Grantee Research Project Results
2016 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.
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, 2016 through May 31,2017
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:
Project 1: The major goals of this project are: 1) to assess sources of exposure to phthalates, bisphenol A (BPA) and other endocrine disrupting chemicals (EDCs) during the prenatal and adolescent periods; 2) to 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) to 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) to 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: The proposed studies were designed to test the hypothesis that bisphenol A (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 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.
Project 3: To examine exposure to BPA or an environmentally relevant phthalate mixture crossed with a high fat diet on offspring during the perinatal or adolescent period. The end points are cognitive and emotional behaviors, neuroanatomical changes in the medial prefrontal cortex, gene expression changes as well as levels of inflammatory cytokines.
Progress Summary:
Project 1: For the prospective birth cohort component of this project, the fourth reporting period has been devoted to five things: (1) continued recruitment of pregnant women into the study, (2) data collection from enrolled women throughout their pregnancies and at birth, (3) cognitive and physical assessments of infants born to study participants, (4) preparation of the dataset collected during the earlier P20 Formative Center stage of our research for statistical analysis and publication, and (5) presentations of our work at national scientific conferences. As of August 1, 2017 500 pregnant women have been enrolled in the study. Of those 16 became ineligible during pregnancy and 40 withdrew from the study during pregnancy. As of August 1, 2017 there were 47 women who were currently pregnant and a total of 397 of study participants had given birth. A total of 337 (85%) of those infants ranging in age from 0-3 years were still actively enrolled in the study as of August 2017. Earlier we developed 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, and following up with mothers to assess behavior and language development in toddlers at 27-29 months of age. All of the infant 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.
For the adolescent component of this project, our research to date 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 urine samples, 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 on these 205 children all of which are key data for this project's analyses. We now have results for urine samples analyzed for ECDs 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) were measured as well as recent phthalate (e.g., DINCH metabolites) and BPA chemical substitutes (e.g, bisphenol S and F). We have begun finalizing the epidemiologic analyses of the association of EDC exposures with adverse neurobehavior in adolescents.
Project 2: We tested the hypothesis that prenatal exposure to DEHP impairs female reproductive outcomes in the F1, F2, and F3 generations of mice. The data indicate that prenatal DEHP exposure has transgenerational effects on time to pregnancy, estrous cyclicity, ovarian follicle numbers, and sex steroid hormone levels. These findings have been presented in abstracts and we plan to submit a manuscript during the next funding period. We also tested the hypothesis that prenatal exposure to DEHP causes abnormal reproductive outcomes in male mice. The findings indicate that prenatal exposure to DEHP induces premature reproductive senescence in the F1 generation and it causes degenerative changes in seminiferous tubules and decreases sperm concentration/motility in the F2 generation, suggesting a multi-generational effect of prenatal DEHP exposure on male reproduction. Some of these data have been published by Barakat, et al., 2017 and we plan to finalize the unpublished data and submit a manuscript during the next funding period. We next determined whether exposure to an environmentally relevant phthalate mixture affects female and male reproductive outcomes. We are particularly excited about our studies on the phthalate mixture because we based the phthalate mixture composition in our animal studies on the results obtained from pregnant women participating in project 1. Thus, the mixture used in our animal studies is directly relevant to the exposures observed in pregnant women. In females, exposure to the phthalate mixture significantly inhibits antral follicle growth, reduces several sex steroid hormone levels, and induces oocyte fragmentation in vitro and it disrupts several aspects of female reproduction in mice in vivo. These data have been published in three manuscripts by Zhou, et al. In males, prenatal exposure to the phthalate mixture significantly decreases sperm concentration compared to control. We plan to expand these findings by determining the effects of the phthalate mixture on testosterone levels and the histological appearance of the testes and epididymis in the next funding period. During the previous three funding periods, we completed most of the proposed studies on the effects of prenatal exposure to BPA on female reproduction. Most of the results from these studies were published and the publications were reported in previous progress reports. However, in the last funding period, we published additional papers on BPA and female reproduction. One of these papers is a review article on BPA exposure and female infertility (Ziv-Gal, et al., 2016) and the other paper indicates that prenatal BPA exposure adversely affects uterine function during pregnancy (Li, et al., 2016).
Project 3:
Perinatal BPA
Gene expression analysis
-A high fat diet fed to dams resulted in offspring with higher Errγ, a BPA binding transcription factor for estrogen. This did not occur if BPA is also present during the perinatal period and it does not continue into adulthood.
-Perinatal BPA increased Erα expression perinatally and this increased continued into adulthood but only in females. Epigenetic markers were not changed.
Cytokines
-There were few changes in the levels of the inflammatory cytokines at the end of the BPA and diet exposure.
Perinatal Phthalate mixture
Behavior
-Dams fed a high fat diet showed increased maternal behavior; phthalates were without effect and there was no interaction between the exposures.
-Periadolescent social play was decreased in males that had been exposed to the lower dose of the phthalate mixture (200 μg/kg); there was a comparable nonsignificant trend in females.
-Adult females that come from dams exposed to high fat diets performed better on a pre-pulse inhibition task, a measure of sensory gating.
-More perseveration errors, indicators of a decrease in cognitive flexibility, were found in males exposed to a low dose of the phthalate mixture.
Cytokines
-There were few changes in the levels of the inflammatory cytokines at the end of the phthalate and diet exposure.
There are few interactions between perinatal exposure a high fat diet and either BPA or an environmentally relevant mixture of phthalates on any measure thus far. The behavior of male rats is somewhat more affected by phthalate exposure than are females.
Future Activities:
Project 1: 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, and 27-29 month and will begin 36-38 month follow ups of the children. We will analyze data collected during the Formative phase, and will continue to submit abstracts for presentation. We will also submit papers for publication. EDC data are now available on the adolescent cohort, thus, the focus in the coming year will be on data analyses to address study aims, as well as preparation of abstracts for presentation at scholarly meetings and manuscripts for publication.
Project 2: During the next funding period, we plan to finalize our work the transgenerational effects of DEHP and the phthalate mixture on female reproduction. Specifically, we plan to finish detailed histological evaluations of follicle numbers in ovaries collected from the F1, F2, and F3 generations. We also plan to finish measurements of sex steroid hormone levels as well as gonadotropin levels in the females from the F1, F2, and F3 generations. Further, we plan to investigate potential change(s) in epigenome of the affected males using tissues (testes and sperm) collected from F3 generation males. Of course, we will continue to complete our work on phenotype characterization of the F2 and F3 generations, and publish the results as manuscripts. In addition, we plan to conduct studies to investigate the impact of high fat diet on DEHP-induced toxicity in female and male reproductive outcomes. A central theme of our Children’s Center is that both high fat diet and exposure to phthalates impact reproductive and neurological/behavior outcomes (projects 1- 3). Thus, we will begin studies to evaluate whether prenatal exposure to DEHP in the presence of a high fat diet impacts female and male fertility. We will use a high fat diet and DEHP exposure paradigm that is similar to that used in project 3 on neurological/behavior outcomes so that we can compare results from both center projects.
Project 3:
Perinatal BPA.
1. A paper on the data from the behavioral, cytokine and genetic effects will be submitted. We are currently working on the microRNA portion that will complete this presentation. We decided that including all of these aspects will be more effective than breaking it up into two papers.
2. We will complete the neuroanatomical analysis of the long term BPA effects (adulthood) on neuron, glia, microglia and synapses (synaptophysin) in the prefrontal cortex. All of these measures are being done with rigorous stereological measures so that they are time and personnel consuming. A paper on the neuroanatomical effects will be written.
Perinatal Phthalates.
1. We will finish the genetic analysis and include it with the behavioral and cytokine results in a paper.
2. We will finish the neuroanatomical analysis of the long term phthalate effects (adulthood) on neuron, glia, microglia and synapses (synaptophysin) in the prefrontal cortex as in A. above, and write a paper on the neuroanatomical effects.
Adolescent Phthalates.
We will start the behavioral and neuroanatomical project of exposure to the phthalate mixture during adolescence. We will be guided by the results of the perinatal exposure so that a smaller range of measures can be taken in a more timely fashion.
References:
Barakat, R., Lin, P-C., Rattan, S., Brehm, E.S., Canisso, I.F., Abosalum, M.E., Flaws, J.A., Hess, R., Ko, C. (2017) Prenatal exposure to DEHP induces premature reproductive senescence in male mice. Toxicological Sciences 156:96-108. PMID: 28082598.
Zhou, C., Gao, L., Flaws, J.A. (2017)Prenatal exposure to an environmentally relevant phthalate mixture disrupts reproduction in the F1 female mice. Toxicology Applied Pharmacology 318: 49-57. PMID: 28126412.
Li, Q., Davila, J., Kannan, A., Flaws, J.A., Bagchi, M.K., Bagchi, I. C. (2016) Chronic exposures to low levels of BPA affect uterine function during early pregnancy. Endocrinology 157:1764-74. PMID: 27022677.
Ziv-Gal A., Flaws, J.A. (2016) Evidence for bisphenol A-induced female infertility-review (2007-2016). Fertility and Sterility 15:827-56. PMID: 27417731.
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) |
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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) |
Exit Exit |
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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) |
Exit Exit |
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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, cognition, endocrine disruptors, EDCs, epidemiology, growth, neurobehavior, phenols, phthalates, prenatal exposure, social behavior, maternal behavior, genetic expressionRelevant Websites:
http://ikids.beckman.illinois.edu 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
- 2015 Progress Report
- 2014 Progress Report
- 2013 Progress Report
- Original Abstract
31 journal articles for this center