Final Report: Novel Methods to Assess Effects of Bisphenol A (BPA) & Phthalates on Child Development

EPA Grant Number: R834593
Center: Novel Methods to Assess Effects of Bisphenol A & Phthalates on Child Development
Center Director: Schantz, Susan L.
Title: Novel Methods to Assess Effects of Bisphenol A (BPA) & Phthalates on Child Development
Investigators: Schantz, Susan L. , Korrick, Susan A. , Juraska, Janice , Flaws, Jodi
Institution: University of Illinois at Urbana-Champaign , Harvard T.H. Chan School of Public Health
EPA Project Officer: Hahn, Intaek
Project Period: February 15, 2010 through February 14, 2014
Project Amount: $1,094,951
RFA: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers (with NIEHS) (2009) RFA Text |  Recipients Lists
Research Category: Children's Health , Health

Objective:

The primary goal of this Formative Children’s Environmental Health Research Center was to conduct pilot studies that would begin to address critical gaps in our knowledge of the risks to children from bisphenol A (BPA) and phthalate exposure. Because these compounds are endocrine disruptors, the research focused on endocrine mediated outcomes including gonadal development and  sexually dimorphic aspects of brain development and behavior. Exposures during two critical developmental windows—prenatal and adolescent—were assessed. The Center included two human cohort studies—a pilot birth cohort in Urbana, IL (Project 1) and a pilot adolescent cohort study that was conducted within an ongoing prospective birth cohort study in New Bedford, MA (Project 2). These studies assessed the relationship between BPA or phthalate exposure and sexually dimorphic aspects of physical development and cognition in infants, and cognition and behavior in adolescents. The Center also included two animal studies that investigated the mechanisms through which BPA influences gonadal development and function (Project 3) and the impact of in utero or adolescent exposure to BPA on development of sexually dimorphic cortical brain regions and cognitive functions (Project 4). The data from these pilot studies formed the basis for a grant application to expand the Formative Center into a full Children’s Environmental Health Research Center, which was funded beginning 6/15/13 (1 P01 ES022848-01 and RD 835434010).

Summary/Accomplishments (Outputs/Outcomes):

The work conducted for Project 1 set the stage for future research by successfully developing the infrastructure upon which to build a larger prospective birth cohort and by demonstrating the feasibility of novel approaches to data collection including cognitive assessments of newborn infants in the hospital setting. Importantly, the results of this pilot work also support the hypothesized associations of prenatal exposures with the targeted contaminants. Specifically, both BPA and anti-androgenic phthalates were associated with altered anogenital distance in preliminary analyses conducted on a subset of the sample for whom exposure data were available. There were also suggestive associations of both BPA and anti-androgenic phthalates with decrements in attention in both newborns and older infants (7 months), and with declines in working memory in the latter age group. These findings are preliminary and will need to be confirmed in the full cohort prior to publication. Furthermore, although our sub- study of variability in urinary concentrations of BPA and phthalate metabolites in repeated samples across pregnancy) suggested that first morning urine collections may provide somewhat improved exposure assessment over random spot urines, the degree of variability within individuals was still considerable. This information was critical in our decision to collect and pool urine from multiple samples across pregnancy in the future, thus providing a measure of average exposure across pregnancy. We will be able to validate and build on the important preliminary findings from this pilot research with much greater statistical power in the full cohort (n = 600 infants) to be studied as part of our recently funded full Children's Center.

The work conducted for Project 2 provides preliminary support for the hypothesized association of adolescent BPA, but not antiandrogenic phthalate exposure, with poorer cognitive function in specific domains with likely sexual dimorphism in performance. Furthermore, the findings provide preliminary support for the secondary hypothesis of potential differential effects of exposure on boys vs. girls for cognitive measures. Both exposures (BPA, antiandrogenic phthalates) were associated with adverse behavior, especially ADHD-like behavior. However, because of small numbers in this pilot study (by design), analyses were adjusted for a limited number of potential confounders and, for many results, confidence limits were wide so it is not yet possible to make definitive conclusions. Most importantly, these formative center findings contributed to a research project proposal for a successful full Children's Environmental Health and Disease Prevention Research Center (P01). With analysis of the full study (n = 205 children) made possible via the full Center P01, we will be able to assess the reproducibility of these preliminary models, use more comprehensive models to account for confounding, and assess associations with functional measures (e.g., reaction time and errors on a continuous performance test, CPT) for which short-term exposure effects are possible.

Project 3 was designed to test the hypothesis that in utero exposure to BPA causes gonadal defects via estrogen receptor alpha (ERα). To test this hypothesis, we proposed the following specific aims: 1) determine whether loss of ERα renders developing gonads insensitive to deleterious effects of BPA, and 2) determine if overexpression of ERα increases the susceptibility of embryos to BPA. Collectively, the data indicate that maternal BPA exposure alters testis development in the offspring, and that the effects of BPA are likely non- monotonic because the low dose of BPA exerts a more dramatic effect than the high dose of BPA. Further, the data indicate that prenatal BPA exposure reduces healthy primordial follicle numbers in the ovary and that it inhibits antral follicle growth. The results also indicate that BPA inhibits progesterone, dehydroepiandrosterone, androstenedione, estrone, testosterone, and estradiol production by the mouse ovary. Finally, the data suggest that BPA may not exert toxicity in ovaries through ER pathways.

Project 4 was a pilot project designed to investigate whether bisphenol A (BPA) exposure during pre/perinatal development or during puberty alters cognitive areas of the brain or cognitive behavior in rats. The results indicate that BPA exposure increased maternal attention to pups at certain doses, which establishes that any effects of BPA are not due to insufficient maternal care. These data are preliminary at this time because of relatively low N. More animals will be added as part of the studies in the Center (P01) grant. Quantitative stereological analysis of the prefrontal cortex revealed that there were significant increases in the number of both neurons and glia in male rats exposed to 400 µg/kg/day of BPA perinatally compared to unexposed controls. In addition, the results indicate that there were no effects on body weight at weaning or in adulthood, or on levels of thyroid hormone or luteinizing hormone at weaning. Both sexes at doses of 4 and 40 µg/kg BPA had decreased follicle-stimulating hormone (FSH) levels, but there were no changes in the timing of puberty compared to controls. Exposure to BPA during adolescence resulted in opposite effects between the sexes in the number of glia in the prefrontal cortex as adults: females that had been exposed to BPA had more glia while males showed a general decrease following exposure. The implications of these changes in glia are being investigated further in the center grant.

 

Conclusions:

Overall, the funded work provided a strong basis for us to expand the Formative Center into a full Children’s Environmental Health Research Center. Completion of Project 1 enabled us to develop the infrastructure required to build a large prospective birth cohort and to obtain preliminary data on the associations of prenatal BPA and phthalate exposure with anogenital distance and infant cognition. Further, the results enabled us to make decisions about how to collect and analyze BPA and phthalate levels in urine samples in the large birth cohort study. Completion of Project 2 allowed us to obtain preliminary data on the association between adolescent BPA and phthalate exposure and cognitive and behavioral outcomes in boys and girls. These preliminary data helped us design the adolescent studies that will be completed in the full Children’s Center. Completion of Project 3 enabled us to determine that BPA exposure adversely affects the development of the testes and ovaries and that it inhibits steroid production by the ovary in mice. We will expand upon these data in the full Children’s Center by determining whether phthalates have similar effects on the gonads and steroidogenesis and by determining whether BPA and phthalates adversely impact fertility in the first and subsequent generations of mice by mechanisms which involve oxidative stress. Finally, completion of Project 4 enabled us to obtain preliminary data indicating that BPA exposure during pre-perinatal development in the rat may affect the number of neurons in the prefrontal cortex and it may affect maternal behavior. We will expand upon these data in the full Children’s Center by staining brain sections for two major types of glia: astrocytes and microglia. Both of these glia types are important for synaptogenesis and pruning which may indicate an effect of BPA on the wiring of the medial prefrontal cortex.

 


Journal Articles: 7 Displayed | Download in RIS Format

Other center views: All 35 publications 7 publications in selected types All 7 journal articles
Type Citation Sub Project Document Sources
Journal Article Brannick KE, Craig ZR, Himes AD, Peretz JR, Wang W, Flaws JA, Raetzman LT. Prenatal exposure to low doses of bisphenol A increases pituitary proliferation and gonadotroph number in female mice offspring at birth. Biology of Reproduction 2012;87(4):82 (10 pp.). R834593 (2012)
R834593 (Final)
R834593C001 (Final)
R834593C003 (2012)
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  • Full-text: Biology of Reproduction-Full Text HTML
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  • Abstract: Biology of Reproduction-Abstract
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  • Journal Article Peretz J, Gupta RK, Singh J, Hernandez-Ochoa I, Flaws JA. Bisphenol A impairs follicle growth, inhibits steroidogenesis, and downregulates rate-limiting enzymes in the estradiol biosynthesis pathway. Toxicological Sciences 2011;119(1):209-217. R834593 (2012)
    R834593 (Final)
    R834593C001 (Final)
    R834593C003 (2012)
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  • Journal Article Peretz J, Craig ZR, Flaws JA. Bisphenol A inhibits follicle growth and induces atresia in cultured mouse antral follicles independently of the genomic estrogenic pathway. Biology of Reproduction 2012;87(3):63 (11 pp.). R834593 (2012)
    R834593 (Final)
    R834593C001 (Final)
    R834593C003 (2012)
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  • Full-text: Biology of Reproduction-Full Text HTML
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  • Journal Article Peretz J, Flaws JA. Bisphenol A down-regulates rate-limiting Cyp11a1 to acutely inhibit steroidogenesis in cultured mouse antral follicles. Toxicology and Applied Pharmacology 2013;271(2):249-256. R834593 (Final)
    R834593C001 (Final)
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  • Journal Article Peretz J, Vrooman L, Ricke WA, Hunt PA, Ehrlich S, Hauser R, Padmanabhan V, Taylor HS, Swan SH, VandeVoort CA, Flaws JA. Bisphenol A and reproductive health: update of experimental and human evidence, 2007-2013. Environmental Health Perspectives 2014;122(8):775-786. R834593 (Final)
    R834593C001 (Final)
    R835434 (2013)
    R835434 (2014)
    R835434 (Final)
    R835436 (2014)
    R835436 (2015)
    R835436 (2017)
    R835436 (Final)
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  • Journal Article Sadowski RN, Park P, Neese SL, Ferguson DC, Schantz SL, Juraska JM. Effects of perinatal bisphenol A exposure during early development on radial arm maze behavior in adult male and female rats. Neurotoxicology and Teratology 2014;42:17-24. R834593 (Final)
    R834593C001 (Final)
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  • Journal Article Sadowski RN, Wise LM, Park PY, Schantz SL, Juraska JM. Early exposure to bisphenol A alters neuron and glia number in the rat prefrontal cortex of adult males, but not females. Neuroscience 2014;279:122-131. R834593 (Final)
    R834593C001 (Final)
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  • Progress and Final Reports:

    Original Abstract
  • 2010 Progress Report
  • 2011 Progress Report
  • 2012 Progress Report
  • Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R834593C001 Prenatal Exposure to BPA/Phthalates: Infant Physical and Behavioral Development
    R834593C002 Adolescent Exposure to BPA/Phthalates Cognitive and Behavioral Development
    R834593C003 Mechanisms of In Utero BPA Exposure on Fetal Gonad Development
    R834593C004 Effects of Bisphenol A on the Developing Cortex