2013 Progress Report: Novel Methods to Assess the Effects of Chemicals on Child Development

EPA Grant Number: R835434
Center: Novel Methods to Assess the Effects of Chemicals on Child Development
Center Director: Schantz, Susan L.
Title: Novel Methods to Assess the Effects of Chemicals on Child Development
Investigators: Schantz, Susan L. , Korrick, Susan A. , Fiese, Barbara , Juraska, Janice , Flaws, Jodi
Current Investigators: Schantz, Susan L.
Institution: University of Illinois at Urbana-Champaign
EPA Project Officer: Nolt-Helms, Cynthia
Project Period: June 1, 2013 through May 31, 2018 (Extended to May 31, 2019)
Project Period Covered by this Report: June 1, 2013 through May 31,2014
Project Amount: $3,962,727
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2012) RFA Text |  Recipients Lists
Research Category: Children's Health , Health

Objective:

R835434C001: Joint Effects of Endocrine Disruptors, Diet and Body Mass Index (BMI) on Child Development
 
The major goals of this project are to: (1) assess sources of exposure to phthalates, bisphenol A (BPA) and other endocrine-disrupting chemicals (EDCs) during prenatal and adolescent periods; (2) examine the association of prenatal or adolescent exposure to phthalates, BPA and other EDCs (and interactions among these exposures) with physical, behavioral and cognitive development in infants and adolescents (we hypothesize that associations of exposure with these outcomes will vary by child sex); (3) assess the potential for a high-fat diet/obesity during two critical periods——prenatal or adolescent——to interact with chemical exposure to influence physical, behavioral and cognitive development; and (4) investigate the association of prenatal exposure to phthalates, BPA and other EDCs with markers of oxidative stress or inflammation in maternal and cord blood.
 
R835434C002: Endocrine-Disrupting Chemicals, Diet and Gonadal Toxicity
 
The proposed studies were designed to test the hypothesis that BPA, phthalates and high-fat diet exposure interact to increase oxidative stress in developing adolescent gonads, leading to infertility, early reproductive senescence and transgenerational effects on fertility in the offspring. To test this hypothesis, the following specific aims will be completed: (1) determine if high-fat diet and BPA/phthalate/phthalate mixture exposure increase oxidative stress in the gonads of female and male mice; (2) determine if high-fat diet and BPA/phthalate/phthalate mixture exposure destroy germ cells and cause epigenetic changes known to reduce germ cell quality in the gonads of female and male mice; and (3) determine if high-fat diet and BPA/phthalate/phthalate mixture exposure cause infertility and early reproductive senescence in the first and subsequent generations in mice.
 
R835434C003: Endocrine Disruptors and Diet — Effects on the Developing Cortex
 
Endocrine disruptors are ubiquitous in the environment as are high-fat diets, and both of these environmental factors could disturb the normal development of the nervous system during early development and during adolescence. This will be directly examined in a rodent model so that the cellular and molecular mechanisms of the effects can be elucidated.
 
The environmental disruptors that are being separately investigated are bisphenol A (BPA) and a phthalate mixture in the presence of either a high- or low-fat diet. The disruptor and diet are imposed at two developmental time points——perinatally and during adolescence——in separate experiments. Endpoints include inflammation markers at the end of exposure and social and cognitive behaviors in adulthood.
 
Community Outreach and Translation Core
 
Aim 1: Develop a strong Community Outreach and Translation Core (COTC) that is informed by the Community Advisory Board (CAB) and Dr. Susan Korrick, the Center'’s Pediatric Health Specialist who works bidirectionally with the principal investigators (PIs) of the Center. The CAB and PIs will work together in an iterative manner using feedback from stakeholders in developing dissemination materials.
 
Aim 2: Through stakeholder partnerships formed in the CAB, disseminate emerging knowledge about the effects of chemical exposure and high-fat diets during the prenatal period on the developing young child, as well as during adolescence.
 
Year 1 was a planning year. We formed the CAB, held our first CAB meetings, and developed the first video public service announcement (PSA). Institutional Review Board (IRB) approval for surveys and interviews with early care providers is secured.

Progress Summary:

R835434C001: Joint Effects of Endocrine Disruptors, Diet and Body Mass Index (BMI) on Child Development

For the prospective birth cohort component of this project, the first reporting period has been devoted to three activities: (1) preparation for and launching of the new recruitment phase; (2) collection of data from 2-year-old children recruited during the initial P20 pilot phase of the study; and (3) analysis of remaining urine samples from women recruited during the pilot phase for BPA, phthalates and other EDCs. We initiated recruiting on a limited, pilot basis at one of the participating clinics in December 2013, and began full recruitment efforts at both clinics in February 2014. Participant contacts to collect 2-year follow-up data from the 134 children from the pilot phase still actively enrolled in the study started in November 2013. As of August 20, 2014, 104 women were enrolled, with 3 of these dropped due to loss of the pregnancy or a change in provider. A total of 6 women withdrew from the study, and currently, 95 women are active in the study. Fourteen babies have been born thus far. 

Based on data from a repeated sampling study we conducted as a supplement to our Formative (P20) Children’s Center and advice from Antonia Calafat at the Centers for Disease Control and Prevention (CDC) exposure assessment laboratory, we modified our strategy for assessing prenatal exposure to BPA, phthalates and other EDCs to include analysis of pooled urine samples. These pooled samples will consist of first morning urine from five different collections across pregnancy. The pilot study looked at the consistency of exposure to BPA and phthalates across pregnancy. A sample of 19 women collected 6 first morning urine samples across the second and third trimesters of pregnancy. Our findings confirmed that there is little consistency in exposure within women over time. Thus, an individual sample collected at a particular time point is not a good indicator of overall exposure across pregnancy. The analyses of pooled samples will allow us to have a measure of average exposure across pregnancy. We also will analyze an individual sample collected at 16-18 weeks of pregnancy because we have specific hypotheses about exposure during this critical window. The CDC has agreed to analyze pooled samples from the women recruited during the earlier pilot phase as well as those currently being recruited in the main study, so we will have pooled exposure data from all participating women.

With regard to the 2-year follow-ups of children enrolled in the pilot phase, 52 assessments have been completed as of August 20, 2014, and mothers continue to be contacted as their children approach 2 years of age. As of August 20, 2014, only two women have refused to participate in the 2-year follow-up, and seven women could not be contacted. These assessments will continue until approximately April 1, 2015.
 
For the adolescent component of this project, the first reporting period has been devoted to completion of data collection. We have leveraged data from an ongoing prospective birth cohort, the New Bedford Cohort (NBC), in combination with work performed as part of our previous Children's Formative Center. For the current project, a key component of this leveraged work was collection of urine samples (for EDC exposure measurements) on 200 NBC adolescents. In this first year of the project, we successfully completed adolescent urine sample collection in February 2014, and now have samples on 205 NBC participants in keeping with our project goal of 200 urine samples. Eight-one percent of adolescents examined during the data collection provided at least one urine sample and 144 (70%) of these provided two urine samples, collected approximately 1 week apart. As part of the parent study assessments, we have completed prospectively collected neurobehavioral assessments and home assessments; and collected height, weight, diet, medical, demographic, lifestyle and exposure information on these 205 children, all of which are key data for this project's analyses.

R835434C002: Endocrine-Disrupting Chemicals, Diet and Gonadal Toxicity

During the previous funding period, we began work described in Specific Aims 1 and 3. Specifically, we began work to test the hypothesis that prenatal exposure to BPA reduces germ cell numbers and causes infertility and early reproductive senescence in the first and subsequent generations in mice. Our data show that all selected doses of BPA cause significantly more germ cells to remain in nests and fewer primordial follicles to form compared to control ovaries. Because germ cell nest breakdown is a natural apoptotic process that is driven by the drop in estrogen levels around birth, we next compared the expression of apoptotic factors in control and BPA-treated ovaries. Our results indicate that the lowest dose of BPA (0.5 μg/kg/day) decreases the expression of pro-apoptotic factor, Bax. Further, the middle dose of BPA (20 μg/kg/day) increases the expression of anti-apoptotic factor, Bcl2l1, whereas it decreases the expression of pro-apoptotic factors, Bax and Bak1. The highest dose of BPA (50 μg/kg/day) increases the expression of anti-apoptotic factors, Bcl2 and Bcl2l1, but decreases the expression of pro-apoptotic factor, Bak1. BPA also decreases the expression of selected factors in tumor necrosis factor signaling pathways. Specifically, BPA 0.5 μg/kg/day and BPA 50 μg/kg/day decreases the expression of Tnfrsf11b, Tnfrsf1a, Tnfsf12 and Ltbr. BPA 20 μg/kg/day also decreases the expression of Tnfrsf11b.

BPA did not significantly change the age of vaginal opening compared to the control group. The age of the first estrus in DES 0.05 μg/kg/day treated females, however, was significantly advanced. Compared to controls, the time span between vaginal opening and the first estrus observed was significantly shorter in DES and BPA 50 μg/kg/day treatment groups compared to controls. Further, females in the BPA 0.5 μg/kg/day treatment group spent less time in proestrus and estrus but more time in metestrus and diestrus compared to controls. Animals in the DES 0.05 μg/kg/day treatment group had significantly shortened proestrus but extended metestrus compared to controls. BPA 20 μg/kg/day caused the females to have shortened estrus compared to controls.

BPA 50 μg/kg/day reduced the litter size at 6 months of age. In the BPA 0.5 μg/kg/day treatment group, only 1 out of 5 females gave birth at 9 months, but all the pups were stillborn. BPA 0.5 μg/kg/day increased the percentage of dead pups at 3 months of age, and no live pups were born at 9 months of age. Also, BPA decreased fertility at all selected levels, and the fertility decline became more severe with age, especially for the BPA 0.5 μg/kg/day treatment group compared to controls.
 
Dams from the F2 generation then were assessed for several reproductive parameters at two breeding cycles that were initiated at the ages of 3 and 6 months. The results indicate that compared to vehicle control, 20 μg/kg/day BPA significantly increased the percent of dead pups as F2 dams aged (3 months 1.9 ± 1.2 vs. 6 months 29.5 ± 8; n ≥ 3, p = 0.02). Further, 0.5 and 50 μg/kg/day BPA resulted in a trend towards an increased percent of dead pups (0.5 μg/kg/day BPA: 3 months 3.5 ± 2.1 vs. 6 months 17.8 ± 7.6; 50 μg/kg/day BPA: 3 months 1.4 ± 0.1 vs. 6 months 35.0 ± 11.5; n ≥ 3, p < 0.1). Moreover, 0.5 μg/kg/day BPA significantly increased average pup weight at 6 months compared to controls (1.4 ± 0.03 vs. 1.6 ± 0.03, respectively; n ≥ 3, p = 0.04).
 
We also examined whether the prenatal exposure of the F1 females to BPA impacted the F2 males. The results indicate that for body weights as well as testis-to-body weight ratios, the F1 and F2 males were not different among the treatment groups, but the testis-to-body weight ratio of the BPA-50 μg/kg/day males was significantly higher than those of DES, BPA-0.5 μg/kg/day and BPA-20 μg/kg/day males (p < 0.005). We currently are conducting testicular histological evaluations to expand these findings.
 
During the previous funding period, we also began work to examine the effects of prenatal exposure to DEHP on the developing gonads. Specifically, we tested the hypothesis that prenatal DEHP exposure (9,200 mg/kg/day) adversely affects gonad development and reproductive outcomes in the offspring of mice. The results indicate that prenatal DEHP exposure did not significantly affect the numbers of pups born in each litter or their weights at birth. Prenatal DEHP exposure also did not affect the numbers of follicles in DEHP-exposed pups compared to controls. Prenatal DEHP exposure altered estrous cyclicity so that the time spent in proestrus was significantly increased in DEHP-exposed pups compared to controls. Preliminary data also indicate that body weights, testis-to-body weight ratios, serum testosterone concentrations, and the histological appearance of the testes and epididymis were similar in control and DEHP-exposed F1 male pups. We now are performing a second stage of experiments using additional doses of DEHP (750 mg/kg/day).

R835434C003: Endocrine Disruptors and Diet — Effects on the Developing Cortex

In work from the P20 grant, we found that pre- and post-natal exposure to a dose of 400 μg/kg of BPA resulted in more neurons and glia in the adult prefrontal cortex in male, but not female, rats. The intriguing parallel with findings from autistic human males has led us to start our investigations with perinatal BPA and the high-fat diet of Aim 1. The design is large: two diet groups (high- and low-fat) x three doses of BPA (0, 40 and 400 mg/kg/day) x two sexes = 12 groups. Managing this is being accomplished with consecutive cohorts of matings that produce litters for each group so that behavioral analysis and sacrifice for neuroanatomical histology are not unwieldy. Rat dams are being fed BPA and rat pups are individually dosed for the first 10 days. Based on preliminary data from work on the preceding P20 grant, we have added observations of maternal behavior during the first 14 days of life to establish whether any effects are due to changes in maternal care. Separate rats are sacrificed at 10 days of age for inflammation markers and in adulthood for epigenetic markers. Other subjects are being run through several behavioral tests (social behavior, social recognition, anxiety, intra/extra-dimensional shifts) and then sacrificed for neural markers (neuron number, types of glia, dopamine axons, number of synapses). This work is underway and the groups will not be decoded until all of the cohorts are run.

An additional set of experiments currently is under way to follow up on results from adolescent exposure to BPA that were run as part of the P20 Exploratory Grant mechanism. Exposure to BPA during adolescence did not change the number of neurons in the medial prefrontal cortex in either sex. However, glia numbers were affected in opposite directions between the sexes with a near to significant sex by treatment interaction (p = .051). The pattern of changes were the opposite between the sexes, and post hoc comparisons between the vehicle and each dose for each sex revealed a significant increase in the number of glia between 0 and 40 μg/kg dose in females and a decrease between 0 and 4 μg/kg in males. Although not significant, this pattern was found for all doses of BPA. We currently are staining the extra sections from these brains for markers of two major types of glia in the gray matter of the cortex: astrocytes and microglia. Stereological analysis has been started to quantify the number of both of these types of glia, which are important for synaptogenesis and pruning and may indicate an effect of BPA during adolescence on the synaptic wiring of the medial prefrontal cortex. These results will be the basis for the P01 studies of adolescent exposure to BPA with a high-fat diet, which are planned for future years.

Community Outreach and Translation Core (COTC)

(a) Community Advisory Board created and convened twice. The CAB for the Illinois COTC includes leaders in early care and education, parenting, child advocacy, and public health in Illinois. In addition, a national leader in online Extension education is on the Board. Having met on two occasions during Year 1, the CAB has begun to advise on strategies and content for translating findings on everyday exposures to endocrine disruptors in food, drinks and consumer goods to practice and policy in child care, public health and parenting. CAB members represent:
  • Erikson Institute Graduate School in Child Development (Chicago, IL).
  • Extension Alliance for Better Child Care (Vancouver, WA).
  • Great Lakes Center for Children’s Environmental Health, Region 5 Pediatric Environmental Health Specialty Unit (PEHSU) (Chicago, IL).
  • Illinois Action for Children (Chicago, IL).
  • Illinois Department of Public Health, Champaign-Urbana Public Health District, Maternal and Child Health Management (Champaign-Urbana, IL).
  • Illinois Network of Child Care Resource and Referral Agencies (Bloomington, IL).
  • Just in Time Parenting (Cooperative Extension online community).
  • Southern Illinois University Child Development Laboratory (Carbondale, IL).
(b) Design and Institutional Review Board (IRB) approval of a formative research protocol. Findings of formative research will inform COTC outreach strategy to stakeholders in child care, parenting and public health (University of Illinois IRB #14497). As Year 2 of the Illinois COTC begins, a survey and series of interviews is under way with 235 child care providers across Illinois. Included in the sample are Head Start providers; teachers at child care centers; and smaller, licensed family child care providers who offer child care in their homes. The aim is to inform the development of COTC translation practices by (1) defining baseline practices related to child endocrine disruptor exposures via plastics, food, drinks, packaging, cleaning products, fragrances and personal care products; and (2) illuminating policies amenable to intervention at the state level as one step in reducing children’s risk.
 
(c) Spring 2015 Illinois COTC conference scheduled. On April 21, 2015, the Illinois COTC will copresent a 1-day conference in Springfield, Illinois, to address environmental health in child care. The primary focus will be on curtailing exposures to endocrine disruptors. The co-host will be Illinois Action for Children, the child care licensing agency for Chicago and Cook County, and preeminent statewide advocacy organization to increase access to quality child care among lower income families. The keynote speaker for the conference will be Dr. Susan Buchanan, M.D., Illinois COTC CAB member and Director, Region 5 PEHSU. Her talk will be followed by breakout sessions in which child care providers will respond to the lessons shared during the keynote.
 
(d) Deliberate outreach to fellow COTCs. To understand past and present activity, the Illinois COTC conducted a series of interviews with COTC leaders from other Children’s Environmental Health Centers whose research also focuses on endocrine disruption, child care as an everyday risk setting for infants and children, and/or medical care as a site for outreach messaging. Interviews and ongoing dialogue are with: (1) University of California-Berkeley (CERCH), (2) University of California-San Francisco; (3) Columbia University (CCCEH); (4) University of Michigan; and (5) Children’s Environmental Health Network (CEHN), whose Eco Healthy Child Care training we observed in May 2014 to inform the child care focus of the Illinois COTC.
 
(e) Completed production of pilot COTC outreach video. The headquarters for the Illinois COTC is the Family Resiliency Center of the University of Illinois Department of Human and Community Development. Monitoring of reach indicates that 48 million households have watched a series of 30-second online videos called Mealtime Minutes, produced by the Family Resiliency Center to translate an evidence base into everyday behavioral messaging. Those videos addressed strategies for creating and navigating family meals as a routine, health-promoting part of the day. Building on the success of this dissemination mechanism, the COTC produced its first outreach video to interpret EDC research for lay viewers (100% complete). The first video is a 1-minute overview introducing the topic of endocrine disruption. The next video in the series will focus on glass baby bottles as an alternative to plastic baby bottles, as discussed next.
 
Significant results, including major findings, developments or conclusions
 
(1) Glass baby bottles as a harm-reducing alternative. The Food and Drug Administration (FDA) and its Canadian and European counterparts have ended the authorized use of bisphenol A in baby bottles, sippy cups and infant formula cans. Still, a few factors lead the Illinois COTC to consider placing one outreach focus on glass baby bottles as a safer alternative to plastic. These factors are:
  • The uncertain safety of BPA “replacers” in BPA-free plastic vessels (Bergman, Heindel, Jobling, Kidd, & Toeller, 2013).
  • Research conducted before the FDA policy change found all other sources of BPA to present far lower risk than baby bottles, when measured relative to body weight (von Goetz, Wormuth, Scheringer, & Hungerbühler, 2010).
  • At prices comparable to plastic bottles, glass baby bottles now come in models resistant to breakage — lined, for example, with a silicone sleeve or with a glass insert placed inside a plastic bottle.
  • A central policy inconsistency impeding risk reduction for children: Illinois state licensing standards for child care prohibit providers from using a glass baby bottle (Department of Children and Family Services, 2013).

 

Future Activities:

R835434C001: Joint Effects of Endocrine Disruptors, Diet and Body Mass Index (BMI) on Child Development

Over the coming year, we will focus on two main activities: (1) measurement of urine EDC concentrations on 155 adolescents to achieve our target of 200 adolescents with biomarkers of exposure. The first 50 already were analyzed via our Formative Children's Center; (2) preliminary data analyses will begin once urine EDC concentrations are available to address study aims.

R835434C002: Endocrine-Disrupting Chemicals, Diet and Gonadal Toxicity

During the next funding period, we will continue histological evaluation of the gonads obtained from the F1-F3 generations of mice. During the previous funding period, we mainly focused on postnatal day (PND) 4-8 gonads, but we will expand our analysis to examine PND 21-PND 60 gonads. Further, we will examine the effects of prenatal BPA exposure on the female fertility of the F3 generation of mice obtained from the breeding study described above. We also will conduct studies to examine male fertility in the F1-F3 generations. Also, we will conduct studies to further determine the effects of DEHP on the developing gonads and fertility of mice. In the studies described above, we used only a single dose of DEHP. During the next funding period, we will use additional doses of DEHP in the experiments. Finally, we will begin studies to assess the effects of the phthalate mixture on the gonads.

R835434C003: Endocrine Disruptors and Diet — Effects on the Developing Cortex

The major objectives for the next year are to finish the cohorts for the perinatal BPA exposure described above and to start the study of perinatal phthalate plus high-fat diet exposure.

Community Outreach and Translation Core (COTC):

Year 2 Goals include:

(1) Continued CAB Meetings to Assist in Developing Dissemination Materials
(2) Presenting Overview of Materials at Early Childhood Conference
(3) Developing Materials for Website
 
Goal 1: We are off to a good start with our CAB. They appear very invested in the COTC and eager to support the project. They will work with us to identify suitable conferences to present information on endocrine disruptors.
 
Goal 2: In collaboration with the CAB, we will identify an early childhood conference to present an overview of endocrine disruptors and early childhood. This outreach will add to the conference the COTC itself will present with Illinois Action for Children in April 2015. We will focus on actionable steps that child care providers can take to reduce exposure in child care settings. The development of our PSAs will facilitate presentation of materials at conferences that are easily accessible to a wide audience of early care and education providers.
 
Goal 3: After completing our surveys and interviews, we will develop materials for the website. The website will provide information for child care providers and potentially, parents on reducing environmental exposures. Drawing from the expertise on our CAB, we will use an age-paced approach so recommendations are matched to different ages (e.g., bottles, diapers, clothing).


Journal Articles: 42 Displayed | Download in RIS Format

Other center views: All 80 publications 42 publications in selected types All 42 journal articles
Type Citation Sub Project Document Sources
Journal Article Barakat R, Lin P-CP, Rattan S, Brehm ES, Canisso IF, Abosalum ME, Flaws JA, Hess R, Ko C. Prenatal exposure to DEHP induces premature reproductive senescence in male mice. Toxicological Sciences 2017;156(1):96-108. R835434 (2016)
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  • Journal Article Berger A, Ziv-Gal A, Cudiamat J, Wang W, Zhou C, Flaws JA. The effects of in utero bisphenol A exposure on the ovaries in multiple generations of mice. Reproductive Toxicology 2016;60:39-52. R835434 (2015)
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  • Journal Article Brehm E, Rattan S, Gao L, Flaws JA. Prenatal exposure to di(2-ethylhexyl) phthalate causes long-term transgenerational effects on female reproduction in mice. Endocrinology 2018;159(2):795-809. R835434 (2017)
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  • Journal Article Drobna Z, Henriksen AD, Wolstenholme JT, Montiel C, Lambeth PS, Shang S, Harris EP, Zhou C, Flaws JA, Adli M, Rissman EF. Transgenerational effects of bisphenol A on gene expression and DNA methylation of imprinted genes in brain. Endocrinology 2018;159(1):132-144. R835434 (2017)
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  • Journal Article Eckstrum KS, Edwards W, Banerjee A, Wang W, Flaws JA, Katzenellenbogen JA, Kim SH, Raetzman LT. Effects of exposure to the endocrine-disrupting chemical bisphenol A during critical windows of murine pituitary development. Endocrinology 2018;159(1):119-131. R835434 (2017)
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  • Journal Article Gal A, Lin P-C, Barger AM, MacNeill AL, Ko C. Vaginal fold histology reduces the variability introduced by vaginal exfoliative cytology in the classification of mouse estrous cycle stages. Toxicologic Pathology 2014;42(8):1212-1220. R835434 (2013)
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  • Journal Article Kougias DG, Cortes LR, Moody L, Rhoads S, Pan Y-X, Juraska JM. Effects of perinatal exposure to phthalates and a high-fat diet on maternal behavior and pup development and social play. Endocrinology 2018;159(2):1088-1105. R835434 (2017)
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  • Journal Article Kougias DG, Sellinger EP, Willing J, Juraska JM. Perinatal exposure to an environmentally relevant mixture of phthalates results in a lower number of neurons and synapses in the medial prefrontal cortex and decreased cognitive flexibility in adult male and female rats. Journal of Neuroscience 2018;38(31):6864-6872. R835434 (2017)
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  • Journal Article Li Q, Davila J, Kannan A, Flaws JA, Bagchi MK, Bagchi IC. Chronic exposure to bisphenol A affects uterine function during early pregnancy in mice. Endocrinology 2016;157(5):1764-1774. R835434 (2016)
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  • Journal Article Li Q, Lawrence CR, Nowak RA, Flaws JA, Bagchi MK, Bagchi IC. Bisphenol A and phthalates modulate peritoneal macrophage function in female mice involving SYMD2-H3K36 dimethylation. Endocrinology 2018;159(5):2216-2228. R835434 (2017)
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  • Journal Article Niermann S, Rattan S, Brehm E, Flaws JA. Prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP) affects reproductive outcomes in female mice. Reproductive Toxicology 2015;53:23-32. R835434 (2014)
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  • Journal Article Oakley OR, Kim KJ, Lin PC, Barakat R, Cacioppo JA, Li Z, Whitaker A, Chung KC, Mei W, Ko C. Estradiol synthesis in gut-associated lymphoid tissue: leukocyte regulation by a sexually monomorphic system. Endocrinology 2016;157(12):4579-4587. R835434 (2016)
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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. R835434 (2013)
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  • Journal Article Rattan S, Zhou C, Chiang C, Mahalingam S, Brehm E, Flaws JA. Exposure to endocrine disrupting chemicals during adulthood: consequences for female fertility. Journal of Endocrinology 2017;233(3):R109-R129. R835434 (2017)
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  • Journal Article Rattan S, Brehm E, Gao L, Niermann S, Flaws JA. Prenatal exposure to di(2-ethylhexyl) phthalate disrupts ovarian function in a transgenerational manner in female mice. Biology of Reproduction 2018;98(1):130-145. R835434 (2017)
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  • Journal Article Rattan S, Brehm E, Gao L, Flaws JA. Di(2-ethylhexyl) phthalate exposure during prenatal development causes adverse transgenerational effects on female fertility in mice. Toxicological Sciences 2018;163(2):420-429. R835434 (2017)
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  • Journal Article Richardson KA, Hannon PR, Johnson-Walker YJ, Myint MS, Flaws JA, Nowak RA. Di(2-ethylhexyl) phthalate (DEHP) alters proliferation and uterine gland numbers in the uteri of adult exposed mice. Reproductive Toxicology 2018;77:70-79. R835434 (2017)
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  • Journal Article Wang W, Hafner KS, Flaws JA. In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse. Toxicology and Applied Pharmacology 2014;276(2):157-164. R835434 (2013)
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  • Journal Article Wise LM, Sadowski RN, Kim T, Willing J, Juraska JM. Long-term effects of adolescent exposure to Bisphenol A on neuron and glia number in the rat prefrontal cortex: differences between the sexes and cell type. Neurotoxicology 2016;53:186-192. R835434 (2014)
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  • Journal Article Wise LM, Hernández-Saavedra D, Boas SM, Pan YX, Juraska JM. Perinatal high-fat diet and bisphenol A:effects on behavior and gene expression in the medial prefrontal cortex. Developmental Neuroscience 2018;21:1-16. R835434 (Final)
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  • Journal Article Yazdy MM, Coull BA, Gardiner JC, Aguiar A, Calafat AM, Ye X, Schantz SL, Korrick SA. A possible approach to improving the reproducibility of urinary concentrations of phthalate metabolites and phenols during pregnancy. Journal of Exposure Science & Environmental Epidemiology 2018;28(5):448-460. R835434 (2017)
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  • Journal Article Zhou C, Wang W, Peretz J, Flaws JA. Bisphenol A exposure inhibits germ cell nest breakdown by reducing apoptosis in cultured neonatal mouse ovaries. Reproductive Toxicology 2015;57:87-99. R835434 (2014)
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  • Journal Article Zhou C, Gao L, Flaws JA. Exposure to an environmentally relevant phthalate mixture causes transgenerational effects on female reproduction in mice. Endocrinology 2017;158(6):1739-1754. R835434 (2016)
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  • Journal Article Zhou C, Flaws JA. Effects of an environmentally relevant phthalate mixture on cultured mouse antral follicles. Toxicological Sciences 2017;156(1):217-229. R835434 (2016)
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  • Journal Article Zhou C, Gao L, Flaws JA. Prenatal exposure to an environmentally relevant phthalate mixture disrupts reproduction in the F1 female mice. Toxicology and Applied Pharmacology 2017;318:49-57. R835434 (2016)
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  • Journal Article Ziv-Gal A, Wang W, Zhou C, Flaws JA. The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice. Toxicology and Applied Pharmacology 2015;284(3):354-362. R835434 (2014)
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  • Journal Article Ziv-Gal A, Flaws JA. Evidence for bisphenol A-induced female infertility: a review (2007-2016). Fertility and Sterility 2016;106(4):827-856. R835434 (2016)
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  • Journal Article Barakat R, Seymore T, Lin PP, Park CJ, Ko CJ. Prenatal exposure to an environmentally relevant phthalate mixture disrupts testicular steroidogenesis in adult male mice. Environmental Research 2019; 194-201. R835434 (Final)
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  • Journal Article Barakat R, Lin PC, Park CJ, Best-Popescu C, Bakry HH, Abosalem ME, Abdelaleem NM, Flaws JA, Ko C. Prenatal Exposure to DEHP Induces Neuronal Degeneration and Neurobehavioral Abnormalities in Adult Male Mice. Toxicological Sciences 2018; 164(2):439-452. R835434 (Final)
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  • Journal Article Strakovsky RS, Schantz SL. Impacts of bisphenol A (BPA) and phthalate exposures on epigenetic outcomes in the human placenta. Environmental Epigenetics 2018;4(3):dvy022 (18 pp.). R835434 (2017)
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  • Journal Article Strakovsky RS, Schantz SL. Using experimental models to assess effects of bisphenol A (BPA) and phthalates on the placenta:challenges and perspectives. Toxicological Sciences 2018 R835434 (2017)
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  • Journal Article Brehm E, Flaws JA. Transgenerational Effects of Endocrine-Disrupting Chemicals on Male and Female Reproduction. Endocrinology 2019; 160:1421-1435. R835434 (Final)
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  • Journal Article Olson MR, Su R, Flaws JA, Fazleabas AT. Bisphenol A impairs decidualization of human uterine stromal fibroblasts. Reproductive Toxicology 2017; 73:339-344. R835434 (Final)
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  • Journal Article Strakovsky RS, Wang H, Engeseth NJ, Flaws JA, Helferich WG, Pan YX, Lezmi S. Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis. Toxicology and Applied Pharmacology 2015; 284:101-112. R835434 (Final)
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  • Journal Article Shoaff JR, Calafat AM, Schantz, SL, Korrick SA. Endocrine Disrupting Chemical Exposure and Maladaptive Behavior during Adolescence. Environmental Research 2019;172:231-241. R835434 (Final)
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  • Journal Article Hatcher KM, Willing J, Chiang C, Rattan S, Flaws JA, Mahoney MM. Exposure to di-(2-ethylhexyl) phthalate transgenerationally alters anxiety-like behavior and amygdala gene expression in adult male and female mice. Physiology and Behavior 2019; 207:7-14. R835434 (Final)
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  • Journal Article Strakovsky RS, Lezmi S, Shkoda I, Flaws JA, Helferich WG, Pan YX. In utero growth restriction and catch-up adipogenesis after developmental di (2-ethylhexyl) phthalate exposure cause glucose intolerance in adult male rats following a high-fat dietary challenge. The Journal of Nutritional Biochemistry 2015;26(11):1208-1210 R835434 (Final)
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  • Journal Article Peretz J, Neese SL, Flaws JA. Mouse strain does not influence the overall effects of bisphenol a-induced toxicity in adult antral follicles. Biology of Reproduction 2013; 89:108. R835434 (Final)
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  • Journal Article Rattan S, Beers HK, Kannan A, Ramakrishnan A, Brehm E, Bagchi I, Irudayaraj JMK, Flaws JA. Prenatal and ancestral exposure to di(2-ethylhexyl) phthalate alters gene expression and DNA methylation in mouse ovaries. Toxicology and Applied Pharmacology 2019:114629. R835434 (Final)
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  • Journal Article Dzwilewski, KL, Schantz, SL. Prenatal chemical exposures and child language development. Journal of Communicative Disorders 57:41-65 2015 PMID:PMC26255253. R835434 (Final)
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  • Journal Article Mahalingam S, Ther L, Gao L, Wang W, Ziv-Gal A, Flaws JA. The effects of in utero bisphenol A exposure on ovarian follicle numbers and steroidogenesis in the F1 and F2 generations of mice. Reproductive toxicology 2017; 74:150-157. R835434 (Final)
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  • Journal Article Wolstenholme JT, Drobna Z, Henriksen AD, Goldsby JA, Stevenson R, Irvin JW, Flaws JA, Rissman EF. Transgenerational Bisphenol A causes deficits in social recognition and alters post-synaptic density genes in mice. Endocrinology 2019; Aug 1;160(8):1854-1867. R835434 (Final)
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  • Supplemental Keywords:

    adolescent health, bisphenol A, BPA, children's health, endocrine disruptors, EDCs, epidemiology, growth, neurobehavior, phenols, phthalates, prenatal exposure, ovary, testis, gonads, oxidative stress, diet, perinatal, neuron number, number of glia, indoor air, food, beverages, plastics, cleaning products, personal care products, manufactured fragrances and scents, exposure, health effects, human health, metabolism, vulnerability, sensitive populations, infants, children, age, sex, susceptibility, cumulative effects, chemicals, toxics, endocrine-disrupting chemicals, baby bottle alternatives, public policy, survey, preferences, social science, public health, surveys, interviews, observation, Great Lakes, Midwest, Illinois, IL, EPA Region 5, Mississippi River watershed, child care, child development, plastics manufacturing, food processing, pediatrics

    Relevant Websites:

    Children's Environmental Health Research Center at Illinois Exit
    Family Resiliency Center | University of Illinois at Urbana-Champaign Exit

    Progress and Final Reports:

    Original Abstract
  • 2014 Progress Report
  • 2015 Progress Report
  • 2016 Progress Report
  • 2017 Progress Report
  • Final Report