Neuropsychological Outcomes of Prenatal Exposure to Phenols and Phthalates in Young Children

Background: Bisphenols and phthalates are endocrine disrupting chemicals (EDCs). The primary route of exposure to these chemicals is through diet. Prenatal maternal exposure is a significant concern as these EDCs cross the blood-brain barrier and placenta. In children, some studies have reported that prenatal exposure to maternal bisphenol A (BPA) has been associated with a broad range of behavioral and cognitive outcomes including higher levels of aggression, hyperactivity, anxiety, depression, poorer emotional control and lower IQ. No previous studies have examined the prenatal effects of maternal exposure to bisphenol S (BPS), a chemical alternative to BPA, on children’s neurodevelopment. Additionally, some studies suggest that prenatal maternal exposure to phthalates has been associated with social impairments, lower IQ, poorer language and motor skills, and poorer psychomotor and mental development in children. In addition, some studies report that the associations between prenatal exposure to maternal BPA and phthalates are more pronounced in girls, whereas others report greater effects in boys. The primary objective for this dissertation was to examine the effects of prenatal maternal bisphenol (BPA, BPS) and phthalate exposure on neurodevelopmental outcomes of children who were three to four years of age. The secondary objective was to examine the possible modifying role of child sex. We hypothesize that higher levels of prenatal exposure to bisphenols and phthalates would be associated with lower performance on measures of behavior, cognition and motor function at three to four years of age. Methods: Two systematic reviews were undertaken to characterize current knowledge and gaps related to the associations between prenatal and childhood exposure to urinary BPA or phthalates, and neurodevelopmental outcomes. Subsequently, mother-child pairs were recruited from the Alberta Pregnancy Outcomes and Nutrition cohort study (APrON). Maternal BPA, BPS and levels for 14 phthalate metabolites were quantified using single spot maternal urine samples that were collected between 14 and 26 weeks of pregnancy in 410 maternal-child pairs who participated in the studies reported here. Children’s neurodevelopment was assessed at three to four years using standardized measures of behavior (i.e., Child Behavioral Checklist (CBCL)), cognition (i.e., Wechsler Preschool and Primary Scale of Intelligence – Fourth Edition (WPPSI-IV)), and motor function (i.e., Movement Assessment Battery for Children – Second Edition (MABC-2)). Sex-stratified analysis and multivariate linear regression were used to assess relationships between prenatal maternal BPA, BPS or phthalate concentrations and neurodevelopmental outcomes. We adjusted for multiple confounding variables including urinary creatinine, maternal age, education and child sex. We also used the Benjamini-Hochberg procedure to correct for multiple statistical comparisons. Results: The two systematic reviews of the literature suggested inconsistent findings, with studies reporting positive, negative or no association between prenatal maternal BPA or phthalates exposure and neurodevelopmental outcomes. Both reviews also suggested inconsistent sex-specific effects. Further, many of the studies that examined the effects of prenatal maternal exposure to phthalates had investigated a limited number of phthalate metabolites. The systematic reviews supported the need for well-designed prospective cohort studies to investigate these gaps. Findings from our prospective cohort study suggested that prior to correction for multiple comparison, higher maternal urinary BPA concentrations were not associated with neurodevelopmental problems and n No associations were found between prenatal maternal bisphenols levels and motor and cognitive development. After correcting for multiple comparisons, only the association between higher BPS and attention remained statistically significant. Prior to correction for multiple comparisons, adjusted models revealed that higher maternal prenatal Mono-benzyl phthalate (MBzP) and more externalizing and aggressive behaviors on the CBCL. On the WPPSI-IV, we found that higher exposure to maternal phthalates (i.e. High Molecular Weight (HMW), (Mono-isobutyl phthalate (MiBP), Mono-carboxyoctyl phthalate (MCOP), and MBzP) during the second trimester in pregnancy were associated with improved cognitive performance (FSIQ, visual spatial and working memory skills). For motor outcomes, we found that higher exposure to Di-ethylhexyl phthalates (DEHP), were associated with poor performance in MABC-2. Correction for multiple comparisons attenuated most of these associations such that they became non-significant. Only the association between DEHP metabolites and lower Balance scores remained significant after corrections. We found sex-specific effects, such that adverse behavioral outcomes were only observed in boys. Lower Verbal Comprehension was found in boys while better Visual Spatial scores were found in girls. Poor overall motor function was found among boys while balance problems was observed among girls. Conclusions: Maternal BPS concentrations during pregnancy may be associated with more attention problems, as measured by CBCL, in children at three to four years of age. The current study is the first child neurodevelopmental study to suggest that BPS may not be a safe alternative for BPA. Also, higher prenatal maternal DEHP concentrations were associated with more balance problems on CBCL. However, we do not have sufficient evidence to support that prenatal maternal exposure to BPA and other phthalate metabolites during the second trimester of pregnancy is associated with adverse neurodevelopmental outcomes in children at three to four years of age. Future research in prospective cohorts who are similar in terms of levels of exposure and sociodemographic and cultural background are needed to corroborate these findings.

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