Final 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 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

Investigators: Susan Schantz (PI); Susan Korrick (MPI), Andrea Aguiar (Co-I), Renee Baillargeon (Co-I), Joseph Gardiner (Co-I), Daniel Hyde (Co-I), Yuan-Xiang Pan (Co-I)

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 other risk factors such as stress or 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: Endocrine Disrupting Chemicals, Diet and Gonadal Toxicity

Investigators: Jodi A. Flaws (PI), CheMyong Ko (Co-I), Yuan-Xiang Pan (Co-I)

The overall goal of these studies was to determine the effects of prenatal exposure to bisphenol A (BPA), di-(2-ethylhexyl) phthalate (DEHP), and a phthalate mixture on both female and male reproductive outcomes.

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

Investigators: Janice Juraska (PI), Yuan-Xiang Pan (Co-I)

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 a 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, as well as quantitative cortical neuroanatomy, in adulthood.

Community Outreach and Translation Core

Investigators: Barbara Fiese (PI), Brenda Koester (Co-I)

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 Centers 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.

Summary/Accomplishments (Outputs/Outcomes):

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

For the prospective birth cohort component of this project, as of January 2019 we met our recruitment goal of 600 pregnant women enrolled. A total of 501 (84%) remained in the study to the birth of their infant. The cohort consists of mothers who are primarily non-Hispanic white (80%), and college educated (78%) with household income greater than $50,000 (79%). Nearly every family (99%) had health insurance and 85% had private or employer provided health insurance. The women were 30 ± 4.3 years of age at enrollment. Child gestational age at birth was 39.3 ± 1.6 weeks and 70% were born via a vaginal delivery. In general, the demographics of the cohort are reflective of the Midwestern college town from which the cohort was recruited. The primary exposure measures for this pregnancy cohort study were average exposures to phthalates and phenols across pregnancy measured by creating a pooled urine sample for each participant from 5 first morning urine samples collected at approximately 10-14, 16-18, 22-24, 28-30 and 34-36 weeks of gestation. The CDC analyzed these urine samples for concentrations of 17 common phthalate metabolites or phthalate substitutes, 11 phenols (bisphenols, triclosan, parabens, benzophenone-3 and dichlorophenols), and triclocarbon. This approach was taken because both bisphenols and phthalates have short half-lives and variable day-to-day exposure, making exposure misclassification a concern when a single sample is used as a biomarker of exposure. In general, urine biomarker concentrations in the women were very similar to those reported in the most recent National Health and Nutrition Examination Survey (NHANES).

An important goal of this research was to develop and implement new state-of-the-art automated procedures for assessing cognition of infants during the first year of life. We did this by using infrared eye-tracking hardware and software to automate stimulus presentation, data collection and data processing. Using this approach we were able to analyze infant looking behaviors to assess specific cognitive domains including recognition memory, attention, information processing speed and physical reasoning. The same infants are currently being followed up via a continuing no cost extension from NIEHS as well as new funding through the NIH ECHO program to assess various neurodevelopmental outcomes at 2, 3 and 4 years of age. Analyses to date have revealed an association of the phthalate, DINP with poorer visual recognition memory at 7-8 months of age and an association of bisphenol F (BPF) with slower information processing at 7-8 months. BPF was also associated with poorer scores on a measure of language development at 2 years of age. Importantly, these are both chemicals that are being used as replacements for other chemicals—DINP is used as a replacement for DEHP (which was not associated with any of the cognitive outcomes) in many products based on animals studies that suggested it may be less toxic. However, those studies assessed reproductive endpoints in male animals. BPF is used as a replacement for BPA (also not associated with any of the cognitive outcomes), and is contained in many plastic products that are labeled "BPA free". These findings are important because they are some of the first results suggesting that some replacement chemicals may have a larger neurodevelopmental impact than the original products. Analyses to date also suggest an association of MEP, the major metabolite of the phthalate, DEP with delayed language development. This finding is consistent with previously published findings suggesting that MEP is associated with delayed language development, and is important because MEP accounts for a large proportion (30-35%) of the phthalates present in maternal urine.

For the adolescent component of this project, we 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. The NBC is a sociodemographically diverse, largely urban population of 788 children who have been followed since their birth in 1993-1998 to mothers residing in the New Bedford area of Massachusetts. For example, 33% of the children are non-white and/or of Hispanic ethnicity; at birth, most (58%) mothers had a high school education or less, 43% were unmarried, and 38% were living in low income households. Of the 788 infants enrolled at birth, 528 completed adolescent neurodevelopmental assessments at ~age 15 years in our parent studies, 252 of whom were asked to provide urine samples for EDC exposure assessment as part of this Center program. 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.

Steroid hormones play an important organizing role in neurodevelopment, including sexually dimorphic neurodevelopment that occurs during adolescence. We hypothesized that exposure to EDCs during this time period may preferentially impact sexually dimorphic neurodevelopmental outcomes. Given this context, the outcomes we have been analyzing are from standardized, validated cognitive and behavioral measures that reflect sexually dimorphic skills. Our approach to analyzing EDC mixtures has been to sum urine biomarker levels based on either: (1) shared mechanism of action (the molar sum of urine metabolites of anti-androgen phthalates); (2) shared exposure pathway (the molar sum of urine metabolites of phthalates commonly found in personal care products); or (3) use as a recent replacement for prevalent EDCs (e.g., DINCH is used as a replacement for the phthalate DEHP so the molar sum of DINCH urine metabolites were considered; bisphenols S and F are used as replacements for bisphenol A so urine levels of these three bisphenols were considered). Analyses to date have revealed that the sum of anti-androgenic phthalates was associated with maladaptive behaviors—both externalizing (aggression, hyperactivity, conduct problems) and internalizing (anxiety, depression, somatization), and with an increased risk of attention deficit hyperactivity disorder (ADHD)-related behaviors. In general, these associations were stronger in males than females. In contrast to findings with phthalates, biomarkers of exposure to phenols were generally not associated with adverse behavior in the NBC adolescents. We also looked at associations of phthalate and phenol biomarkers with measures of executive functions including working memory, but associations with symbolic working memory were modest and not significant, and there were no associations with verbal working memory. These findings, in combination with our behavioral findings, highlight the possibility that maladaptive behavior may be more sensitive to adolescent EDC exposures than cognitive skills. Further research will be needed to confirm and refine this initial observation

Project 2: Endocrine Disrupting Chemicals, Diet and Gonadal Toxicity

During the funding period, we first examined the effect of BPA on the developing ovary and we determined that BPA exposure inhibits the process of germ cell nest break down in the ovary. We also expanded our work to examine the mechanisms by which BPA inhibits germ cell nest break down. Specifically, we tested the hypothesis that BPA exposure directly inhibits germ cell nest breakdown by inhibiting oxidative stress and/or apoptotic pathways. Collectively, the data suggest that low doses of BPA exposure significantly inhibit germ cell nest breakdown by inhibiting the expression of key ovarian apoptotic genes, but not by interfering with the oxidative stress pathway.

We also tested the hypothesis that prenatal exposure to BPA has transgenerational effects on female fertility. The results indicate that BPA exposure significantly delayed the age at vaginal opening in the F3 generation compared to vehicle control. BPA also significantly delayed the age at first estrus in the F3 generation compared to vehicle control. BPA exposure reduced gestational index in the F1 and F2 generations compared to control. Further, BPA exposure compromised the fertility index in the F3 generation compared to control. Finally, in utero BPA exposure reduced the ability of female mice to maintain pregnancies as they aged. Collectively, these data suggest that BPA exposure affects reproductive function in female mice and that some effects may be transgenerational in nature.

We also expanded our work to determine if prenatal exposure to BPA reduces male fertility in the F1-F3 generations. The results indicate that prenatal exposure to BPA does not affect male fertility in the F1-F3 generations. However, prenatal BPA exposure may decrease serum testosterone levels compared to control. These data suggest that prenatal BPA exposure has transgenerational effects on hormone levels, but not male fertility.

During the funding period, we also tested the hypothesis that prenatal exposure to DEHP disrupts ovarian functions in the F1, F2, and F3 generations of female mice. In the F1 generation, prenatal exposure to DEHP disrupted body and organ weights, decreased folliculogenesis, and increased serum 17β-estradiol levels. In the F2 generation, exposure to DEHP decreased body and organ weights, dysregulated folliculogenesis, and disrupted serum progesterone levels. In the F3 generation, DEHP exposure accelerated folliculogenesis. These data suggest that prenatal exposure to DEHP leads to adverse multigenerational and transgenerational effects on ovarian function.

We also tested the hypothesis that prenatal exposure to DEHP accelerates the onset of puberty, disrupts birth outcomes, and reduces fertility-related indices in the F1, F2, and F3 generations of female mice. In the F1 generation, prenatal DEHP exposure accelerated the onset of puberty and disrupted fertility-related indices. In the F2 generation, DEHP exposure accelerated the onset of puberty, increased the female to male sex ratio, and disrupted fertility-related indices. In the F3 generation, DEHP exposure accelerated the onset of puberty, increased the female to male sex ratio, decreased female pup anogenital index, and reduced fertility-related indices. Collectively, the data show that prenatal DEHP exposure at environmentally relevant doses accelerates the onset of puberty, disrupts birth outcomes, and disrupts fertility-related indices; thus, suggesting that DEHP causes female reproductive problems in a multigenerational and transgenerational manner.

Further, we tested the hypothesis that prenatal DEHP exposure affects follicle numbers, estrous cyclicity, and hormone levels in multiple generations of 1-year-old mice. Prenatal DEHP exposure altered estrous cyclicity, increased the presence of ovarian cysts, and decreased total follicle numbers in the F1 generation. It also decreased anogenital distance) and altered follicle numbers in the F2 generation, and it altered estrous cyclicity and decreased folliculogenesis in the F3 generation. Further, prenatal DEHP increased estradiol, decreased testosterone levels (F1, F2, and F3), decreased progesterone levels (F2), altered gonadotropin hormone levels (F1 and F3), and decreased inhibin B levels (F1 and F3). Collectively, these data show that prenatal exposure to DEHP has multi- and transgenerational effects on female reproduction, and it accelerates reproductive aging.

During the funding period, we also determined the effects of prenatal and ancestral DEHP exposure on various ovarian pathways in the F1, F2, and F3 generations of mice. Overall, the data show that prenatal and ancestral DEHP greatly suppresses gene expression of pathways required for folliculogenesis and steroidogenesis in the ovary in a transgenerational manner and that gene expression may be in influenced by DNA methylation.

In addition to conducting studies on DEHP, we conducted studies on the effects of the phthalate mixture on female reproduction. Specifically, we tested the effects of prenatal exposure to this mixture on reproductive outcomes in the F1, F2, and F3 generations of female mice and found that it impaired reproductive outcomes by increasing uterine weight, altering anogenital distance, inducing enlarged cystic ovaries, disrupting estrous cyclicity, altering hormone levels, and causing fertility complications in multiple generations. Overall, these data suggest that prenatal exposure to an environmentally relevant phthalate mixture induces some multi- and transgenerational effects on sex steroid hormone levels in female mice.

During the funding period, we also tested the hypothesis that prenatal exposure to DEHP lays the foundation for premature gonadal dysfunction and subsequent reproductive senescence in male mice. As early as 7 months of age, the 750 mg/kg/day group of mice exhibited significantly reduced fertility. At 19 months of age, 86% of the 750 mg/kg/day mice became infertile, whereas only 25% of the control mice were infertile. At this age, all of the DEHP-exposed mice had lower serum testosterone levels, higher serum estradiol levels, and higher LH levels compared with control mice. Histological evaluations showed that mice prenatally exposed to DEHP displayed a wide array of gonadal and epididymal abnormalities such as increased germ cell apoptosis, degenerative seminiferous tubules, oligozoospermia, asthenozoospermia, and teratozoospermia in comparison to age-matching control mice. Taken together, this study found that prenatal exposure to environmentally relevant doses of a phthalate mixture caused a life-long impact on the reproduction in male mice.

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

Exposure to BPA or to an environmentally relevant phthalate mixture perinatally (during gestation and for the first 10 days after birth) had undesirable effects on the cortex and on behavior including social play during adolescence in rats. There were some subtle indications of an increase in inflammatory markers. The effects of the same exposures during adolescence were far more subtle.

The most notable effects came from the perinatal exposure to the phthalate mixture when the exposed pups became adults. In both males and females, there were fewer neurons in the prefrontal cortex, a portion of the cerebral cortex that is important for higher order cognitive behavior and is involved in virtually all forms of psychiatric problems. Concomitantly, the phthalate exposure also resulted in impairments in the performance of a cognitive flexibility task.

What makes this especially relevant to humans is that the dose per body weight and the composition of the phthalate mixture was based on values derived from the urine of pregnant females in the local area. Thus this close model of human exposure of an environmentally relevant mixture of phthalates results in negative effects for development that last into adulthood.

Community Outreach and Translation Core

Accomplishments:
Community Advisory Board (CAB):
The CAB for the Illinois COTC included 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 foundational research on childcare providers and the development of dissemination materials.

Foundational Research on childcare providers: 1) Survey of childcare providers across the state of Illinois (n=79) regarding baseline knowledge and practices related to endocrine disruptor exposures. Initial findings revealed that childcare providers had limited knowledge of endocrine disrupter exposures and required foundational knowledge of children’s environmental health. 2) In-depth semi-structured interviews (n=40) child care providers across Illinois to assess providers’ conceptualization and baseline knowledge of children’s environmental health, understanding of environmental toxins and their effects on children, and the health behaviors they engage in to protect children’s environmental health. Results indicated that providers were unfamiliar with the term "children’s environmental health" and that they associate the "environment" with wide-ranging factors such as climate change and children’s socio-emotional development. 3) Survey of childcare providers (ongoing) on baseline knowledge of children’s environmental health, understanding of environmental toxins and their effects on children, and the health behaviors they engage in to protect children’s environmental health. This ongoing work is focused on developing a reliable and valid measurement of childcare provider environmental health literacy that can inform future research.

Engagement with childcare providers: 1) Spring Into Action conference (April, 2015). Two-day conference in Springfield, Illinois to address environmental health in childcare. The primary focus on curtailing exposures to endocrine disruptors and was co-hosted by Illinois Action for Children. Keynote speaker Dr. Susan Buchanan, MD, Illinois COTC CAB member and Director, Region 5 PEHSU presented "Children’s Environmental Health: How pollutants affect children’s growth and development". Breakout sessions featured semi-structured discussions with childcare providers about current resources and beliefs on protecting children’s environmental health in childcare settings. Conference attendees participated in an interactive learning activity that focused on strategies to reduce exposures based on the Eco-Friendly Child Care checklist. 2) Child Nutrition Conference (April, 2019). Environmental Influences on Children’s Health. Healthy habits training for child care providers and other early care and education professionals. 3) Provide technical assistance and consultation with Illinois Action for Children on upcoming regulations requiring mandatory water testing for childcare providers. 4) Contributed to the Illinois Action for Children Early Care & Education Caucus meeting that brought together childcare providers and early care and education advocates. A major focus of the meeting was new water testing (for lead) requirements and the health effects on children of lead exposure.

Social Media Workgroup: (University of Illinois, University of Southern California, Emory University). 1) Social Media Workshop (held in conjunction with 2018 CEHC Annual Meeting) – over 50 in attendance that featured a speaker panel and three breakout workshops. The focus of the workshop was to learn about incorporating social media into outreach and translation work and targeted at beginners to advanced users. 2) Webinars conducted for CEHC, PEPH, and PEHSU networks on using social media toolkit, message campaign, and how to use social media for outreach and translation work. 3) Survey of CECH/PEHSU network completed on current social media practices and knowledge. 4) Social media toolkit and monthly social media posts made available to CECH/PEHSU network.

Dissemination products: 1) Disrupt the Disruptors micro-video. One-minute overview introducing the topic of endocrine disruptors https://www.youtube.com/watch?v=JKVXCTpxkEg 2) Social media messaging on Facebook, Twitter, and Pinterest. 3) Environmental Influences on Children’s Health – Healthy Habits Training Module developed and delivered to childcare providers and early care and education professionals. 4) Small changes make BIG differences. A suite of five micro-videos highlighting environmental health risks and behavior. There is an overview video of what exposures are and how small changes can make a big difference and four additional videos focused on exposures found in water, indoor air, personal care products, and household products (i.e., toys). There are also accompanying printed material and social media messages. http://familyresiliency.illinois.edu/exposures/ 5) Archived webinar through the University Based Child and Family Consortium – Environmental Influences on Children’s Health and Development https://www.youtube.com/watch?v=rwcXOYkw0Z8. 6) Archived presentations from the Midwest Children’s Health Symposium http://familyresiliency.illinois.edu/midwest-childrens-health-symposium.


Journal Articles: 42 Displayed | Download in RIS Format

Other center views: All 80 publications 42 publications in selected types All 42 journal articles
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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)
    R835434 (2015)
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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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  • Abstract: PubMed Abstract
  • Supplemental Keywords:

    adolescent health, bisphenol A, children's health, cognition, endocrine disruptors, epidemiology, growth, neurobehavior, phenols, prenatal exposure, DEHP, phthalate, ovary, testes, reproduction, transgeneration, perinatal, neuron number, number of glia, phthalate, cognitive flexibility, adolescence, maternal licking

    Relevant Websites:

    Children's Environmental Health Center's Community Outreach and Translation Core Exit

    Children's Environmental Health Research Center at Illinois Exit

    IKIDS- Illinois Kids Development Study Exit

    Progress and Final Reports:

    Original Abstract
  • 2013 Progress Report
  • 2014 Progress Report
  • 2015 Progress Report
  • 2016 Progress Report
  • 2017 Progress Report