In this longitudinal cohort study we examined the association between prenatal BPA exposure and child behavior in preschool-age children, accounting for postnatal BPA and other potential confounders. Among boys, prenatal BPA exposure was positively associated with higher scores on all syndromes and significantly associated with Emotionally Reactive and Aggressive Behavior. Inverse associations were seen in girls for all syndromes and these associations were significant for Anxious/Depressed and Aggressive Behavior.
The present finding that prenatal exposure to BPA is associated with more symptoms of certain behavioral problems in 3- to 5-year-old boys is consistent with some, but not all, prior studies in laboratory animals. Some animal studies have shown that in male mice, prenatal BPA exposure is associated with increased aggression (Kawai et al. 2003
) and with memory impairment and hyperactivity (no female offspring were tested) (Miyagawa et al. 2007
; Mizuo et al. 2004
). Others have reported changes in behavior or related pathways have included greater anxiety-like behavior in female mice (male mice were not tested) (Ryan and Vandenbergh 2006
), changes in the dopaminergic and N
-aspartate-ergic (NMDA) systems (associated with memory and behavior) (Tian et al. 2010
), and reduction of activity and desire to explore in both sexes (Farabollini et al. 1999
). In addition, mice of both sexes exposed to low doses of BPA prenatally (20 µg/kg of BPA daily from embryonic day until postnatal day 21) and throughout lactation had an increase in serotonin and dopamine (involved in mood, memory, and learning) levels in certain brain regions compared with a control group not exposed to BPA (Nakamura et al. 2010
). In one study of rats, maternal BPA exposure inhibited the protein expression of NMDA receptor subunits and estrogen receptor beta of the hippocampus of male offspring during postnatal development, suggesting that BPA may affect the male developing brain; data on females were not reported (Xu et al. 2010
). Rats prenatally exposed to BPA have an increase in anxiety-like behavior and a decrease in desire to explore, with the effects more pronounced in females than in males (Poimenova et al. 2010
). BPA has also been found to abrogate sexual dimorphism in brain structure and behavior in rats (determined by estrogen signaling) (McCarthy 2008
) and to disrupt cognition, social behaviors, and other aspects of brain function (Richter et al. 2007
Male cynomolgus monkeys who were prenatally exposed to BPA behaved like non-BPA exposed female infants rather than non-BPA exposed males, suggesting that BPA affects behavior and sexual differentiation in male monkeys (Nakagami et al. 2009
). Although interspecies variation in internal dose and response to BPA is a concern (Doerge et al. 2010
), BPA pharmacokinetics appear to be similar in women, female monkeys, and mice (Taylor et al. 2011
Our findings are inconsistent with reports by Braun et al. (2009
). Although these investigators also examined sex-specific effects of prenatal BPA exposure on some dimensions of child behavior, they reported evidence of adverse effects predominantly in girls. Specifically, Braun et al. found a relationship between prenatal BPA exposure and externalizing behavior in 2-year-old girls but not boys using the Behavioral Assessment System for Children (BASC) (Braun et al. 2009
). At the age 3 years follow-up, they also found that gestational BPA concentrations were associated with anxiety, depression, and hyperactivity among girls but not boys in their population. Including childhood BPA concentrations in the models did not significantly change the results (Braun et al. 2011b
). They collected maternal spot urine samples twice during pregnancy and at delivery, with urinary concentrations of BPA being similar to those in the present study (median concentrations of 1.8, 1.7, and 1.3 µg/L at 16 and 26 weeks of pregnancy and at birth, respectively). Child spot urine samples were collected at 1, 2, and 3 years of age. The 16-week BPA (early second trimester) prenatal urinary concentrations were more highly correlated with behavioral outcomes than were the prenatal 26-week (early third trimester) or birth BPA measurements. We note that when we compare the results of Braun et al. for urinary BPA measures at 26 weeks and at birth [i.e., the measurement times closest to our prenatal measurement (34.0 weeks on average)], both boys and girls had lower (i.e., better) scores on Internalizing and Externalizing scales, though the results were not statistically significant.
Although these would not fully explain the discrepant findings, there were a number of differences between the study designs, especially the differences in the timing of sample collection. We measured BPA at a single time point in the third trimester of pregnancy, whereas Braun et al. (2011b)
took three serial measurements. In their analysis the prenatal exposure with the greatest associations with child behavior at age 2 and 3 years was measured in samples taken at 16 weeks, with BPA measurements taken later in pregnancy having weaker associations. In addition, the children in the CCCEH cohort at assessment were older (3–5 years vs. 2 and 3 years) than in those studied by Braun et al. (2011b)
. Also, different instruments were used to assess child behavior, and different statistical models were used to analyze the data. The children in the two study populations also differed by both ethnicity and socioeconomic status. Specifically, our population is a low-income minority population, whereas most of the participants included in the Braun study were white with a household income of > $40,000. Finally, prior research has shown that the two instruments (CBCL and BASC-2) give similar, but not identical, results (Myers et al. 2010
). Because the mechanisms of the association between early BPA exposure and child behavior are currently not understood, further research is needed to identify the factors that influence the expression of BPA behavioral toxicity in children.
A strength of our study is the ability to control for a number of variables based on medical record, questionnaire, biomarker, and air monitoring data that may affect neurobehavioral development. Because we measured BPA concentrations in child urine, we were able to compare results before and after adjusting for postnatal BPA exposure. The finding that the results were similar before and after adjusting for postnatal exposure suggests that the prenatal period may be a more sensitive window for BPA exposure [see Supplemental Material, Tables S2, S3
)]. In addition, we were able to adjust for prenatal phthalate exposure as a potential confounder. A limitation of our study is the use of a single measurement of BPA in urine to categorize exposure. Data are lacking on the time points during fetal development that are most susceptible to BPA. It would have been preferable to have had multiple BPA measures in repeated urine samples over the pregnancy and during childhood. Although we recognize the limitation of using a single spot urine sample as a measurement of chronic BPA exposure (Braun et al. 2011a
), we would expect the noise in measurements to bias associations toward the null. Another limitation of this study is the relatively small sample size (n
= 198), particularly for assessing interactions by sex. In addition, because our research focused on minority women and children living in an urban setting, the effects may not be generalizable to other racial and ethnic groups, nor to other exposed populations. However, the distribution of CBCL scores in our study is similar to that for other low-income populations (Gross et al. 2006
Additionally, because the CBCL is a parent account of child behavior, it is subject to limitations inherent in such instruments including reporting bias or a difficulty inferring a child’s internal state. Finally, although we adjusted for other exposures and potential confounders, there is the possibility of residual confounding by unmeasured exposures or other stressors.
In conclusion, we report an association between prenatal BPA exposure and child behavior at age 3–5 years, with sex-specific associations. Among boys we found significant positive associations between prenatal BPA and CBCL scores of Emotionally Reactive and Aggressive Behavior. In contrast, among girls prenatal BPA was associated with significantly lower scores for the Aggressive Behavior and Anxious/Depressed syndromes.
Follow-up of the cohort is ongoing to further evaluate these sex-specific associations at older ages. Behavioral problems such as those observed here may be of concern for future academic performance and social functioning (Hinshaw 1992
; Wood 2006