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Reproductive Toxicology Division
Reproductive Toxicology Division
Long Term Effects Team (LTE)
Overview
The developmental environment plays an important role in determining a number of physiological parameters in the developing individual that, in turn, affect adult health and risk of diseases including coronary heart disease, hypertension, type II diabetes, and stroke. Birth weight is often used as a biomarker, and studies have also provided evidence that a female's in utero and early postnatal environments influence her own reproductive success later in life (transgenerational effects). With the exception of administered glucocorticoids, chemically-induced low fetal or birth weight has not been explored in animal models for its relationship to fetal programming and risk of adult onset of disease. Studies in the LTE projects involve developmental exposures in rodents followed by long-term monitoring of health parameters in the offspring. Undernutrition, dexamethasone treatment, and exposure to known developmental toxicants have been used in this work to examine long term effects of specific developmental exposures.
The team's research is focused on these the following Long-Term Goals (LTG) in EPA's Multi-Year Plans (MYP):
- MYP: Human Health
- LTG 3: Characterize and provide adequate protection for susceptible subpopulations (susceptibility)
- Team Lead
- John Rogers, Supervisory Research Biologist Biosketch
- Principal Investigators
- Bob Zucker, Research Biologist Biosketch
- Research Support
- Michael Gage, Scientist (SEEP)*
- Brian Grey, Biologist Biosketch
- Joel Norwood, Biologist Biosketch
- Ellen Rogers, Biologist Biosketch
- Post-Doctoral Trainee Rob Ellis-Hutchings Biosketch
*Senior Environmental Employment Program
LTE Team Projects
Long Term Effects of Adverse Environments During Development: Effects in Adulthood in Rats Exposed to Toxicants or Under-nutrition In Utero
Contact: John Rogers
Clinical epidemiological studies have shown significant inverse correlations between birth weight and incidence of various diseases later in life, including hypertension, coronary heart disease, diabetes, obesity, schizophrenia, and early onset chronic renal failure. The general hypothesis for this project is: the physiologic and metabolic development of an organism is shaped in part by its developmental environment, and adverse developmental conditions can produce permanent and deleterious physiological changes. To test the hypothesis, rodents are subjected to toxic insult or undernutrition during development, and their health is monitored throughout life. Physiological measurements are carried out at a variety of ages including assessments of the cardiovascular system, glucose metabolism, body composition, aging and lifespan, and tumor development or other pathology. This project has the potential to change the basic study designs for assessing developmental toxicity and to reveal latent toxic effects not before seen. This work may also bring significant improvements to the risk assessment process.
Prenatal Perfluoroalkyl Acid (PFAA) Exposure and Adult Health Outcomes
Contact: Suzanne Fenton
To address the scientific question of whether there are long term health effects of early life exposure to perfluorooctanoic acid (PFOA), objectives of this project's research are to (1) evaluate the latent effects of PFOA exposure in a mouse model; (2) identify sensitive health endpoints following developmental exposure that can be used for risk assessment; and (3) determine underlying factors, such as obesity, hormonal changes, chemical body burden, and reproductive aging time, that may lead to the adverse health effects. To evaluate the long term health effects of PFOA under this project, a developmental exposure paradigm has been implemented. Endpoints monitored in offspring of treated animals in some of the studies include estrous cyclicity and monthly body weights, and sera is collected monthly in order to examine mode(s) of action for long term health outcomes (hormones, growth factors, triglycerides, etc.) Among the aims for future efforts are to: (1) determine the sensitive tissues responding at low doses; (2) describe PFOA effects on hormonally controlled tissues, and (3) determine the mechanisms of action for PFOA in these tissues. These studies are in direct response to the needs of the EPA Office of Pollution Prevention and Toxics for risk assessment.
Intergenerational Effects in the Sprague-Dawley Rat: Long Term Effects of Pre- and Post-natal Undernutrition
Contact: Neil Chernoff
This project addresses two significant issues: (1) the intergenerational effect in female reproduction; and (2) long term effects of pre- and postnatal under-nutrition. In recent years an extensive body of data has been generated in both epidemiology and laboratory animal studies indicating that prenatal "imprinting" is responsible for increased cardiovascular disease, type II diabetes, and obesity later in life. The most commonly noted adverse effect in human newborns is reduced birth weight. The designation "small for gestational age" (SGA) is based on the size of the infants, and "intrauterine growth retardation" (IUGR) is based on weight. Intergenerational effects are indicated by a correlation between the pre- and postnatal environments of women and their own pregnancy outcomes. Rationales for study of this phenomenon in animals include: (1) the study of maternal undernutrition-induced IUGR populations of laboratory animals is essential for valid interpretations of data from xenobiotic exposed IUGR populations; and (2) the effects of IUGR and/or early undernutrition on cognitive and cardiovascular processes as people reach old age should receive increased attention as the number of older people increases. The approach in this project includes the creation of populations of animals with IUGR under prenatal conditions with or without food restriction under postnatal conditions, and vice versa.
Relationships of Maternal and Fetal Toxicity: Analysis of the NTP Developmental Toxicity Bioassays
Contact: Neil Chernoff
Studies have shown that maternal food restriction during gestation results in significant reduction in fetal weight at term. This relationship is important because the in utero fetal weight reduction is the most common form of agent-induced developmental toxicity and is often used to determine the No Observed Adverse Effect Level (NOAEL) used to set exposure limits. The question arises of whether a given adverse fetal effect is due to the direct actions of the test agent or if it is due to general maternal toxicity. This project utilizes bioassay data sets generated by the National Toxicology Program (NTP) to tabulate maternal and fetal toxicity endpoints. Several questions are addressed through analysis of these data including: (1) is there an association between patterns of maternal weight loss during gestation and the type and extent of adverse fetal effects? (2) are there general conclusions about maternal and fetal weights that apply to the various species of commonly used laboratory animals? and (3) can the analysis of the NTP data sets be used to develop hypotheses concerning the relationship of maternal and fetal toxicity that can be tested experimentally? An understanding of the relationship between maternal weight changes during gestation and fetal weight at term would add greatly to our ability to interpret the biological significance of adverse fetal effects.
Lactational Transfer of Xenobiotics: Animal Studies and Human Data
Contact: Suzanne Fenton
Because of the importance of milk as a means of nutrition for developing offspring, it is critical to understand transference of environmental compounds to this nutrient source. Environmental compounds may be on the rise in human serum and milk, and only limited information is available for these lipophilic, water soluble, and protein binding agents. Questions arising include: (1) is milk a significant source of infant exposure to known endocrine disruptors? and (2) can known endocrine disrupting compounds adversely affect functional differentiation of the mammary gland? Research objectives are to (1) evaluate the effects of selected endocrine disrupting compounds on mammary gland development and functional differentiation; (2) determine if mammary gland development is a sensitive health endpoint which can be used for risk assessment; and (3) measure endocrine disrupting compounds of concern in milk of humans and compare with data from animal models. Data from the Methods Advancement in Milk Analyses (MAMA) study will provide the first reports of levels of some classes of compounds in breast milk in the world. Data from atrazine studies in this project are useful for the Office of Water and the Office of Prevention, Pesticides, and Toxic Substances for use in their risk assessments. Studies on perfluorooctanoic acid's (PFOA) developmental effects are fulfilling a need expressed in a PFOA Science Advisory Board report for understanding the timing of exposure with respect to effects.
Recent Publications
Publications are listed in reverse chronological order. The names of current RTD employees are in bold.
Rogers JM, Kavlock RJ. In press. Developmental toxicology. In: Casarett & Doull, editors. 7thed. New York, (NY): McGraw-Hill Companies.
Rayner J, Enoch R, Wolf DC, Fenton SE. 2007. Atrazine-induced reproductive tract alterations after transplacental and lactational exposure in male Long-Evans rats. 218:238-248. Abstract
Hines EP, Raynor JL, Barbee RR, Moreland RA, Valcour A, Schmid JE, Fenton SE. 2007. Assays for endogenous components of human milk: comparison of fresh and frozen samples and corresponding analytes in serum. J Hum Lact. 23:144-56. Abstract
Enoch R, Stanko J, Greiner S, Youngblood G, Rayner J, Fenton SE. 2007. Mammary gland development as a sensitive end-point following acute prenatal exposure to a low dose atrazine metabolite mixture in female Long-Evans rats. Environ Health Perspect. 115:541-547. Abstract
Moon HJ, Fenton SE, Shin JH, Kang IH, Kim TS, Hong JH, Kim SH, Han S. 2007. Gestational exposure to nonylphenol causes precocious mammary gland development in female rat offspring. J Reprod Dev. 53:333-344. Abstract
Rogers JM. 2006. The Barker Hypothesis: Implications for future directions in toxicology research. 13:536-540. Abstract
Fenton SE. 2006. Endocrine disrupting compounds (EDCs) and mammary gland development: early exposure and later life consequences. Endocrinology. 147:s18-s24. Abstract
Wang X, Bartolucci-Page E, Fenton SE, You L. 2006. Altered mammary gland development in male rats exposed to genistein and methoxychlor. Toxicol Sci. 91:93-103. Abstract
Berlin CM, Lakind JS, Fenton SE, Wang RY, Bates MN, Brent RL, Condon M, Crase BL, Dourson ML, Ettinger AS, Foos B, Furst P, Giacoia GP, Goldstein DA, Haynes SG, Hench KD, Kacew S, Koren G, Lawrence RA, Ma A. 2005. Conclusions and recommendations of the expert panel: technical workshop on human milk surveillance and biomonitoring for environmental chemicals in the United States. 68:1825-1831. Abstract
Rogers JM, Chernoff N, Keen CL, Daston GP. 2005. Evaluation and interpretation of maternal toxicity in segment II studies: issues, some answers and data needs. Toxicol Appl Pharmacol. 207:367-374. Abstract
Fenton SE, Condon M, Ettinger AS, Lakind JS, Mason A, McDiarmid M, Qian Z, Selevan SG. 2005. Collection and use of exposure data from human milk biomonitoring in the United States. J Toxicol Environ Health. 68:1691-1712. Abstract
Lau C, Rogers JM. 2004. Embryonic and fetal programming of physiological disorders in adulthood. 72:300-312. Abstract
Abbott BD, Buckalew AR, Leffler KE. 2005. Effects of epidermal growth factor (EGF), transforming growth factor-alpha (TGFalpha), and 2,3,7,8-tetrachlorodibenzo-p-dioxin on fusion of embryonic palates in serum-free organ culture using wild-type, EGF knockout, and TGFalpha knockout mouse strains. Birth Defects Res A Clin Mol Teratol. 73:447-454. Abstract
Abbott BD, Best DS, Narotsky MG. 2005. Teratogenic effects of retinoic acid are modulated in mice lacking expression of epidermal growth factor and transforming growth factor-alpha. Birth Defects Res A Clin Mol Teratol. 73:204-217. Abstract
Rayner JL, Enoch RR, Fenton SE. 2005. Adverse effects of prenatal exposure to atrazine during a critical period of mammary gland growth. Toxicol Sci. 87:255-266. Abstract
Rogers EH, Hunter ES, Rosen MB, Rogers JM, Lau C, Hartig PC, Francis BM, Chernoff N. 2003. Lack of evidence for intergenerational reproductive effects due to prenatal and postnatal undernutrition in the female CD-1 mouse. Reprod Toxicol. 17:519-525. Abstract