2014 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.
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, 2014 through May 31,2015
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:

Project 1: Joint Effects of Endocrine Disruptors, Diet and 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; (3) assess the potential for a high fat diet (HFD)/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. In addition, we hypothesize that associations of exposure with these outcomes will vary by child sex.

Project 2: Endocrine Disrupting Chemicals, Diet and Gonadal Toxicity

The proposed studies were designed to test the hypothesis that BPA, phthalate, and high fat diet exposure interact to increase oxidative stress in developing and 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 a high fat diet and BPA/phthalate/phthalate mixture exposure increase oxidative stress in the gonads of female and male mice, (2) determine if a 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 a high fat diet and BPA/phthalate/phthalate mixture exposure cause infertility and early reproductive senescence in the first and subsequent generations in mice.

Project 3: 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. To 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, and that works bi-directionally with the 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, and during adolescence.

Progress Summary:

Project 1Joint Effects of Endocrine Disruptors, Diet and BMI on Child Development

For the prospective birth cohort component of this project, the second reporting period has been devoted to four things: (1) continued recruitment of pregnant women into the study, (2) tracking of enrolled women throughout pregnancy, (3) setting up the infant cognition lab and beginning the infant cognitive assessments in babies born to study participants, and (4) preparation of the dataset collected during the earlier Formative Center stage of our research for statistical analysis and publication. As of July 31, 2015, 254 pregnant women have been enrolled in the study. Of those, 8 became ineligible during pregnancy and 13 withdrew from the study during pregnancy. Another 11 women withdrew after their infants were born. Thus, as of July 31, 2015, there were 222 women actively enrolled in the new phase of the study. A total of 165 of study participants had given birth and 154 of those infants were still actively enrolled in the study.

During the reporting period, we successfully set up and implemented new state-of-the-art procedures for assessing cognition of infants during the first year of life. We are currently assessing cognitive functions including recognition memory, attention and information processing speed at 1-5 weeks of age, 4-5 months of age and 7-8 months of age in infants born to women in this study. All assessments are computer automated and the 4-5 and 7-8 month assessments make use of infrared eye tracking technology to track the infant’s looking behavior. We also recently began follow-up assessments of children recruited during the initial Formative Center phase of our research as they research 46-48 months of age. The test battery includes assessments of working memory, attention, inhibition, cognitive flexibility, numbers and counting, and language development.

For the adolescent component of this project, the second 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. We successfully completed adolescent urine sample collection in 2014 and now have samples on 205 NBC participants in keeping with our project goal of 200 urine samples. Eighty one % of adolescents examined during the data collection provided at least one urine sample and 144 (70%) of these provided 2 urines, collected approximately one week apart. As part of the parent study assessments, we have completed prospectively collected neurobehavioral assessments, home assessments, height, weight, diet, medical, demographic, lifestyle and exposure information available on these 205 children all of which are key data for this project's analyses. The urine samples are now pending EDC analyses at the CDC where levels of 11 common phthalate metabolites and 8 phenols (BPA, triclosan, butyl paraben, methyl paraben, propyl paraben, benzophenone-3, 2,4-dichlorophenol and 2,5-dichlorophenol) will be measured.

In August of this past year, we successfully recruited a postdoctoral fellow, Dr. Mahsa Yazdy, to work on this project. Dr. Yazdy is trained as an Epidemiologist with particular expertise in risk factors for birth defects and related developmental abnormalities. She has been an outstanding addition to our research group, contributing quantitative expertise, data analysis and data management skills, and her rapidly growing insights into the exposures and child outcomes we are studying. She is working with Drs. Korrick and Schantz on data analyses building on our Formative Center and ongoing P01 work.

Project 2Endocrine Disrupting Chemicals, Diet and Gonadal Toxicity

In the previous funding period, we tested the hypothesis that prenatal exposure to bisphenol A causes infertility and early reproductive senescence in the second and third generations of female mice. The results indicate that in utero BPA exposure significantly reduced pregnancy rates in the F1 generation, with a lower pregnancy rate occurring in the 0.5 μg/kg/day treatment group, and being the lowest (50%) at 9 months. In the F2 generation, in utero BPA exposure decreased pregnancy rates in the entire F2 cohort, but the most notable BPA-induced decrease in pregnancy rate started at 6 months instead of 9 months in 50 μg/kg/day BPA treatment group (56%), whereas the control and the other BPA treatment groups had higher pregnancy rates (71% and above). At 9 months of age, all BPA treatment groups had a reduced pregnancy rate (60% and less) compared to controls (80%). When dams with a weight less than 40 grams prior to mating were examined at 6 months of age, only BPA 50 μg/kg/day still caused a severely reduced pregnancy rate (50%) compared to the control group (100%), whereas the other BPA treatment groups had pregnancy rates similar to the control group (86% and above). At 9 months of age, BPA 0.5 and 50 μg/kg/day reduced pregnancy rate (67% and 63% respectively) compared to controls, whereas the other treatment groups had pregnancy rates of 71% and above. In the F3 generation, in utero BPA exposure did not affect pregnancy rate compared to controls in the whole cohort at 3 months. As the females aged, the control group had a relatively low pregnancy rate (42% and 50% at 6 and 9 months respectively). However, when dams with a weight less than 40 grams prior to mating were examined, in utero BPA exposure (0.5 μg/kg/day) reduced pregnancy rate (60%) compared to controls (83%) at 6 months. Similarly, in utero BPA exposure (0.5 μg/kg/day) reduced pregnancy rate (33%) compared to controls (100%) at 9 months.
 
In the F1 generation, the mating index was 100% in all treatment groups at 3 and 6 months. However, both the DES and BPA (0.5 μg/kg/day) treatment groups had a slightly lower mating index (72% and 80%, respectively) compared to the control group (100%) at 9 months. In the F2 generation, the mating index was similar (> 80%) in all treatment groups at 3 and 6 months of age, but slightly lower in the 50 μg/kg/day BPA treatment group (75%) compared to controls at 9 months. In the F3 generation, all treatment groups had a mating rate of 83% and higher at 3, 6, and 9 months. Collectively, these data suggest that BPA exposure affects reproductive function in female mice and that some effects may be transgenerational.
 
During the previous funding period, we also began to test the hypothesis that prenatal DEHP exposure causes infertility and early reproductive senescence in mice. The results indicate that DEHP exposure did not significantly affect the number of live pups or birth weight when compared to controls (n = 5-18 dams/treatment group). However, DEHP exposure (200 μg/kg/day) significantly increased the ratio of males to females compared to controls (n = 5-15 dams/treatment group; p ≤ 0.05).
 
Interestingly, prenatal DEHP exposure increased the percentage of F1 dams with some breeding complications at 3 months compared to controls. For example, none of the control dams took longer than 5 days to get pregnant, whereas 22.2% of the dams exposed to 20 μg/kg/day DEHP took longer than 5 days to get pregnant (n = 9-19 dams per treatment group; p < 0.05). Prenatal DEHP exposure also increased the percentage of F1 dams with some breeding complications at 6 months. For example, none of the control dams lost pups, but 25% of the dams exposed to 20 mg/kg/day (n = 4-10; p <0.06) and 28.6% of the dams exposed to 750 mg/kg/day lost some pups (n = 4-10 dams/treatment group; p ≤ 0.05). Interestingly, 25% of the control dams took longer than 5 days to become pregnant, but all of the dams treated with 200 mg/kg/day DEHP became pregnant in less than 5 days. In contrast, prenatal DEHP did not significantly affect the ability of the dams to produce a litter at 6 months. It also did not significantly affect the ability of dams to get pregnant, the time to pregnancy, and the loss of pups at 9 months.
 
For the determination of prenatal DEHP exposure on males, testes (and epididymis) from F2 generation were collected on PND1, 8, 21 and 60, used for histological examination of their gonadal and epididymal development. Measurement of the body and gonadal weights did not show any differences in their body and gonadal weights. Histological examinations of the fixed tissues are underway, but available data do not show any obvious defect in the structural organization of the gonad and epididymis, indicating that the prenatal DEHP exposure may not impact male gonadal or epididymal development. In support, fertility tests with the F2 generation, males at the age of 4 months did not differ among the treatment groups (80 ± 20 to 100%). Furthermore, no significant difference in litter sizes was found (10 ± 2.7 to 15 ± 1.3 pups/litter). The testis weights were not different between the control group and any treatment group. However, there were statistically significant differences when we compared testis weights between 500 mg and 200 μg (6.71 ± 0.46 vs 5.12 ± 0.16) and between 750 mg and 200 μg groups (5.91±0.31 vs 5.12±0.16).). We will look into the reasons for these differences during the next funding period. Currently, fertility tests on the F3 generation are underway.
 
Finally, during the previous funding period, we began studies to examine the effects of a phthalate mixture on the ovary. Most previous studies on phthalates have focused on single phthalates and not mixtures. It is important to study mixtures because humans are exposed to phthalate mixtures on a daily basis. Thus, we tested the hypothesis that exposure to an environmentally relevant phthalate mixture alters folliculogenesis and induces oxidative stress in the ovary. The results indicate that the highest dose of phthalate mixture (500 μg/mL) significantly decreases the numbers of germ cells, primordial follicles, and primary follicles compared to control (p < 0.01). The results also indicate that exposure to the phthalate mixture (500 μg/mL) significantly decreases expression of superoxide dismutase (p < 0.01) and increases the expression of catalase (p < 0.05), but does not affect glutathione peroxidase expression compared to control. These data suggest that exposure to a phthalate mixture significantly affects early folliculogenesis and interferes with the expression of key antioxidant enzymes.

Project 3Endocrine Disruptors and Diet, Effects on the Developing Cortex

In work from the P20 grant we found that pre- and postnatal exposure to a dose of 400 μg/kg of BPA resulted in more neurons and glia in the adult prefrontal cortex if 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. The design is large: 2 diet groups (high and low fat) x 3 doses of BPA (0, 40 and 400 mg/kg/day) x 2 sexes = 12 groups. Managing this has been accomplished with consecutive cohorts of matings that produce litters for each group so that behavioral analysis and sacrifice for neuroanatomical histology are not unwieldy. We are currently raising the last cohort of five. 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 at this time we have preliminary results that do not include the last cohort. This was done so that we could submit abstracts for the Society for Neuroscience meeting this November. All of the behavior to be reported at the meeting will be done by that time, but other portions of the project will be ongoing.
 
Set Shifting Task. Performance on this task requires cognitive flexibility and uses the medial prefrontal cortex, which is the cortical area under investigation in this grant. Preliminary analysis indicates that rats exposed to 0 μg/kg BPA and a high-fat diet acquired the original task in fewer trials than other groups, while no other doses had significant effects. However, on the day of shifting to another set of stimuli, there were no significant differences in accuracy between doses, diets or sex, though there was a trend for the 0 μg/kg and control diet group to make fewer perseverative errors. These results suggest that exposure to BPA and/or a high fat diet may impair cognitive flexibility in a rodent model. More animals will be added to the analysis.
 
Maternal Behavior. Maternal behavior was observed daily during dark hours from postnatal day 3 through 15. The high-fat diet increased the maternal licking and nursing and decreased the time the dams spent away from the nest. BPA exposure marginally decreased the amount of nursing and reduced activity of the dam during maternal behavior observations. Again, more animals are about to be added.
 
Adolescent Social Play. Same-sex social play behavior was observed on four days in the offspring from postnatal days 26 through 40. The offspring of dams fed the high-fat diet showed decreased amounts of sniffing and increased chasing during the play. Also, rats perinatally exposed to BPA showed decreased sniffing, wrestling and chasing in play sessions. This interacted with the day of play such that differences were seen in the later but not earlier days.

Community Outreach and Translation Core:

(a) Community Advisory Board (CAB): 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. The CAB was instrumental in providing feedback on the development of the child care survey for our formative research project as well as for the development of the first video public service announcement. They met once in Year 2 of the project with another meeting scheduled for the very beginning of Year 3.

(b) Design and 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. As Year 2 of the Illinois COTC begins, a survey and series of interviews is underway with child care providers (Head Start, Center, and licensed family child care) across Illinois. 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. We currently have responses from 89 providers.

(c) Spring 2015 Illinois COTC conference held. On April 21, 2015, the Illinois COTC co-presented a two-day conference in Springfield, Illinois to address environmental health in child care. The primary focus was on curtailing exposures to endocrine disruptors and was co-hosted by Illinois Action for Children, the child care licensing agency for Chicago and Cook County, and preeminent statewide advocacy organization. The keynote speaker for the conference was Dr. Susan Buchanan, MD, Illinois COTC CAB member and Director, Region 5 PEHSU. Her talk, “Children’s Environmental Health: How pollutants affect children’s growth and development,” was followed by breakout sessions, in which child care providers participated in semi-structured discussions about current resources and beliefs on protecting children’s environmental health in child care settings. Additionally, there was an opportunity for conference attendees to participate in an interactive learning activity that focused on strategies to reduce exposures based on the Eco-Friendly Child Care checklist.

(d) Deliberate outreach to fellow COTC’s. To understand past and present activity, the Illinois COTC has continued dialogue 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. The COTC has also participated in monthly Children’s Environmental Health Center ETOCC & COTC conference calls hosted by NIEHS.

(e) Launch of pilot COTC outreach video. The COTC produced its first outreach video to interpret EDC research for lay viewers (100% complete). The first video is a one-minute overview introducing the topic of endocrine disruption and was launched at the child-care conference in April. The COTC is currently working with a media specialist on a national dissemination plan.

Future Activities:

Project 1: Joint Effects of Endocrine Disruptors, Diet and BMI on Child Development

Over the coming year, we will continue to recruit pregnant women into the cohort, and will assess infants at 1-5 weeks, 4-5 months and 7-8 months. We will also continue our assessments of 46-48 month-old children recruited during the earlier Formative phase, and we will analyze data collected during the Formative phase. We will focus the adolescent research 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 were already analyzed via our Formative Children's Center; (2) once urine EDC concentrations are available, begin full scale data analyses to address study aims

Project 2: Endocrine Disrupting Chemicals, Diet and Gonadal Toxicity

During the next funding period, we will examine whether prenatal BPA and DEHP exposure cause oxidative stress in the gonads. Further, we will conduct studies to further determine the effects of BPA and DEHP on the developing gonads and fertility of mice in the second and third generation of mice. Finally, we will continue studies to assess the effects of the phthalate mixture on the gonads. Specifically, we will determine if the phthalate mixture causes germ cell loss and oxidative stress in the gonads.

Project 3: Endocrine Disruptors and Diet, Effects on the Developing Cortex

There are 2 major objectives for the next year: 1) finish the cohorts for the perinatal BPA exposure described above, publish the behavioral results and make significant progress on the neuroanatomical and epigenetic analyses; 2) raise all of the cohorts for the study of perinatal exposure to phthalates plus high fat diet and finish the behavioral testing on them.

Community Outreach and Translation Core:

1. Continued CAB meetings—The CAB continues to be engaged in the COTC and remain eager to support the project. They will work with us to identify other key collaborators, professional conferences to present at as well as appropriate targets for our messaging and outreach.
2. Complete Formative Research & Disseminate Findings—After completing surveys and interviews we will disseminate the findings to key child care professional organizations as identified by our CAB as well as academic conferences and journals. We will be presenting study findings at the American Public Health Association Annual Meeting.
3. Continue to Collaborate with other COTC’s and CEHN—We will continue to participate in monthly CEHC COTC calls. We will also continue our nascent partnership with the CEHN Eco-Friendly Child Care.
4. Develop Additional Dissemination Products
     a. Targeted materials for child care providers
     b. Podcasts/videos featuring Illinois CEHC research
     c. PSA videos
     d. Children’s Environmental Health Webinar
     e. Just in Time Parenting and eExtension
5. Statewide taskforce—Building on the interest developed at the spring child care conference, we will work with state administrators, child advocates, and child care professionals to convene a task force with the purpose of assessing current administrative and legislative policies and how they align, or do not, with accepted environmentally healthy practices for children.


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, Hern├índez-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, cognition, endocrine disruptors, epidemiology, growth, neurobehavior, phenols, phthalates, prenatal exposure, social behavior, maternal behavior, cognitive flexibility

    Relevant Websites:

    Children's Environmental Health Research Center at Illinois Exit
    Illinois Children's Environmental Health Research Center Community Outreach & Translation Core Exit

    Progress and Final Reports:

    Original Abstract
  • 2013 Progress Report
  • 2015 Progress Report
  • 2016 Progress Report
  • 2017 Progress Report
  • Final Report