2010 Progress 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. , Baillargeon, Renee L. , Aguiar, Andrea , Juraska, Janice , Flaws, Jodi , Gardnier, Joseph
Current 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 , Michigan State University
Current 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 Period Covered by this Report: February 15, 2010 through February 14,2011
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:

This award establishes a Formative (P20) Children’s Environmental Health and Disease Prevention Research Center. The primary goal of the Center is to address critical gaps in our knowledge of the risks to children from bisphenol A (BPA) or phthalate exposure. Because both BPA and phthalates disrupt steroid hormone action, the studies are focused on endocrine-mediated outcomes, including gonadal development and sexually dimorphic aspects of brain development and behavior. The impact of exposures during two developmental windows, —the prenatal and adolescent periods,— are under study in the Center. At the heart of the research are two human cohort studies—a pilot birth cohort in Urbana-Champaign, IL (Project 1; S. Schantz, PI), and a pilot adolescent cohort that is being studied in the context of an ongoing study in New Bedford, MA (Project 2; S. Korrick, PI). These studies are assessing the relation of BPA or phthalate exposure with sexually dimorphic aspects of physical development and cognition in newborn infants and with cognition in adolescent children. The Center also includes animal studies that model the timing of exposure in the human cohorts. These studies are investigating mechanisms through which BPA disrupts male and female gonad development using transgenic and knockout mouse models (Project 3; H. Flaws, PI), and the impact of in utero or peripubertal BPA exposure on development of sexually dimorphic cortical brain regions and cognitive functions in a rat model (Project 4; J. Juraska, PI). While the two human studies are assessing both phthalates and BPA, the animal studies are focused on BPA and later will be expanded to include phthalates. Innovative use of analogous tests in animal and human studies, combined with mechanistic investigation (Projects 3, 4), will optimize our ability to synthesize human and animal findings. Data from these pilot studies will provide the basis for an application for a full-fledged Children’s Environmental Health Research Center to expand the research. Central to the Center's long-term goals will be expansion of the pilot birth cohort into a larger prospective study with followup through puberty. This study would incorporate novel methods and approaches developed in the Formative Center. Another long-term goal will be to expand the adolescent studies. Studies in laboratory animal models would continue to play a key role, and would be used both to explore mechanisms of action and to identify key physical, biological and behavioral outcomes to assess in the children as they mature.

Progress Summary:

R834593C001-—Pilot Birth Cohort
 
Description: Pregnant women are exposed to endocrine-disrupting chemicals such as phthalates and bisphenol A (BPA) through their use of personal care products and plastics. In animal models, phthalates and BPA cause developmental abnormalities, but little is known about whether these chemicals are associated with adverse developmental outcomes in humans. This pilot study is developing novel methods to assess the impact of prenatal BPA or phthalate exposure on sexually dimorphic physical and behavioral endpoints during the first few months of life. An important goal is to identify reliable and valid measures of cognitive function in newborns that are sensitive to prenatal chemical exposure and predictive of lasting cognitive deficits. To complete the proposed work, 150 pregnant women and their infants are being recruited from a local clinic. The pregnant women complete a 24-hour product use diary and provide urine samples for assessments of total BPA and 9 phthalate metabolites at 16 to 18 and 36 weeks of gestation. Pregnant women also donate cord blood for measurement of selected ER polymorphisms. Key physical and cognitive outcomes are assessed at birth, 4.5, 7.5 and 10.5 months of age. The relationship between measures of exposure and reported product use, and the relationship between maternal exposures and physical or cognitive outcomes in infants, will be examined. This study will provide important pilot data about the nature of phthalate and BPA exposure in pregnant women and the risk of developmental abnormalities in their infants. The results will provide a strong basis for expansion of the pilot birth cohort into a larger prospective birth cohort with longitudinal followup of the children from birth through puberty.
 
Progress: This study is still in progress and results are not yet available. Recruitment of participants was initiated in August of 2010 and is still ongoing. As of September 28, 2011, 144 pregnant women were enrolled in the study. Of these, 24 were dropped from active participation for the following reasons: 3 moved out of the area, 2 withdrew from the study, 1 is no longer a patient at our partner obstetrical clinic, 10 began taking medication for a chronic health condition, 6 gave birth to infants requiring admission to the neonatal intensive care unit (NICU) and 2 experienced preterm births. As of September 28, 2011, 120 women remained actively enrolled in the study, 81 births had occurred, and 71 of the 81 infants were still actively enrolled in the study; 10 had been dropped from the study. As outlined above, 6 were dropped because they developed health problems requiring admission to the NICU and 2 were dropped due to preterm birth (< 37 weeks). Two additional infants were lost to followup because their families moved out of the area shortly after birth. Cord blood samples were successfully obtained from 69 of the 73 infants that remained enrolled in the study at birth, and physical measurements were obtained on all 73 infants.
 
Sixty of the 73 healthy, full-term newborn infants born to study participants were available for cognitive testing at birth. Visual attention and visual recognition memory tasks were successfully performed on 52 of the 60 infants that were available for assessment. Most of the infants that could not be tested failed to open their eyes during several attempts at testing. As of September 2011, the infants are beginning to undergo the 4.5 month followup assessments: 18 infants had completed the assessment and 7 were currently scheduled for testing. The two infants whose families moved out of the area are the only infants to be lost to followup since birth, and 16 of the 18 infants assessed at 4.5 months successfully completed the cognitive testing; 2 infants were too fussy and could not be tested. Physical measurements were successfully collected on all 18 babies. The 7.5-month assessments are scheduled to begin in October 2011. Urine samples from the mothers of all infants actively enrolled in the study to date were shipped to the CDC for analysis of BPA and phthalates on September 12, 2011. Results from these initial chemical analyses are expected by January 2012 for this initial set of samples.
 
R834593C002—-Adolescent Study
 
Description: Adolescence is a key period of vulnerability to gonadal hormones, which profoundly affect not only the transition to reproductive maturity but also the adolescent transition to cognitive and behavioral maturity. Underlying this adolescent transition is substantial brain organizational development and growth, including growth in brain regions demonstrating sexual dimorphisms likely related to gonadal steroid effects. The primary aim of this pilot project is to assess the relation of adolescent exposure to phthalates and BPA with adolescent neurobehavior. The proposal builds on an ongoing longitudinal study of 788 children who have been followed since birth to assess the relation of early-life contaminant exposures (organochlorines and metals) with subsequent neurodevelopment. The study uses this parent study'’s established infrastructure (including adolescent neurobehavioral exams) and wealth of existing data to address two new themes: (1) the potential developmental toxicities of adolescent phthalate and BPA exposures; and (2) the identification of adolescent neurobehavioral outcomes likely to be sensitive to these exposures based on: (a) experimental studies of gonadal steroids and brain function, (b) animal or human evidence of sexual dimorphism in performance, or (c) analogy with Project 4’s rodent model. Urine samples are being collected (at adolescent, 1,3–15 years neurobehavior testing) for measurement of phthalate and BPA metabolites. The relation of these exposures with psychometric measures of visual motor abilities, verbal abilities, working memory, behaviors related to Attention Deficit Hyperactivity Disorder (ADHD) and psychiatric symptoms (e.g., depression, anxiety) will be assessed. Secondary aims will be assessment of whether associations of phthalates or BPA with neurobehavior differ by sex or by pubertal status. This will be among the first studies to provide insight into the role of these compounds as risk factors for adverse neurodevelopment in adolescence.
 
Progress: This study is still in progress and results are not available yet. Enrollment to the BPA/phthalate study began in the spring of 2011 and is still ongoing. As of September 2011, 48 children from the parent study had provided urine, representing a 90% participation rate. When children provide urine, they also complete a detailed product use questionnaire focused on dietary habits, personal care product use and other experiences in the previous 24 hours.
 
R834593C003—-Gonadal Development and Function
 
Description: The main objective of this research project is to understand how in utero bisphenol A (BPA) exposure affects fetal gonadal development and reproduction in mice. In utero exposure to estrogenic endocrine disruptors such as diethylstilbestrol (DES) is known to cause sex organ malformation, reproductive carcinogenesis, and fertility defects in both male and female humans and rodents. Based on DES studies, it was proposed that in utero exposure to other endocrine disruptors, particularly those that work through estrogen receptors, may lead to reproductive diseases in adulthood. BPA exhibits estrogenic activities and deleterious effects on reproduction when given to adult rodents. BPA is detected in the serum of pregnant women, umbilical cord blood and fetal plasma, indicating that developing fetuses are exposed to BPA. Although effects of BPA on adult reproductive organs have been studied extensively, impacts of in utero BPA exposure on fetal gonadal development are not well understood. The main goal of this Research Project is to test the hypothesis that in utero exposure to BPA causes gonadal defects via ERs. The two specific aims are to (1) investigate whether loss of ERα or β in fetal gonads renders embryos insensitive to deleterious effects of BPA, and (2) study whether overexpression of ER increases the susceptibility of embryos to deterious effects of BPA. The proposed experiments take advantage of the power of transgenic mouse models in combination of classic toxicological approaches.
 
Key Findings: Experiments to test the hypothesis that overexpression of ERa increases the susceptibility of pups to in utero exposure to BPA were conducted. The time period for exposure coincided with sex determination and covered subsequent testis cord organization and expansion in males and ovarian formation in females. The data suggest that ERα overexpressors may be more sensitive than control mice to BPA-induced changes in pup weight, anogenital distance and spleen weight. The data also suggest that BPA may inhibit apoptosis of germ cells and primordial follicles in ovaries from control mice, but not in ovaries from ERα-overexpressing mice. Preliminary histological evaluations indicate that BPA may inhibit testis cord formation in control mice. However, evaluation of testis cord formation in ERα overexpressors has not been completed yet, so it remains unknown whether BPA causes different effects in the male gonads of control and ERα-overexpressing mice.
 
We also conducted in vitro experiments to examine the direct effects of BPA on the ovary. Few studies have investigated the effects of BPA on antral follicles, the main producers of sex steroid hormones and the only follicles capable of ovulation. The results indicate that BPA (440 µM) inhibits follicle growth and that pregnenolone co-treatment is unable to restore/maintain growth. BPA 44 µM and 440 µM inhibit progesterone, dehydroepiandrosterone, androstenedione, estrone, testosterone and estradiol production. Pregnenolone co-treatment was able to increase production of pregnenolone, progesterone and dehydroepiandrosterone and maintain androstenedione and estrone levels in BPA-treated follicles compared to DMSO controls, but was unable to protect testosterone or estradiol levels. Collectively, these data show that BPA targets the estradiol biosynthesis pathway in the ovary.
 
R834593C004-—Neural Development and Function
 
Description: Besides the potential consequences for reproductive functions, cognitive neural functions, which are also influenced by gonadal hormones, may be altered by endocrine disruptors, including BPA. This pilot project models the effects of BPA in hooded rats, an animal model where sex differences in the cerebral cortex have been documented and are known to be influenced by the hormonal milieu during both the perinatal and peripubertal period. The effects of BPA on neuron number, a very basic building block of function, will be explored in two cortical areas: the visual cortex and the medial prefrontal cortex, where sex differences have been found. The number of neurons in each cortical area will be quantified with stereological methods. Rats exposed to BPA either perinatally or peripubertally will be evaluated. In addition to their established sex differences in neuron number, the cortical regions we are examining play a role in behaviors analogous to those that are being assessed in human infants and adolescents in Projects 1 and 2. Thus, the behavioral consequences of cortical alterations also will be investigated in a visual spatial task, the radial arm maze, which consistently shows sex differences in several laboratories. Within animal comparisons between behavioral performance and neuron number will be made.

Progress and Key Findings: In the perinatal exposure groups, maternal behavior was monitored for the first 15 postnatal days. Some doses of BPA were found to increase maternal licking over controls. The group exposed to 40 µg/kg/day had more significantly more licking than controls, and the 4 µg/kg/day group also showed a trend toward more licking. The group exposed to 400 µg/kg/day did not exhibit more licking. No other behavioral category was affected by BPA in these dams. In some dose groups, the weights of perinatally BPA-exposed rats were increased both at weaning and in young adulthood, especially in females. Cognitive data from the perinatally BPA-exposed groups are currently undergoing statistical analysis, and brains have been harvested cut and stained for cell counting. The adolescent exposure studies are also underway.


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)
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  • Full-text: Biology of Reproduction-Full Text HTML
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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)
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    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)
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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)
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    R835436 (2014)
    R835436 (2015)
    R835436 (2017)
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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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  • Supplemental Keywords:

    Health effects, sensitive populations, genetic polymorphisms, epidemiology

    Progress and Final Reports:

    Original Abstract
  • 2011 Progress Report
  • 2012 Progress Report
  • Final 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