2012 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 , 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, 2012 through February 14,2013
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:

Project 1: Prenatal Exposure to Phthalates/BPA: Infant Physical and Behavioral Development

Project 1 was undertaken to develop 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 and young infants that are sensitive to prenatal chemical exposure and predictive of lasting cognitive deficits. To complete the proposed work, a cohort of pregnant women was 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 11 phthalate metabolites at 16-18 and 35-37 weeks of gestation. Key physical and cognitive outcomes are being assessed in the infants at birth, 4-5, 7-8 and 10-11 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 physical and neurodevelopmental 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 follow-up of the children from birth through puberty.

Project 2: Adolescent Exposure to Bisphenol A/Phthalates: Cognitive & Behavioral Development

The aim of this pilot project is to assess the relation of adolescent phthalate and bisphenol A (BPA) exposure with adolescent neurobehavior. The proposal builds on an ongoing study designed to assess the relation of early life organochlorine and metal exposures with subsequent development among 788 children followed since birth. Children participating in the parent study were born to mothers residing in towns adjacent to a Superfund site, the New Bedford Harbor, in New Bedford, MA. This pilot study takes advantage of the parent study's established infrastructure and rich data to address the following primary hypothesis: Adolescent exposure to phthalates and BPA (assessed as urine metabolite concentrations) are each independently associated with adolescent visual motor abilities, verbal abilities, working memory, and attention deficit hyperactivity disorder (ADHD)-related behaviors and psychiatric symptoms. As a secondary hypothesis, we will address the potential for phthalate or BPA associations with adolescent behavior and cognitive function to differ between boys and girls or by pubertal status.

Project 3: Mechanisms of In Utero BPA Exposure on Fetal Gonad Development

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 to investigate whether: 1) loss of ERα renders developing gonads insensitive to deleterious effects of BPA and 2) overexpression of ERα increases the susceptibility of embryos to BPA.

Project 4: Effects of Bisphenol A on the Developing Cortex

Cognitive neural functions are influenced by gonadal hormones and may be altered by endocrine disruptors including BPA. This pilot project models the effects of bisphenol A 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, is being explored in the medial prefrontal cortex, where sex differences have been found. The number of neurons are being quantified with stereological methods. Rats exposed to BPA either perinatally or peripubertally are being evaluated. In addition to its established sex differences in neuron number, the medial prefrontal cortex plays 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 are being investigated in a visual spatial task, the radial arm maze, which consistently shows sex differences in several laboratories. Four doses of BPA (0, 4, 40 or 400 µg/kg/day) are fed to male and female rats during early development (prenatally to dams and 10 days postnatally) or during adolescence (days 27-46). Both cognitive behavior (17-arm radial maze) and cortical neuron number are quantified when the animals are adults (>90 days). An addendum onto the original design is that observations of maternal behavior over the first 15 postnatal days has been added to the early development experiment.

Progress Summary:

Project 1: Prenatal Exposure to Phthalates/BPA: Infant Physical and Behavioral Development

Recruitment for the study was completed in April 2013. A total of 188 pregnant women were enrolled between 16-18 weeks of gestation, exceeding our goal of 180 women. Eligible women were 18-40 years of age, fluent in English, not carrying multiples, and not taking prescription medication for a chronic condition; planned to stay in the hospital for 48 hrs after delivery and resided within a 45 mi radius of the clinic; and planned to stay in the area for at least 1 year after birth. Maternal first morning urine samples were collected at 16-18 and 35-37 weeks for analysis of phthalates and BPA. All participants had given birth as of October 31, 2012. During pregnancy 3 women withdrew from the study and 14 women became ineligible because they developed a chronic health condition, moved out of the area or changed to a non-participating obstetrical clinic. At birth, 13 mother-infant pairs became ineligible because of premature birth or because the infant was admitted to the neonatal intensive care unit. One mother did not notify us of her birth. A total of 157 healthy full-term infants were assessed at birth, exceeding our original target of 150 infants. Physical measures assessed at birth included birth weight, body length, head circumference, anogenital distance (AGD) and second to fourth finger ratio. Visual attention and visual recognition memory also were assessed. A total of 143 of the 157 infants (91%) were successfully followed up at 4-5 months of age. Assessments included physical measures as well as a sexually dimorphic cognitive task that assessed the infant’s ability to reason about the physical relationships between objects. The 4-5 month assessments were completed in March 2013. At this time, follow-up assessments of physical and cognitive development at 7-8 months and 10-11 months still are underway. Currently, 117 infants have completed the 7-8 month assessment and 100 infants have completed the 10-11 month assessment.

Preliminary analysis of demographic data conducted in June 2012, showed that the sample is mostly middle class, Caucasian and well-educated. Two first morning urines collected from the first 69 women in the cohort at 16-18 and 35-37 weeks of gestation were analyzed for BPA and 11 phthalate metabolites at the CDC Division of Laboratory Sciences. BPA was detectable in 94% of samples and phthalate metabolites (except MEHP) were present in 99-100%. The creatinine corrected concentrations of total BPA and metabolites from the two most prevalent phthalates (DEP and DEHP) were: BPA 1.91 ng/mg Cr, MEP 42.4 ng/mg, MEHP 1.94 ng/mg, MECPP 17.02 ng/mg, MEHHP 10.24 ng/mg, and MEOHP 7.87 ng/mg.

In preliminary analyses of outcome data, birth weight, body length, and head circumference were not associated with either BPA or phthalate exposure. However, both phthalates and BPA were associated with AGD. The phthalate effect was consistent with previous human and rodent studies. Boys with higher exposure to anti-androgenic phthalates had shorter AGD. In contrast, girls with higher BPA exposure had longer AGD.

A visual attention task administered to newborns was modeled after a task used in a longitudinal study showing that information processing speed at birth correlated with intelligence test scores in childhood and adolescence. Infants were shown two black and white checkerboards on a computer screen and we assessed whether they were attending to and processing information about the stimuli including the number of looks per minute (fixations) and the shift rate (number of shifts in gaze between the two boards). A higher number of fixations indicated that infants were less attentive (looking away more frequently). A higher shift rate indicated that infants were attending to and comparing the stimuli. Phthalates and BPA were associated with lower shift rates and higher fixation, respectively, indicating that more highly exposed infants were less attentive.

A visual recognition memory task was administered at 7 months. Infants were familiarized to two identical faces, and then saw the familiar face paired with a novel one. In models adjusted for multiple covariates including maternal IQ, phthalate exposure was negatively associated with novelty preference although the association was not significant in this small sample. This finding, together with the association of phthalate exposure with shift rate at birth suggests that prenatal phthalate exposure may be associated with deficits in basic cognitive abilities including attention and working memory.

These preliminary analyses suggest that several of physical and cognitive measures we assessed in this cohort are sensitive to prenatal phthalate and/or BPA exposure. However, it will be very important to assess the reproducibility of these initial findings in the full cohort using comprehensive multivariable models before any firm conclusions are drawn.

Project 2: Adolescent Exposure to Bisphenol A/Phthalates: Cognitive & Behavioral Development

A key component of this pilot is collection of urine samples from the New Bedford Birth Cohort (NBC) participants at the time of an extensive neurodevelopmental assessment, with the latter conducted via an ongoing NIEHS funded R01 (ES014864; PI: Korrick). To date, 146 (82% of R01 exams since this P20 Formative Children's Center recruitment began) have participated in the urine collection with mean age of 16 years. The NBC is a sociodemographically diverse population with approximately 25% of mothers and almost 35% of children of non-white or Latino ethnicity, most parents with a high school education or less, and a substantial proportion of unmarried mothers (45%) and low income households (38%).

The CDC laboratory measured urine total BPA and 11 phthalate metabolites in the first 50 adolescents assessed using a random urine sample collected in our study clinic (at the time of neurobehavioral testing) and a second sample collected about 1 week later at a study home visit. BPA was detectable in 98% of clinic and 94% of home urine samples; and, except for MEHP, phthalate metabolites were detected in 100% of urine samples. For a more stable measure (given variability in these biomarkers over time), we used the average of the two urine levels (corrected for specific gravity) to estimate exposure. The median (range) of urine BPA and antiandrogenic phthalate metabolite levels were 4.2 (1.0-32.2) ng/mL and 0.7 (0.1-2.0) µmol/L, respectively.

For cognitive outcomes, there were suggestive (but not statistically significant) associations of higher urine BPA with poorer visual spatial and verbal memory skills as well as poorer reading and math achievement with girls showing generally greater BPA-associated decrements on cognitive measures than boys. Urine levels of anti-androgenic phthalates were not associated with cognitive measures in this preliminary analysis. For adolescent behavior measures, both higher urine anti-androgen phthalates and BPA were associated with greater teacher-reported ADHD-like behavior. In addition, antiandrogenic phthalates were associated with increased risk of other adverse behaviors such as social difficulties.

Differences in effect by sex were not seen for these behavioral measures. Because of small numbers in this pilot study (by design), analyses were adjusted for a limited number of potential confounders and confidence limits were wide so it is not yet possible to make definitive conclusions.

Project 3: Mechanisms of In Utero BPA Exposure on Fetal Gonad Development

Before we could properly design experiments to determine if maternal BPA exposure exerts its toxicity through ER pathways in gonads of offspring, we needed to determine whether maternal exposure to BPA affects testis or ovarian development in mice. Pregnant CD-1 dams were orally dosed with tocopherol-stripped corn oil (vehicle) or BPA from E10.5-E17.5. This time period covers sex determination, testis cord organization/expansion and ovarian formation. Pups were collected via Caesarean section at E19.0, shortly before birth. All pups were counted, weighed, and subjected to measurements of anogenital distance (AGD). The gonads were subjected to histological evaluations.

In utero exposure to BPA did not alter litter size or AGD compared to controls. Histological analysis revealed abnormal testis morphology in 80% of testes exposed to 0.5 µg/kg/day of BPA and 50% of testes in the 50 g/kg/day BPA treatment groups. Dysgenic BPA-exposed testes contained fewer testis cord cross-sections and increased interstitial area compared to vehicle controls. Underdevelopment of the testis cords was particularly evident near the rete testes, where uncoiled lengths of testis cord appeared as finger-like projections. Collectively, these 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.

Ovaries from BPA-exposed mice were less cellular with more dense and congested vascularization than ovaries from vehicle exposed mice. The percentage of abnormal primordial follicles in the BPA exposed ovaries was significantly increased compared to the vehicle control (vehicle control = 16.19 ± 1.99 %; BPA 0.5 µg/kg/day = 36 ± 3.36%; BPA 50 µg/kg/day = 27.55 ± 1.65%, n=3, p<0.05). Collectively, these data indicate that prenatal BPA exposure reduces healthy primordial follicle numbers.

Next, we examined whether neonatal BPA exposure alters the developing ovary. This was important to do because the mouse ovary continues to form primordial follicles during the early neonatal period (PND1-8). Neonatal ovaries were collected, individually cultured in media ± dimethylsulfoxide (DMSO; vehicle) or BPA at 0.01-10 µg/ml for 8 days, and morphologically examined. This system best allows us to test the direct effects of BPA on two critical processes in ovarian development: germ cell nest breakdown and primordial follicle formation. Ovaries treated with BPA (1-10 µg/ml) had more germ cells in nests, and fewer primordial and primary follicles compared to control. This suggests that neonatal BPA exposure interferes with germ cell nest breakdown and inhibits primordial follicle assembly.

We also used a validated follicle culture system to test whether BPA exposure directly causes toxicity to adolescent ovarian follicles. Antral follicles (10-15 follicles/ovary) from adolescent ovaries were cultured in media containing DMSO or BPA for 96-120 hours. Every 24 hours, we measured follicular growth. After 96-120 hours, follicles were processed for histological evaluation of atresia and media were collected for measurements of sex steroid hormones. Antral follicles treated with vehicle remained viable and grew for the entire culture period. Antral follicles treated with BPA (100 µg/ml) did not grow, and instead had an increased incidence of atresia, suggesting that BPA inhibits growth and induces atresia of adolescent antral follicles. BPA (10-100 µg/ml) inhibited 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. Further, pregnenolone was unable to protect follicles from BPA induced inhibition of steroidogenic enzymes compared to the DMSO control. Collectively, these data show that BPA targets the estradiol biosynthesis pathway in the ovary.

To determine whether loss of ERα renders gonads insensitive to BPA during adolescence, we co-treated adolescent antral follicles with BPA and estradiol (E2) to examine if E2 binding to ERs blocks BPA-induced growth inhibition. Exposure to BPA (100 µg/ml) decreased follicle growth compared to DMSO and E2 controls. E2 co-treatment did not protect antral follicles from BPA-induced inhibition of growth. Further, we pre-treated antral follicles with the ER antagonist ICI to examine if ICI blocks BPA-induced growth inhibition. Exposure to BPA (100 µg/ml) decreased follicle growth compared to DMSO and ICI controls. Pre-treatment with ICI did not protect antral follicles from BPA-induced inhibition of growth. These data suggest that BPA may not exert toxicity in ovaries through ER pathways.

We then tested the hypothesis that ERα overexpression increases the susceptibility of pups to BPA. Pregnant control and ER overexpressing dams were orally dosed with tocopherol-stripped corn oil (vehicle) or BPA from E10.5 to birth. On PND 0, pup weight was decreased in the pups from BPA 0.5 µg/kg/day treated ER overexpressing dams compared to BPA 0.5 µg/kg/day treated control dams. AGDs of males from BPA 50 µg/kg/day treated ERα overexpressing dams were smaller than pups from BPA 50 µg/kg/day treated control dams. In female pups from control mice, BPA 50 µg/kg/day significantly increased the numbers of dying germ cells compared to vehicle controls. In female pups from ERα overexpressing dams, BPA did not affect germ cells and primordial follicles compared to vehicle. BPA did not alter testes cord formation in pups from ERα overexpressing dams. These data suggest that ERα overexpressors may be more sensitive than control mice to BPA-induced changes in pup weight and AGD, but not in gonadal parameters.

To further determine if ERα overexpression makes the ovary more sensitive to BPA, we treated ERα overexpressing and control antral follicles from adolescent mice with vehicle or BPA. BPA (100 µg/ml) decreased follicle growth compared to DMSO in control and ERα overexpressing follicles from 72-120 hrs. BPA (1-10 µg/ml) did not affect growth in either control or ERα overexpressing follicles. Collectively, these data suggest that overexpression of ERα does not render antral follicles more sensitive to BPA than controls.

Project 4: Effects of Bisphenol A on the Developing Cortex

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 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.

The 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. No effects were found in exposed female rats. There is a report of an increase in the number of neurons in the prefrontal cortex of male children with autism (Courchesne, et al., 2011), which may indicate that prenatal exposure to BPA is a predisposing factor for this syndrome.

The results from the radial maze, on the other hand, revealed only minor impairments late in training in male rats exposed to the 40 µg/kg/day dose of BPA. Female performance was not significantly affected. It appears that this cognitive task does not reflect the effects of BPA on the number of neurons. Given the nature of the neural results, more emotional/social tasks might yield effects of pre/perinatal exposure. The experiments examining exposure to BPA during the pubertal period are underway. Preliminary results from the radial arm maze indicate only modest effects of BPA exposure. The neural quantification has just been started and there are no results to report at this time.

Future Activities:

Project 1: Prenatal Exposure to Phthalates/BPA: Infant Physical and Behavioral Development

Planned activities include completion of all 7-8 and 10-11 month follow-up assessments of the infants. The 7-8 month assessments will be completed by June 30, 2013. The 10-11 month assessments will be completed by September 30, 2013. Additional goals are to complete data entry and data coding, including the abstraction of health data from medical records for the mothers during pregnancy and the infants during the first year. As data collection, entry and coding are completed, the focus will shift to data analysis and manuscript preparation.

Project 2: Adolescent Exposure to Bisphenol A/Phthalates: Cognitive & Behavioral Development

In the next funding period (no-cost extension), we will complete urine (and urine questionnaire) collection on ~200 of the New Bedford Cohort children. Urines will be processed and stored, and questionnaire data entered and cleaned to complete our pilot work. Once this pilot data collection is complete, we anticipate doing analyses of the full cohort in a larger scale study, funding for which currently is pending. In this planned full study, we will use comprehensive multivariable models to account for potential confounding and to assess reproducibility of our initial pilot findings.

Project 3: Mechanisms of In Utero BPA Exposure on Fetal Gonad Development

During the next funding period, we plan to follow-up on studies conducted during this funding period. Specifically, we plan to conduct experiments designed to help determine why BPA exerts different effects on the ovaries from ERα overexpressing and control mice. Such experiments will include comparing the effects of BPA on the expression of key genes involved in ovarian development and function in ERα overexpressing and control mice. Further, we plan to examine the effects of BPA on the gonads at additional time points. During the current funding period, we only examined gonads at birth so we plan to conduct dosing experiments in which we collect and examine gonads at embryonic time points as well as additional post-natal time points. Also, we plan to further analyze the testes and diethylstilbestrol (DES)-treated tissues collected during the experiment conducted during this funding period. Specifically, we will determine if BPA affects testes development in both control and ERα overexpressing mice. We also will examine the effects of DES on the developing gonads. Further, we plan to follow up on our findings that BPA inhibits steroidogenesis in the ovary. Such experiments will be designed to determine how BPA inhibits steroidogenesis in vitro and to determine whether it has similar effects in vivo.

Project 4: Effects of Bisphenol A on the Developing Cortex

The final cohort of rats that were exposed to BPA during puberty will be run on the radial arm maze in adulthood. Their brains then will be harvested, and the stereological analysis of the number of neurons and glia in the prefrontal cortex will occur in this cohort as well as in the previous cohorts. A graduate student, Leslie Wise, has been trained to perform this analysis but she has not yet begun to gather data. Given prior work from our laboratory that ovarian hormones decrease the number of neurons in the prefrontal cortex, the estrogenic properties of BPA should alter the final number of neurons in this area.


Journal Articles: 7 Displayed | Download in RIS Format

Other center views: All 35 publications 7 publications in selected types All 7 journal articles
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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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  • 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)
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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)
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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)
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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:

    BPA, phthalates, child development, cognition, sex differences, adolescent health, children's health, behavior, ovary, testis, gonads, estrogen receptors, perinatal, adolescence, neuron number, prefrontal cortex

    Relevant Websites:

    Children's Environmental Health Research Center at Illinois Exit

    Progress and Final Reports:

    Original Abstract
  • 2010 Progress Report
  • 2011 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