Susan L. Schantz - US grants

polychlorinated biphenyls (PCBs) and methylmercury (MeHg) are widespread environmental contaminants that tend to accumulate in aquatic ecosystems and are known to be neurotoxic. Maternal consumption of fish or marine mammals high in PCBs and/or MeHg has been associated with neurobehavioral deficits in children. Recent evidence from laboratory studies suggests that MeHg and PCBs may be acting in an additive or synergistic fashion to produce some of these effects. Specifically, MeHg appears to potentiate PCB-induced reduction in brain dopamine. The potential behavioral consequences of this are unknown. Hmong and Laotian refugees in northeastern Wisconsin are at risk of elevated PCB and MeHg exposure because a large percentage of them cash and eat fish from the Fox river and other contaminated waters. The proposed animal studies are designed to complement Project 1, which will evaluate neurological outcomes in Hmong and Lao children born to mothers who regularly eat locally caught fish. Long Evans rats will be used as an animal model to characterize in detail the cognitive, motor and sensory effects of exposure to PCBs alone, MeHg alone, or PCBs and MeHg in combination. Congener specific fish contaminant data will be used for formulate a PCB mixture that models the PCB congener profile in Fox River fish as closely as possible. Data on the levels of MeHg that best models the ratio of PCBs to MeHg present in the fish. In depth analyses of the behavioral response data will be used to identify the types of error patterns or deficits that contribute to poor performance on specific behavioral tasks. Pharmacological challenges with dopamine agonists and antagonists will be used to gain a better understanding of the role of change sin dopamine function in mediated specific PCB- and MeHg-related behavioral impairments. Project 3 will complement these studies by investigating specific dopamine-related mechanisms through which PCBs and MeHg could be acting to alter behavioral function. The results of these animal experiments will be used to guide the selection of behavioral and sensory endpoints that should be assessed in the Hmong and Laotian children exposed to PCBs through maternal consumption of Fox River fish.

The overall research objectives of the FRIENDS Children's Environmental Health Center are to: (1) study the impact of exposure to polychlorinated biphenyls (PCBs) and methylmercury (McHg) on cognitive, sensory and motor development of children, (2) develop effective educational strategies to reduce exposure to these neurotoxic contaminants, and (3) undertake laboratory studies to better understand the mechanisms by which these contaminants induce neurological deficits in children. The Center will build on several long-standing research collaborations and will be organized around an exposure cohort that is already being recruited. The cohort consists of Hmong and Laotian refugees who are consuming PCB- and MeHg- contaminated fish from the Fox River in northeastern Wisconsin. The Center includes an administrative core, a community-based project, two biomedical research projects and an analytical toxicology core. The two primary goals of the community-based project are: (1) to evaluate the impact of PCB and MeHg exposure on reproductive health and child development and (2) to provide families with practical information that will help them to reduce their exposure to PCBs and MeHg. The assessments of the children will focus on specific aspects of behavioral and sensory function that have not been adequately addressed in previous human studies. These goals will be accomplished in partnership with community resource groups in the area. The biomedical research projects will complement the community-based project by characterizing the cognitive, sensory, motor and neurochemical effects of exposure to PCBs alone, MeHg alone or PCBs and MeHg combined in a rodent model. Moth projects will used a mixture of PCBs that models the PCB congener profile in Fox River fish, and a ratio of PCBs to MeHg similar to that found in the fish. The findings from the animal studies will guide the selection of additional behavioral and sensory endpoints for use in the children exposed to PCBs and MeHg via maternal consumption of Fox River fish. The analytical toxicology will formulate the PCB mixture to be used in the animal studies and provide congener specific PCB analysts, heavy metal analysis, and pesticide analysis in human and animal samples from the three research projects. The administrative core will provide oversight, coordination and integration of all Center activities.

[unreadable] DESCRIPTION (provided by applicant) [unreadable] [unreadable] This is a proposal to continue funding of the research Training Program in Environmental Toxicology. Established in 2000 to help recruit new scientists into this important discipline, the Program educates pre- and postdoctoral trainees in reproductive, developmental and endocrine toxicology. Outstanding new faculty members will join the Program as preceptors, resulting in a total of 14 members from six departments (Animal Sciences, Chemistry, Crop Sciences, Food Science and Human Nutrition, Molecular and Integrative Physiology and Veterinary Biosciences) in three colleges (Liberal Arts and Sciences, Agriculture, Consumer and Environmental Sciences and Veterinary Medicine). Research disciplines range from neurobehavioral effects of environmental endocrine disruptors to molecular toxicology of the estrogen receptor. The 14 preceptors are a subset of a larger group of 35 faculties who participate in the interdisciplinary Environmental Toxicology Program. This Program, in existence since the 1980s, focuses on training doctoral students from a wide range of disciplines in Environmental Toxicology. The Program includes a weekly seminar series and a broad range of graduate level courses in toxicology. In addition to their departmental requirements, all postdoctoral trainees will take basic toxicology and at least one other advanced toxicology course related to their field of study. Postdoctoral trainees will conduct independent research in toxicology. All trainees attend weekly toxicology research seminars, participate in the toxicology journal club and take a course on research ethics in toxicology. Trainees will be required to present and discuss their research in the seminar and strongly encouraged to present their research at national meetings. Preference will be given to pre-doctoral trainees in their first or second year. Selection will be based on academic success, relevance of proposed research to Program goals and commitment to toxicology. This effort to recruit under-represented minorities will continue. [unreadable] [unreadable] [unreadable]

This Program Project will use rodent models to evaluate the effects of exposure to dietary estrogens at various points in the lifespan on disease processes associated with aging. These include breast tumor growth, obesity and cognitive decline, which is the focus of this project. The central premise is that the dose, timing of exposure during the lifespan and target tissue will determine whether the biological effects are beneficial or detrimental. Doses and exposure periods that have beneficial effects in one tissue may have detrimental effects in others. The initial specific aim of this project is to characterize the effects of low and high physiologic doses of estrogen replacement on cognitive function in ovariectomized young, middle-aged and old female rats. These studies will establish a detailed profile of estrogen actions on a broad range of cognitive functions, determine whether the profile of effects differs in young, middle-aged and old rats, and elucidate the effects of low vs. high physiologic levels of estrogen in young middle-aged and old rats. The focus will be on tests of executive functions such as cognitive flexibility, working memory, attention, and response inhibition. The role of estrogens in regulating these aspects of cognition is not well understood, particularly in rodent models. Detailed analysis of response patterns across trials will help to identify the underlying behavioral mechanisms response for estrogen-mediated changes in cognition. The second aim is to test ovariectomized young, middle-aged and old rats exposed to low, medium or high physiologic doses of soy isoflavones on the same battery of tests. Pure soy isoflavones including genistein and equol will be tested first followed by the commercial mixture, Novasoy. These studies will establish a profile of soy effects of soy isoflavones on cognition and identify differences between these compounds and estradiol. An ancillary goal is to measure adipose deposition in the same rats that are tested for cognitive function. Assessing two critical health endpoints in the same animals will allow us to determine how the dose-response and pattern of beneficial vs. harmful effects for the two endpoints are related. The final aim is to use selective estrogen receptor alpha (ERalpha) and beta (ERbeta) antagonists to investigate the role of ERalpha and ERbeta in mediating the actions of soy isoflavones on cognition. Because soy isoflavones show selectivity for ERbeta, we expect them to differentially effect cognitive functions regulated primarily by ERbeta. Together with the other projects in this program these studies will help to define the risk and benefits to older women from consuming dietary estrogens.

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to evaluate neuropsychological outcomes in Asian Americans exposed to polychlorinated biphenyls (PCBs) and methyl mercury (MeHg) via consumption of fish from polluted waters in northeastern Wisconsin. This research will expand our Agency for Toxic Substances and Disease Registry (ATSDR)-funded study of neuropsychological function in adults from this population to include similar evaluations in their adolescent children. The entire project is designed to synergize with our National Institute of Environmental Health Sciences/U.S. Environmental Protection Agency (NIEHS/USEPA)-funded Children's Environmental Health Center, which focuses on understanding the neuropsychological effects of combined exposures to polychlorinated biphenyls (PCBs) and methyl mercury (MeHg). The Center includes research in animal models and humans. The centerpiece project involves recruitment of reproductive age Hmong and Laotian couples in Green Bay and Appleton, Wisconsin for a prospective study that will follow babies born to them during the study period longitudinally from birth to assess neurodevelopmental outcomes associated with prenatal exposure to these contaminants. Our current award from Agency for Toxic Substances and Disease Registry (ATSDR) has allowed us to build on this initial study design by including neuropsychological assessments of the reproductive-age couples in our sample. Continued funding will allow us to take this a step further to a "lifespan" perspective, assessing the impact of these contaminants on neuropsychological function in infants (through the National Institute of Environmental Health Sciences/U.S. Environmental Protection Agency (NIEHS/USEPA) funding) and older children and adults from the same families (through the Agency for Toxic Substances and Disease Registry (ATSDR) funding). Adolescents aged 14-16 who are the children of couples participating in our study will be assessed on a battery of tests of cognitive function, including many of the same tests currently being used to assess the adults in the sample. Blood samples will be collected for contaminant analysis. The study will help us to understand the risks from exposure to these chemicals in individuals of different ages (infants, adolescents, and adults) within families, as well as the similarities and differences in the profile of neuropsychological effects at these three stages of development.

The overall goal of the FRIENDS Children's Environmental Health Center is to understand the impact of[unreadable] prenatal exposure to contaminants found in fish-including polychlorinated biphenyls (PCBs),[unreadable] polybrominated diphenyl ethers (PBDEs) and methyl mercury (MeHg)-on cognitive, motor and auditory[unreadable] function of children. The animal studies described in this proposal will complement a parallel prospective[unreadable] birth cohort study (Project 2) in which children born to women consuming fish contaminated with these[unreadable] chemicals will be followed longitudinally from birth. The animal studies will'use an experimental PCB mixture[unreadable] that mimics the PCB congener profile in the fish consumed by women in the epidemiological study. One[unreadable] major goal is to elucidate the effects of PCBs and PBDEs on important executive processes including[unreadable] attention and inhibitory control. Drug challenges with methylphenidate and amphetamine will determine if[unreadable] commonly prescribed ADHD pharmacotherapies improve the performance of PCB- or PBDE-exposed rats[unreadable] on tests of attention and response inhibition, and measures of DA D4 and DA D1 receptor expresion and[unreadable] drug challenges using specific DA D4 and DA D1 receptor agonists will indicate whether these receptor[unreadable] pathways are involved in mediating the behavioral effects. These studies will be conducted in parallel with[unreadable] another laboratory study (Project 4) which will investigate the effects of PCB and PBDE exposure on central[unreadable] catecholamine function and the extent to which these effects are mediated indirectly through PCB or PBDE[unreadable] effects on circulating thyroid hormones. A second major goal is to understand the mechanisms through[unreadable] which PCBs damage the cohclea and produce hearing loss. Histological examinations of the cochlea will[unreadable] confirm whether hearing deficits are due to outer hair cell damage. The contribution of reductions in[unreadable] circulating thyroid hormones or alterations in ryanodine receptor expression in the cochlea to PCB-induced[unreadable] hearing loss will be investigated by utilizing two specific PCB congeners having opposing effects on thyroid[unreadable] hormones and ryanodine channel activity. Because the outer hair cells are believed to protect against noise[unreadable] induced hearing loss, studies will also be conducted to determine if early PCB exposure increases[unreadable] susceptibility to noise-induced hearing loss later in life. As in the past, findings from these animal studies will[unreadable] guide the selection of outcome measures for use in the birth cohort.

[unreadable] DESCRIPTION (provided by applicant) [unreadable] [unreadable] This is a proposal for funding to support a 1.5 day symposium that would be held at the annual meeting of the Neurobehavioral Teratology Society (NBTS), June 29-July 2, 2008 in Monterey, CA. NBTS will meet jointly with two "sister" societies, the Teratology Society (TS) and the Organization of Teratology Information Specialists (OTIS) whose members will also have the opportunity to attend the symposium. The symposium will focus on neurodevelopmental effects of pesticides and metals and will bring together some of the leading epidemiologists and laboratory animal scientists studying these exposures. One two-part session would feature new epidemiological research from prospective birth cohort studies examining agricultural pesticide exposures, urban indoor pesticide exposures, and exposures to metals including lead, mercury and manganese. Confirmed speakers include Dr. Brenda Eskenazi, Dr. Virginia Rauh, Dr. Mary Wolff, Dr. Elaine Faustman, Dr. Robert Wright, Dr. Kim Dietrich, Dr. Jerry Reiter and Dr. Irva Hertz- Picciotto. A second session would highlight parallel research addressing similar exposures in animal models. Confirmed speakers include Dr. Edward Levin, Dr. Barbara Strupp, Dr. Deborah Rice, Dr. Jason Richardson and Dr. Tim Maher. The goal of the proposed symposium is not only to convey the newest research findings on pesticides and metals, but also to bridge the gap between human and animal research perspectives. The symposium is timely because the neurodevelopmental risks from early pesticide exposure in human populations are just beginning to become known. Similarly, the focus on new issues related to metal exposures including the potential role of mercury in autism spectrum disorders, the role of early lead exposure in later antisocial behavior, and the role of gene-environment interactions in metal neurotoxicity is very timely. Bringing together epidemiologists and animal researchers focused on the same exposures and developmental outcomes will provide each of these research communities with a broader perspective and create fertile ground for the development of research collaborations. A majority of the speakers are not members of NBTS, TS or OTIS and do not regularly attend this meeting. This symposium will provide an opportunity for them to present their research to a new audience and get their input. Proceedings of the symposium will be published in the journal Neurotoxicology and Teratology as a series of three peer-reviewed articles. Each will summarize, integrate and discuss the findings presented in one of the three sessions on: (i) pesticides, (ii) metals and (iii) animal models of pesticide and metal exposure. Since much of the research that will be presented focuses on under-represented minority populations the Society will advertise widely at nearby college campuses, particularly those with high percentages of minority students and will waive conference registration fees for any minority students interested in attending the symposium. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant) This is a competing continuation application to renew the Research Training Program in Environmental Toxicology. Established in 2000 to help recruit new scientists into this important discipline, the Program educates pre- and postdoctoral trainees in reproductive, developmental and endocrine toxicology. The need to train students and postdoctoral fellows in these aspects of toxicology is every bit as urgent today as it was 10 years ago when the training program was first conceived. Environmental chemicals that act as endocrine disrupters continue to dominate environmental health concerns. The program unites two long recognized areas of research excellence on the University of Illinois campus, environmental toxicology and reproductive biology, and the investigators can count among their preceptors some of the brightest stars on the University of Illinois campus. Several outstanding new preceptors have joined the Program since the last submission (Flaws, Hofmann) and two additional preceptors are added in this renewal application (Boppart, Freund) resulting in a total of 15 preceptors from seven departments (Animal Sciences, Bioengineering, Chemistry, Crop Sciences, Food Science and Human Nutrition, Molecular and Integrative Physiology and Veterinary Biosciences). Together these faculty currently have over 40 federally funded research grants totaling more than $9 million dollars per year direct costs. The preceptors are researching endocrine active chemicals using a broad multidisciplinary perspective. Collaborations among laboratories working at the molecular, cellular, whole animal and human health levels provide trainees with the unique opportunity to directly observe and participate in translational research. Selection of trainees is based on academic success, relevance of proposed research to Program goals and commitment to toxicology. Preference is given to pre-doctoral trainees in their first or second year of graduate study. The Program offers a broad range of graduate level courses in toxicology. In addition to their departmental requirements, all pre-doctoral trainees take basic toxicology, systems toxicology and at least one other advanced toxicology course related to their field of study. Postdoctoral trainees conduct independent research in toxicology. All trainees are required to attend weekly toxicology research seminars, career development workshops, a toxicology journal club and a course on research ethics in toxicology. Trainees are also required to present their research in the seminar and strongly encouraged to present their research at national meetings. The investigators have a strong record of recruiting and retaining qualified students from underrepresented groups and we will continue and expand these efforts. Relevance: This Training Program will train pre- and postdoctoral students to become the next generation of research scientists in endocrine, developmental and reproductive toxicology, subdisciplines of toxicology that are directly relevant to human health.

Description (provided by applicant): The primary goal of this Formative Center is to assemble a multidisciplinary team of experts to address the critical gaps in our knowledge of the risks to human development from bisphenol A and phthalate exposure. We will actively involve junior investigators in this research effort, and actively communicate our research findings to the healthcare community and the public. At the heart of the research effort will be two pilot human cohort studies-a birth cohort to be recruited in Urbana-Champaign, IL (S. Schantz, principal investigator) and an adolescent cohort to be assessed as part of an ongoing study in New Bedford, MA (S. Korrick, principal investigator). The Formative Center will also include laboratory animal projects (J. Juraska, principal investigator and H. Yao, principal investigator) which will model the timing of exposures in these human cohorts. This Administrative Core will organize and facilitate the overall program of research, including oversight, coordination and integration of all Center-related activities. This will include organizing and scheduling monthly meetings of the internal advisory committee and monthly joint lab meetings of the Center investigators, organizing yearly meetings of the Center scientists with the six-member External Advisory Committee, coordinating Community Engagement activities, and working with the Pediatric Health Specialists to translate relevant information for those in the pediatric health care community. Statistical support for the two pilot human cohort studies (Projects 1 and 2) will be provided via a subcontract to Dr. Joseph Gardiner at Michigan State University, which will be managed through the administrative core. As Director and Associate Director of the Formative Center, Drs. Susan Schantz and Jodi Flaws will be responsible for conducting Internal and External Advisory Committee meetings and regularly evaluating the research progress of each of the projects. They will also be responsible for general fiscal oversight of the Center. Dr. Flaws will have full authority to make decisions in Dr. Schantz's absence.

Pregnant women are exposed to endocrine disrupting chemicals such as phthalates and bisphenol A (BPA) through their use of personal care products and plastics. In animal models, phthalates and BPA cause developmental abnormalities, but littie is known about whether these chemicals are associated with adverse developmental outcomes in humans. The proposed pilot study will develop novel methods to assess the impact of prenatal BPA or phthalate exposure on sexually dimorphic physical and behavioral endpoints during the first few months of life and it will identify reliable and valid measures of cognitive function in newborns that are sensitive to prenatal chemical exposure and predictive of lasting cognitive deficits. The overall hypothesis of the proposed pilot study is that maternal exposure to phthalates and/or BPA is associated with adverse developmental outcomes in their offspring. The specific objectives of the proposed project are to: 1) assess exposure to phthalates and BPA in a sample of pregnant women, 2) examine the association between prenatal phthalate and BPA exposure and physical development in infants, 3) examine the association between prenatal phthalate and BPA exposure and cognition in infants, and 4) investigate whether polymorphisms in estrogen receptor (ER) alpha and ER beta increase susceptibility to prenatal phthalate or BPA exposure. To complete the proposed work. 150 pregnant women age 18-40 and their infants will be recruited from a local hospital. The pregnant women will complete a 24-hour product use diary and provide urine samples for assessments of total BPA and 9 phthalate metabolites. In addition, pregnant women will donate cord blood for measurement of selected ER polymorphisms. Key physical and cognitive outcomes will be assessed at birth, and cognitive outcomes will also be assessed at 4.5 and 7.5 months of age. The relationship behween measures of exposure and reported product use, and the relationship behween maternal exposures and physical or cognitive outcomes in infants will be examined in statistical regression models. The proposed study will provide important pilot data about the nature of phthalate and BPA exposure in pregnant women and the risk of developmental abnormalities in their infants. The results will provide a strong basis for expansion of the pilot birth cohort into a larger prospective birth cohort with longitudinal follow-up of the children from birth through puberty.

The primary goal of this Formative Center is to assemble a multidisciplinary team of experts to address the critical gaps in our knowledge of the risks to human development from bisphenol A and phthalate exposure. We will actively involve junior investigators in this research effort, and actively communicate our research findings to the healthcare community and the public. At the heart of the research effort will be two pilot human cohort studies¿a birth cohort to be recruited in Urbana-Champaign, IL (S. Schantz, PI) and an adolescent cohort to be assessed as part of an ongoing study in New Bedford, MA (S. Korrick, PI). The Formative Center will also include laboratory animal projects (J. Juraska, PI and H. Yao, PI) which will model the timing of exposures in these human cohorts. This Administrative Core will organize and facilitate the overall program of research, including oversight, coordination and integration of all Center-related activities. This will include organizing and scheduling monthly meetings of the internal advisory committee and monthly joint lab meetings of the Center investigators, organizing yearly meetings of the Center scientists with the six-member External Advisory Committee, coordinating Community Engagement activities, and working with the Pediatric Health Specialists to translate relevant information for those in the pediatric health care community. Statistical support for the two pilot human cohort studies (Projects 1 and 2) will be provided via a subcontract to Dr. Joseph Gardiner at Michigan State University, which will be managed through the administrative core. As Director and Associate Director of the Formative Center, Drs. Susan Schantz and Jodi Flaws will be responsible for conducting Internal and External Advisory Committee meetings and regularly evaluating the research progress of each of the projects. They will also be responsible for general fiscal oversight of the Center. Dr. Flaws will have full authority to make decisions in Dr. Schantz's absence.

Description (provided by applicant): The primary goal of this Formative Center is to assemble a multidisciplinary team of experts to address the critical gaps in our knowledge of the risks to human development from bisphenol A and phthalate exposure. We will actively involve junior investigators in this research effort, and actively communicate our research findings to the healthcare community and the public. At the heart of the research effort will be two pilot human cohort studies-a birth cohort to be recruited in Urbana-Champaign, IL (S. Schantz, principal investigator) and an adolescent cohort to be assessed as part of an ongoing study in New Bedford, MA (S. Korrick, principal investigator). The Formative Center will also include laboratory animal projects (J. Juraska, principal investigator and H. Yao, principal investigator) which will model the timing of exposures in these human cohorts. This Administrative Core will organize and facilitate the overall program of research, including oversight, coordination and integration of all Center-related activities. This will include organizing and scheduling monthly meetings of the internal advisory committee and monthly joint lab meetings of the Center investigators, organizing yearly meetings of the Center scientists with the six-member External Advisory Committee, coordinating Community Engagement activities, and working with the Pediatric Health Specialists to translate relevant information for those in the pediatric health care community. Statistical support for the two pilot human cohort studies (Projects 1 and 2) will be provided via a subcontract to Dr. Joseph Gardiner at Michigan State University, which will be managed through the administrative core. As Director and Associate Director of the Formative Center, Drs. Susan Schantz and Jodi Flaws will be responsible for conducting Internal and External Advisory Committee meetings and regularly evaluating the research progress of each of the projects. They will also be responsible for general fiscal oversight of the Center. Dr. Flaws will have full authority to make decisions in Dr. Schantz's absence.

Pregnant women are exposed to endocrine disrupting chemicals such as phthalates and bisphenol A (BPA) through their use of personal care products and plastics. In animal models, phthalates and BPA cause developmental abnormalities, but littie is known about whether these chemicals are associated with adverse developmental outcomes in humans. The proposed pilot study will develop novel methods to assess the impact of prenatal BPA or phthalate exposure on sexually dimorphic physical and behavioral endpoints during the first few months of life and it will identify reliable and valid measures of cognitive function in newborns that are sensitive to prenatal chemical exposure and predictive of lasting cognitive deficits. The overall hypothesis of the proposed pilot study is that maternal exposure to phthalates and/or BPA is associated with adverse developmental outcomes in their offspring. The specific objectives of the proposed project are to: 1) assess exposure to phthalates and BPA in a sample of pregnant women, 2) examine the association between prenatal phthalate and BPA exposure and physical development in infants, 3) examine the association between prenatal phthalate and BPA exposure and cognition in infants, and 4) investigate whether polymorphisms in estrogen receptor (ER) alpha and ER beta increase susceptibility to prenatal phthalate or BPA exposure. To complete the proposed work. 150 pregnant women age 18-40 and their infants will be recruited from a local hospital. The pregnant women will complete a 24-hour product use diary and provide urine samples for assessments of total BPA and 9 phthalate metabolites. In addition, pregnant women will donate cord blood for measurement of selected ER polymorphisms. Key physical and cognitive outcomes will be assessed at birth, and cognitive outcomes will also be assessed at 4.5 and 7.5 months of age. The relationship behween measures of exposure and reported product use, and the relationship behween maternal exposures and physical or cognitive outcomes in infants will be examined in statistical regression models. The proposed study will provide important pilot data about the nature of phthalate and BPA exposure in pregnant women and the risk of developmental abnormalities in their infants. The results will provide a strong basis for expansion of the pilot birth cohort into a larger prospective birth cohort with longitudinal follow-up of the children from birth through puberty.

The primary goals of this Children's Center are to use a mulfidisciplinary approach to address crifical gaps in our knowledge about the impact of exposure to endocrine disrupting chemicals (phthalates/BPA) on child development, to actively involve junior invesfigators in this research effort, and to actively communicate our research findings to parents, childcare providers and healthcare providers. There are three common themes that unite the three research projects and the Outreach and Translation Core (COTC) of this Center: (1) assessment of exposures during two critical developmental windows (prenatal and adolescent), (2) investigation of joint effects of phthalate/BPA exposure and a high fat diet/obesity, and (3) investigation of the role of oxidative stress and infiammation in mediafing effects. At the heart of the research effort will be two human cohorts (Project 1)¿a prospective pre-birth cohort currently in progress in Urbana, Illinois and an adolescent cohort to be assessed as part of a long-standing prospecfive study in New Bedford, Massachusetts. The Center will also include laboratory animal projects (Projects 2 and 3) which will model the timing of exposures in these human cohorts, a COTC, and this administrative core which will provide oversight, coordination and integration of all Center-related activities. The responsibilites ofthe Administrafive Core will include organizing and scheduling monthly meefings ofthe Internal Advisory Committee and monthly research team meetings ofthe Center investigators, organizing yearly meetings of the Center scientists with the six-member External Advisory Committee, coordinating the career development activities ofthe center, and facilitating interactions ofthe Pediatric Health Specialist with the COTC to communicate research findings to the healthcare community. As Director and Associate Director of the Children's Center, Drs. Susan Schantz and Jodi Flaws will be responsible for conducting Internal and External Advisory Committee meetings and regularly evaluating the research progress of each of the projects, as well as the outreach activites ofthe COTC. They will also be responsible for general fiscal oversight of the Center. Dr. Flaws will have full authority to make decisions in Dr. Schantz's absence.

DESCRIPTION (provided by applicant) The primary goals of this Children's Center are to use a multidisciplinary approach to address critical gaps in our knowledge about the impact of exposure to endocrine disrupting chemicals (phthalates/BPA) on child development, to actively involve junior investigators in this research effort, and to actively communicate our research findings to parents, childcare providers and healthcare providers. There are three common themes that unite the three research projects and the Outreach and Translation Core (COTC) of this Center: (1) assessment of exposures during two critical developmental windows (prenatal and adolescent), (2) investigation of joint effects of phthalate/BPA exposure and a high fat diet/obesity, and (3) investigation of the role of oxidative stress and inflammation in mediating effects. At the heart of the research effort will be two human cohorts (Project 1)-a prospective pre-birth cohort currently in progress in Urbana, Illinois and an adolescent cohort to be assessed as part of a long-standing prospective study in New Bedford, Massachusetts. The Center will also include laboratory animal projects (Projects 2 and 3) which will model the timing of exposures in these human cohorts, a COTC, and this administrative core which will provide oversight, coordination and integration of all Center-related activities. The responsibilities of the Administrative Core will include organizing and scheduling monthly meetings of the Internal Advisory Committee and monthly research team meetings of the Center investigators, organizing yearly meetings of the Center scientists with the six-member External Advisory Committee, coordinating the career development activities of the Center, and facilitating interactions of the Pediatric Health Specialist with the COTC to communicate research findings to the healthcare community. As Director and Associate Director of the Children's Center, Drs. Susan Schantz and Jodi Flaws will be responsible for conducting Internal and External Advisory Committee meetings and regularly evaluating the research progress of each of the projects, as well as the outreach activities of the COTC. They will also be responsible for general fiscal oversight of the Center. Dr. Flaws will have full authority to make decisions in Dr. Schantz's absence. Relevance: Phthalates and BPA are endocrine disrupting chemicals that are found in many consumer products. Exposure is widespread, but the impact of this exposure on child health and development is not well-understood. This Center's research will fill an important gap in our knowledge by investigating the effects of these chemicals, both alone and combination with a high fat diet on reproductive and neural development.

PROJECT SUMMARY We propose to integrate two pregnancy cohorts currently under recruitment at the University of Illinois and the University of California, San Francisco (UCSF) to form a larger geographically, socio-economically, racially and ethnically diverse cohort (ECHO.CA.IL) to study the cumulative impact of chemical exposures and maternal psychosocial stress on birth outcomes and early neurodevelopment. We will focus on two groups of high- production volume endocrine disrupting chemicals (EDCs) regularly detected in pregnant women, which research suggests may impact development, but for which data on child health outcomes is sparse: phenols (bisphenols, benzophenone, dichlorophenols, parabens, triclosan, triclocarban) and perfluorinated alkyl substances (PFAS). We will measure three indices of chronic stress and resilience: 1) Perceptual - perceptions of social standing and stress exposures in household, neighborhood, and work environments; 2) Place-based ? neighborhood level socioeconomic status, civic engagement, green space and built environment; and 3) Biomarkers - telomere length in maternal and umbilical cord leukocytes and corticotropin releasing hormone (CRH) levels in maternal plasma. We will measure birth outcomes (birth weight and gestational age) and we will use innovative approaches to assess basic cognitive functions including working memory, attention, information processing, and social cognition in infancy and early childhood. We will address three specific aims: (1) Evaluate the relationship between prenatal exposures to EDCs and measures of adverse birth outcomes and cognitive development of offspring. (2) Evaluate the relationship between measures of prenatal stress and measures of adverse birth outcomes and cognitive development of offspring. Importantly, for this aim we will also assess whether biomarkers of stress response mediate the relationship between perceptual and place-based stress and developmental outcomes. (3) Evaluate whether maternal stress modifies observed relationships between EDC exposures and measures of adverse birth outcomes or cognitive development of offspring. During the planning period, we will harmonize data collection and management (including biospecimens, stress measurements, and measurements of birth outcomes and cognitive functions) across our two cohorts to prepare for merging our two data sets and for sharing our data with the ECHO Data Analysis Center. During UG3 stage we will also actively participate in development and implementation of the ECHO-wide study protocol contributing expertise and methodology for assessing maternal stress, offspring cognitive development and our experiences integrating and harmonizing data collection across our two geographically distinct pregnancy cohorts. In summary, our innovative research approach will contribute to ECHO by providing a framework for integrating cumulative chemical exposures with chronic psychosocial stress and sources of resilience in order to understand the complex set of prenatal etiologic factors that shape developmental outcomes in infancy and early childhood.

Project Summary/Abstract The placenta is an essential organ in human development, and disruption of its function can result in problems in pregnancy including miscarriage, preterm labor, preeclampsia and intrauterine growth restriction. Additionally, disrupted placenta function during pregnancy has been associated with a great number of disorders and diseases that do not present until much later in the offspring's life such as metabolic syndrome, cardiovascular diseases, developmental delay and other neurodevelopmental and psychiatric disorders. How the exposures encountered in the environment drive alterations in placenta structure and function is poorly understood, and placenta function is difficult to assess in vivo using noninvasive methods. We propose to understand how gene expression is altered in the placenta during gestation by noninvasively characterizing the placenta transcriptome in association with exposure to chemicals known to alter endocrine signaling. These chemicals, called phthalates, are commonly found in a variety of commercial products such as plastics and personal care products, and phthalate exposure has also been shown to effect neurodevelopment. The link between phthalate exposure and placenta gene expression in vivo is not yet clear; therefore we have assembled a team comprised of neuroscientists, placenta biologists, environmental epidemiologists, and genomics experts do address how phthalate exposure and gestational age effects gene that are expressed in the placenta but not in other tissues. One of the advantages of the proposed research is that we will assess placenta gene expression noninvasively through RNA molecules contained in extracellular vesicles that are secreted into the urine of pregnant women. Collecting gene expression data and chemical exposure data from urine is highly clinically relevant, and we expect our approach will have clear translational applications just as home pregnancy tests that rely on the detection of placenta produced hormones in urine have become common. Our proposed study will provide the basic science background for the development of rapid, noninvasive tests for assessing placenta function, chemical exposures, and ultimately problems in neurodevelopment and other danger signals during pregnancy.

? DESCRIPTION (provided by applicant): This is a competing continuation application to renew the Illinois Research Training Program in Environmental Toxicology. The Program, established in 2000 educates pre-and post-doctoral trainees in reproductive, developmental and endocrine toxicology. The need for training in these aspects of toxicology is every bit as urgent today as it was 15 years ago when the Training Program was first conceived. Chemicals that act as endocrine disruptors continue to dominate environmental health concerns. The Program unites two long- standing areas of research excellence on the University of Illinois campus-environmental toxicology and reproductive biology. Nineteen faculty members from eight departments in four colleges will serve as preceptors, making this a truly interdisciplinary training program. Eleven, including the Program director and associate director, have been affiliated with the Training Program since its early days, providing long-term stability and continuity. Four joined around the time of our last competitive renewal and five joined within the past year. The recent addition of new preceptors has allowed us to expand training opportunities into important new research areas including environmental obesogens, environmental impacts on the microbiome, environmental impacts on neuro-immune function, and interactions of environmental exposures with drugs of abuse. The preceptors are well funded, collaborate extensively, and have a wealth of experience mentoring students and post-docs. Together they currently have over 40 federally funded research grants totaling more than 8 million dollars/year direct costs, and 27 grants from other sources totaling over 2 million dollars/year direct costs. Collaborations among labs working at the molecular, cellular, whole animal and human health levels provide trainees with the unique opportunity to directly observe and participate in translational research. Selection of the 4 pre- and 3 post-doctoral trainees thi Program supports is based on academic success, strength of the proposed research, relevance of the research to Program goals, and commitment to toxicology. Trainees are appointed for 2 years. The Program offers a broad range of graduate level courses in toxicology. In addition to fulfilling departmental requirements, all pre-doctoral trainees take basic toxicology, systems toxicology, and at least one other advanced toxicology course. Post-doctoral trainees conduct independent research. All pre- and post-doctoral trainees attend weekly toxicology research seminars, a monthly toxicology journal club, and a course on research ethics in toxicology, coordinated by the director and team taught by the preceptors. Trainees also attend career development workshops and take a grant writing class. They are required to present their research in the toxicology seminar and strongly encouraged to attend international meetings to present their work. Recruitment of trainees from under-represented groups is a high priority and strong efforts to diversify the Training Program will continue in the next funding period. Trainees are expected to pursue toxicology-related careers in academia, government or industry.

PROJECT SUMMARY ? Parent UH3 OD023272 We propose to integrate two pregnancy cohorts currently under recruitment at the University of Illinois and the University of California, San Francisco (UCSF) to form a larger geographically, socio-economically, racially and ethnically diverse cohort (ECHO.CA.IL) to study the cumulative impact of chemical exposures and maternal psychosocial stress on birth outcomes and early neurodevelopment. We will focus on two groups of highproduction volume endocrine disrupting chemicals (EDCs) regularly detected in pregnant women, which research suggests may impact development, but for which data on child health outcomes is sparse: phenols (bisphenols, benzophenone, dichlorophenols, parabens, triclosan, triclocarban) and perfluorinated alkyl substances (PFAS). We will measure three indices of chronic stress and resilience: 1) Perceptual - perceptions of social standing and stress exposures in household, neighborhood, and work environments; 2) Place-based ? neighborhood level socioeconomic status, civic engagement, green space and built environment; and 3) Biomarkers - telomere length in maternal and umbilical cord leukocytes and corticotropin releasing hormone (CRH) levels in maternal plasma. We will measure birth outcomes (birth weight and gestational age) and we will use innovative approaches to assess basic cognitive functions including working memory, attention, information processing, and social cognition in infancy and early childhood. We will address three specific aims: (1) Evaluate the relationship between prenatal exposures to EDCs and measures of adverse birth outcomes and cognitive development of offspring. (2) Evaluate the relationship between measures of prenatal stress and measures of adverse birth outcomes and cognitive development of offspring. Importantly, for this aim we will also assess whether biomarkers of stress response mediate the relationship between perceptual and place-based stress and developmental outcomes. (3) Evaluate whether maternal stress modifies observed relationships between EDC exposures and measures of adverse birth outcomes or cognitive development of offspring. During the planning period, we will harmonize data collection and management (including biospecimens, stress measurements, and measurements of birth outcomes and cognitive functions) across our two cohorts to prepare for merging our two data sets and for sharing our data with the ECHO Data Analysis Center. During UG3 stage we will also actively participate in development and implementation of the ECHO- wide study protocol contributing expertise and methodology for assessing maternal stress, offspring cognitive development and our experiences integrating and harmonizing data collection across our two geographically distinct pregnancy cohorts. In summary, our innovative research approach will contribute to ECHO by providing a framework for integrating cumulative chemical exposures with chronic psychosocial stress and sources of resilience in order to understand the complex set of prenatal etiologic factors that shape developmental outcomes in infancy and early childhood.

PROJECT SUMMARY This Administrative Supplement will contribute important findings related to dietary predictors of newborn outcomes in the Cumulative Effects of Prenatal Stress and Chemical Exposures on Child Development (ECHO.CA.IL, NIH 5UH3OD023272) parent study. ECHO.CA.IL is co-led by researchers at the University of Illinois, Urbana-Champaign and the University of California, San Francisco and is a part of the nation-wide Environmental influences of Child Health Outcomes Program (ECHO). The mission of the ECHO program is to enhance the health of children for generations to come, and a critical goal of ECHO.CA.IL is to use innovative methods to address gaps in our knowledge of the impacts of prenatal exposures to ubiquitous endocrine disrupting chemicals (EDC) and chronic maternal stress (as well as the interaction of these) on birth outcomes and child development. The proposed Supplement aims align with both the parent study and with two of the five target health-related goals in the ECHO program: (1) pre-, peri-, and postnatal outcomes, and (2) positive health. The proposed research will utilize data from the Illinois Kids Development Study (I-KIDS), which is the prospective pregnancy cohort being recruited at the University of Illinois. I-KIDS, enrolls women in the first trimester of pregnancy and longitudinally follows mothers and their children during pregnancy and throughout childhood. In addition to evaluating the impacts of EDCs and maternal stress on child outcomes, we also have a strong interest in assessing diet in I-KIDS mothers to understand whether diet could buffer the negative effects of EDCs and stress during pregnancy. To that end, a novel preliminary finding from I-KIDS mothers and babies demonstrates that high maternal diet quality may mitigate the negative effects of one class of EDCs (parabens) on birth outcomes, suggesting that maternal diet may protect pregnant women and their infants from the deleterious effects of EDCs. However, while almost all (99%) of pregnant women in our cohort consume some type of vitamin/mineral supplement and 97% consume a prenatal supplement, we have not investigated how supplements contribute to pregnancy outcomes in our cohort, or whether certain patterns of supplement intake modify relationships between EDCs and birth outcomes. Therefore, the overarching goal of the current research will be to use an innovative statistical approach developed to deal with complex mixtures of environmental chemicals (weighted quantile sum regression) to 1) evaluate associations between patterns of micronutrient intake from supplements in pregnancy and birth outcomes (birth weight, length, head circumference, gestational age at birth), and 2) understand how these patterns of micronutrient intakes from supplements interact with maternal diet quality and EDC exposures to influence birth outcomes.

PROJECT SUMMARY ? Parent UH3 OD023272 We propose to integrate two pregnancy cohorts currently under recruitment at the University of Illinois and the University of California, San Francisco (UCSF) to form a larger geographically, socio-economically, racially and ethnically diverse cohort (ECHO.CA.IL) to study the cumulative impact of chemical exposures and maternal psychosocial stress on birth outcomes and early neurodevelopment. We will focus on two groups of highproduction volume endocrine disrupting chemicals (EDCs) regularly detected in pregnant women, which research suggests may impact development, but for which data on child health outcomes is sparse: phenols (bisphenols, benzophenone, dichlorophenols, parabens, triclosan, triclocarban) and perfluorinated alkyl substances (PFAS). We will measure three indices of chronic stress and resilience: 1) Perceptual - perceptions of social standing and stress exposures in household, neighborhood, and work environments; 2) Place-based ? neighborhood level socioeconomic status, civic engagement, green space and built environment; and 3) Biomarkers - telomere length in maternal and umbilical cord leukocytes and corticotropin releasing hormone (CRH) levels in maternal plasma. We will measure birth outcomes (birth weight and gestational age) and we will use innovative approaches to assess basic cognitive functions including working memory, attention, information processing, and social cognition in infancy and early childhood. We will address three specific aims: (1) Evaluate the relationship between prenatal exposures to EDCs and measures of adverse birth outcomes and cognitive development of offspring. (2) Evaluate the relationship between measures of prenatal stress and measures of adverse birth outcomes and cognitive development of offspring. Importantly, for this aim we will also assess whether biomarkers of stress response mediate the relationship between perceptual and place-based stress and developmental outcomes. (3) Evaluate whether maternal stress modifies observed relationships between EDC exposures and measures of adverse birth outcomes or cognitive development of offspring. During the planning period, we will harmonize data collection and management (including biospecimens, stress measurements, and measurements of birth outcomes and cognitive functions) across our two cohorts to prepare for merging our two data sets and for sharing our data with the ECHO Data Analysis Center. During UG3 stage we will also actively participate in development and implementation of the ECHO- wide study protocol contributing expertise and methodology for assessing maternal stress, offspring cognitive development and our experiences integrating and harmonizing data collection across our two geographically distinct pregnancy cohorts. In summary, our innovative research approach will contribute to ECHO by providing a framework for integrating cumulative chemical exposures with chronic psychosocial stress and sources of resilience in order to understand the complex set of prenatal etiologic factors that shape developmental outcomes in infancy and early childhood.

Project Summary We propose to integrate two pregnancy cohorts currently under recruitment at the University of Illinois and the University of California, San Francisco (UCSF) to form a larger geographically, socio-economically, racially and ethnically diverse cohort (ECHO.CA.IL) to study the cumulative impact of chemical exposures and maternal psychosocial stress on birth outcomes and early neurodevelopment. We will focus on two groups of high production volume endocrine disrupting chemicals (EDCs) regularly detected in pregnant women, which research suggests may impact development, but for which data on child health outcomes is sparse: phenols (bisphenols, benzophenone, dichlorophenols, parabens, triclosan, triclocarban) and perfluorinated alkyl substances (PFAS). We will measure three indices of chronic stress and resilience: 1) Perceptual ? perceptions of social standing and stress exposures in household, neighborhood, and work environments; 2) Place-based ? neighborhood level socioeconomic status, civic engagement, green space and built environment; and 3) Biomarkers - telomere length in maternal and umbilical cord leukocytes and corticotropin releasing hormone (CRH) levels in maternal plasma. We will measure birth outcomes (birth weight and gestational age) and we will use innovative approaches to assess basic cognitive functions including working memory, attention, information processing, and social cognition in infancy and early childhood. We will address three specific aims: (1) Evaluate the relationship between prenatal exposures to EDCs and measures of adverse birth outcomes and cognitive development of offspring. (2) Evaluate the relationship between measures of prenatal stress and measures of adverse birth outcomes and cognitive development of offspring. Importantly, for this aim we will also assess whether biomarkers of stress response mediate the relationship between perceptual and place-based stress and developmental outcomes. (3) Evaluate whether maternal stress modifies observed relationships between EDC exposures and measures of adverse birth outcomes or cognitive development of offspring. During the planning period, we will harmonize data collection and management (including biospecimens, stress measurements, and measurements of birth outcomes and cognitive functions) across our two cohorts to prepare for merging our two data sets and for sharing our data with the ECHO Data Analysis Center. During UG3 stage we will also actively participate in development and implementation of the ECHO-wide study protocol contributing expertise and methodology for assessing maternal stress, offspring cognitive development and our experiences integrating and harmonizing data collection across our two geographically distinct pregnancy cohorts. In summary, our innovative research approach will contribute to ECHO by providing a framework for integrating cumulative chemical exposures with chronic psychosocial stress and sources of resilience in order to understand the complex set of prenatal etiologic factors that shape developmental outcomes in infancy and early childhood.