact the brain and behavior of rats at doses near to or even below the current TDI33,46, and it has been suggested that EFSA’s temporary tolerable daily intake of 4µg/kg bw/day may not be “sufficiently protective” for humans in the general population46. EFSA’s forthcoming assessment will be an opportunity to integrate new experimental and epidemiologic data and provide evidence in support of action to protect children’s behavior.
BPA is commonly found in food packaging materials, being used in the manufacture of polycarbonate plastics and in the epoxy resin liners of food cans. The greater public awareness around BPA has been reflected by the increased popularity of “BPA-free” products47. However, many of these products are manufactured using bisphenol analogues, including bisphenol S and F (BPS and BPF), which have been shown to be at least as hormonally active as BPA48. Furthermore, experimental studies of bisphenol substitutes such as BPS and BPF suggest similar and in some cases greater adverse neurobehavioral effects than those associated with BPA49.
It may never be possible to establish a causal link between a specific EDC and a particular neurobehavioral endpoint50. Nevertheless, it is impossible to ignore the consistent and accumulating human evidence on the effects of BPA on child neurobehavior. While future research will provide greater clarity, the mounting experimental and epidemiologic data on its neurobehavioral effects support more than ever the need to apply the precautionary principle during development, especially in relation to pregnant women and children5,51. It seems that the time to act has arrived52.
Conflict of interest: The authors declare no actual or potential financial conflicts of interest.
Acknowledgements: This work was supported by research grants from the European Union Commission (H2020-EJP-HBM4EU), the Biomedical Research Networking Center-CIBER de Epidemiología y Salud Pública (CIBERESP). This article will form part of the thesis developed by Vicente Mustieles in the context of the “Clinical Medicine and Public Health Program” of the University of Granada.
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