Grantee Research Project Results
2013 Progress Report: Novel Methods to Assess the Effects of Chemicals on Child Development
EPA Grant Number: R835434Center: Water Innovation Network for Sustainable Small Systems
Center Director: Reckhow, David A.
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 Urbana-Champaign
EPA Project Officer: Hahn, Intaek
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 , Human Health
Objective:
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.
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.
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.
Community Outreach and Translation Core (COTC)
- 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).
- 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:
Journal Articles: 31 Displayed | Download in RIS Format
Other center views: | All 68 publications | 31 publications in selected types | All 31 journal articles |
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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) R835434 (2017) |
Exit Exit Exit |
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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) |
Exit Exit Exit |
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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) |
Exit Exit |
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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) |
Exit Exit |
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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) |
Exit Exit |
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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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Kiester B, Sloane S, Fujimoto E, Fiese B, Su L. What Do Childcare Providers Know about Environmental Influences on Children's Health? Implications for Environmental Health Literacy Efforts. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021;18(10):5489. |
R835434 (Final) |
Exit Exit |
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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) |
Exit Exit |
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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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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) |
Exit Exit |
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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) |
Exit Exit |
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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) R835434 (2015) |
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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) |
Exit Exit |
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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) R835434 (2014) R834593C001 (Final) R835436 (2014) R835436 (2015) R835436 (2017) |
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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) |
Exit Exit Exit |
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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) |
Exit Exit |
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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) |
Exit Exit |
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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) |
Exit Exit Exit |
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Sellinger E, Kougias D, Drzewiecki C, Juraska J. Behavioral effects in adult rats exposed to low doses of a phthalate mixture during the perinatal or adolescent period. NEUROTOXICOLOGY AND TERATOLOGY 2020;79(106886). |
R835434 (Final) |
Exit Exit |
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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) R835434 (2014) |
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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) R835434 (2015) |
Exit Exit Exit |
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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) |
Exit Exit |
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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) R835434 (Final) |
Exit Exit |
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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) R835434 (2015) |
Exit Exit Exit |
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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) |
Exit Exit |
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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) |
Exit Exit |
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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) |
Exit Exit Exit |
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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) R835434 (2015) |
Exit Exit Exit |
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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) |
Exit Exit Exit |
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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) |
Exit Exit Exit |
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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) |
Exit |
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, pediatricsRelevant Websites:
Children's Environmental Health Research Center at Illinois ExitFamily Resiliency Center | University of Illinois at Urbana-Champaign Exit
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2017 Progress Report
- 2016 Progress Report
- 2015 Progress Report
- 2014 Progress Report
- Original Abstract
31 journal articles for this center