Grantee Research Project Results
2001 Progress Report: Use of a Transgenerational Model to Evaluate Threshold Effects of Endocrine Disrupting Chemicals in Fish
EPA Grant Number: R827098Title: Use of a Transgenerational Model to Evaluate Threshold Effects of Endocrine Disrupting Chemicals in Fish
Investigators: Foran, Christy M. , Slattery, Marc
Institution: University of Mississippi
EPA Project Officer: Hahn, Intaek
Project Period: October 1, 1998 through September 30, 2001
Project Period Covered by this Report: October 1, 2000 through September 30, 2001
Project Amount: $406,024
RFA: Exploratory Research - Environmental Biology (1998) RFA Text | Recipients Lists
Research Category: Biology/Life Sciences , Environmental Justice , Human Health , Aquatic Ecosystems
Objective:
The primary objective of this research project is to link whole animal reproductive impairment to alterations in morphological development and/or endocrine function following exposure to model endocrine disrupting chemicals. These model chemicals have different mechanisms of action, but will be assessed with the same endpoints to determine if there are common predictors of developmental or reproductive toxicity, or if different mechanisms induce different suites of biochemical/endocrine changes, thereby providing a "fingerprint" of the mechanisms.Progress Summary:
We currently have finished testing the effects of the third model endocrine disruptor on reproduction in Japanese medaka. Each model chemical was chosen based on its distinct mechanism of action. To meet the objective set forth in the grant, we have exposed medaka to purported endocrine disrupters during three critical life stages: in ovo, at sexual differentiation, and during reproduction. Because of the role of natural estrogens in sexual differentiation (Crews, 1994), it is necessary to explore whether exposure to estrogenic chemicals during critical periods of differentiation can alter the permanence and severity of the consequences of exposure. Early exposure, neonatally in mammals, has the potential to change the regulation of gene transcription producing long-term and even epigenetic changes in response to excess hormonal signaling (McLachlan, et al., 2001). These changes in gene regulation, or imprinting, have been implicated in the susceptibility to environmentally related diseases, including cancer (Jirtle, et al., 2000). The earliest exposure of developing nonmammalian embryos to steroid hormones is the sequestering of maternal steroids in egg yolk prior to fertilization.Cadmium has been tested as a model compound representing centrally acting endocrine disruptors. Cadmium exposure did not result in reproductive impairment, despite producing some changes circulating steroid concentration. Reexposure of in ovo treated males and females tended to increase estradiol levels in plasma. In addition, 1 µg/L cadmium exposure in ovo elevated male hepatic vitellogenin (VTG) relative to controls. Hence, steroid parameters were a better biomarker of cadmium exposure than changes in VTG. However, reproductive impairment was not correlated to either change in VTG or plasma steroids.
In addition, ethinylestradiol (EE), a potent estrogen used in oral contraceptives, has been tested. Developmental exposure produced no changes in adult vitellogenin or estrogen receptor content in the liver or circulating steroid concentrations, nor was reproduction effected. Reexposure of these adults inhibited reproduction, increased hepatic VTG and estrogen receptor (ER), and increased estrogen concentration measured in male plasma. The response to EE of developmentally exposed adult was similar to the response of untreated adult animals. Early developmental exposure of medaka does not appear to produce lasting effects on the endocrine system and reproduction. In ovo treatment with EE did not alter the reproductive capacity of Japanese medaka or the relationship between adult estrogen exposure and reproduction. However, parental treatment did change the relationship between adult exposure, ex vivo steroidogenesis, and circulating steroid concentrations. Surprisingly, parental exposure produced permanent changes in hepatic content of ER and VTG in the resulting adults, and was related to a diminishing of the response of males to estrogen exposure. The potential for transgenerational exposure to decrease the responsiveness of males to EE is supported by comparing the concentration-response curves for hepatic VTG and ER in males exposed in ovo and as hatchlings. Our results indicate that the relationship between biomarkers and estrogen exposure will be altered by the timing and frequency of exposure.
Currently, we are finishing our assessment of the cattle androgenic supplement, trebalone, on endocrine function in medaka. The adults raised as a result of each developmental exposure (F2 from adult exposure or mature animals from hatchling exposure) have been assessed for changes in reproductive endpoints. These animals are exposed for 14 days at concentrations ranging from 2.0 ng/L to 2000 ng/L, including a concentration in what is expected to be the environmentally relevant range (20 ng/L). We are currently evaluating the biochemical changes related to exposure. We will be presenting this data at the upcoming Society of Environmental Toxicology and Chemistry meeting.
References:
Crews D. Animal sexuality. Scientific American 1994;270:109-114.
Jirtle RL, Sander M, Barrett JC. Genomic imprinting and environmental disease susceptibility. Environmental Health Perspectives 2000;108(3):271-278.
McLachlan JA, Burow M, Chaing TC, Li SF. Gene imprinting in developmental toxicology: a possible interface between physiology and pathology. Toxicology Letters 2001;120:161-164.
Future Activities:
Our goals for the final year of the "Threshold Effects" grant include finishing the trenbalone work we have begun and looking transgenerationally at the effects of a weak estrogen, atrazine. Atrazine is a triazine herbicide with important agriculturial uses, and has been reported in runoff from fields and in groundwater. We do not anticipate major changes in our use of equipment, techniques, or materials.Journal Articles on this Report : 7 Displayed | Download in RIS Format
Other project views: | All 20 publications | 8 publications in selected types | All 7 journal articles |
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Type | Citation | ||
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Foran CM, Bennett ER, Benson WH. Developmental evaluation of a potential non-steroidal estrogen: triclosan. Marine Environmental Research 2000;50(1-5):153-156. |
R827098 (1999) R827098 (2000) R827098 (2001) |
Exit Exit Exit |
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Foran CM, Bennett ER, Benson WH. Exposure to environmentally relevant concentrations of different nonylphenol formulations in Japanese medaka. Marine Environmental Research 2000;50(1-5):135-139. |
R827098 (1999) R827098 (2000) R827098 (2001) |
Exit Exit Exit |
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Foran CM, Peterson BN, Benson WH. Influence of parental and developmental cadmium exposure on endocrine and reproductive function in Japanese medaka (Oryzias latipes). Comparative Biochemistry and Physiology C-Toxicology & Pharmacology 2002;133(3):345-354 |
R827098 (2001) |
not available |
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Foran CM, Peterson BN, Benson WH. Transgenerational and developmental exposure of Japanese medaka (Oryzias latipes) to ethinylestradiol results in endocrine and reproductive differences in the response to ethinylestradiol as adults. Toxicological Sciences 2002;68(2):389-402. |
R827098 (2001) |
Exit Exit |
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Foran CM, Peterson BN, Benson WH. Effects of ethinylestradiol on reproduction and endocrine function in Japanese medaka (Oryzias latipes): I. Developmental exposure. Toxicological Sciences. |
R827098 (2001) |
not available |
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Foran CM, Peterson BN, Benson WH. Effects of ethinylestradiol on reproduction and endocrine function in Japanese medaka (Oryzias latipes): II. Transgenerational exposure. Toxicological Sciences. |
R827098 (2001) |
not available |
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Metcalfe TL, Metcalfe CD, Kiparissis Y, Niimi AJ, Foran CM, Benson WH. Gonadal development and endocrine responses in Japanese medaka (Oryzias latipes) exposed to o,p′-DDT in water or through maternal transfer. Environmental Toxicology and Chemistry 2000;19(7):1893-1900. |
R827098 (1999) R827098 (2000) R827098 (2001) |
Exit |
Supplemental Keywords:
water, risk assessment, health effects, dose-response, metabolism, indicators, aquatic, environmental chemistry, biology, zoology, analytical, agriculture, wastewater, development, critical period, steroidogenesis, pituitary function, hatching success,, RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Toxics, Geographic Area, Health Risk Assessment, Environmental Chemistry, Endocrine Disruptors - Environmental Exposure & Risk, pesticides, State, endocrine disruptors, Risk Assessments, Biochemistry, Physical Processes, Endocrine Disruptors - Human Health, Biology, predictors of reproductive toxicity, testosterone, fish, altered sexual development, endocrine disrupting chemicals, Japanese medaka, plasma hormone levels, exposure, Mississippi (MS), cellular level endocrine status, atrazine, estrogen receptors, gonad morphology, transgenerational model, concentration-effect resposnses, epidemiologic studies, animal reporductive impairment, exposure assessmentRelevant Websites:
http://www.olemiss.edu/depts/pharmacology/etrp/index.html (Environmental Toxicology Research Program, University of Mississippi)
http://www.setac.org/ (Society of Environmental Toxicology and Chemistry)
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.