Evaluation of Endocrine-Distrupting Chemical Effects Across Multiple Levels of Biological Organization: Integration of Physiology Behavior and Population Dynamics In FishesEPA Grant Number: R827399
Title: Evaluation of Endocrine-Distrupting Chemical Effects Across Multiple Levels of Biological Organization: Integration of Physiology Behavior and Population Dynamics In Fishes
Investigators: Thomas, Peter
Current Investigators: Thomas, Peter , Rose, Kenneth A. , Fuiman, Lee A.
Institution: The University of Texas at Austin
EPA Project Officer: Klieforth, Barbara I
Project Period: October 1, 1997 through September 30, 1999 (Extended to February 29, 2004)
Project Amount: $862,290
RFA: Endocrine Disruptors (1997) RFA Text | Recipients Lists
Research Category: Economics and Decision Sciences , Health , Safer Chemicals , Endocrine Disruptors
The overall aim of the proposed research is to understand the nature, extent and mechanisms of reproductive and endocrine toxicity of a representative xenobiotic estrogen, o,p'-DDT, and a putative xenobiotic antiandrogen, p,p'-DDE, in an established vertebrate model, the teleost Atlantic croaker. The following specific hypotheses will be tested: (1) Embryological development, gonadal differentiation, puberty and gonadal growth are sensitive stages of the teleost reproductive life history cycle to disruption by estrogenic and antiandrogenic chemicals; (2) The reproductive toxicities of o,p'-DDT and p,p'-DDE in both male and female croaker are primarily due to their estrogenic and antiandrogenic activities, respectively; (3) Endocrine disruption in males by xenoestrogens is mediated by their binding to the testicular estrogen receptor (ER) and disruption by antiandrogens in females is caused by binding to the ovarian androgen receptor (AR) in addition to the more traditional sites of estrogen and androgen action on the hypothalamus-pituitary-gonadal-liver axis; (4) Males in general are more sensitive than females to the reproductive effects of estrogenic chemicals.
The effects of in vivo administration o,p'-DDT will be compared to those of a synthetic estrogen, diethylstilbestrol and the effects of o,p'-DDE will be compared to those of an antiandrogen, cyproterone acetate (hypothesis 2). The effects of both DDT analogs will be compared to those of p,p'-DDD which does not bind to either the ER or AR in croaker (hypothesis 2) and a DDT mixture which approximates the analog composition in fish samples collected from the Southern California Bight. Both male and females will be exposed to the model compounds throughout their life cycles to obtain a comprehensive understanding of how chemicals impair teleost reproduction (hypothesis 1) and which reproductive life cycle stage is the most sensitive (hypothesis 4). Indices of reproductive function such as gametogenesis, sex differentiation, hatching success and sperm motility, as well as indices of endocrine function such as steroid and gonadotropin secretion and receptor concentrations will be measured after exposure to the model compounds. The sites of estrogen action will be determined by in situ hybridization of the ER mRNA and androgen action by AR assays (hypothesis 3). Estrogenic and antiandrogenic actions of the model compounds will be assessed by specific assays (hypothesis 2). Interactions of the model compounds with the ER and AR and will be examined in competition studies (hypothesis 2 and 3).
It is expected that the results will support the 5 hypotheses outlined above. We expect to demonstrate for the first time the involvement of an ER in fish testes in mediating the adverse effects of xenobiotic estrogens on testicular function and the involvement of the AR in mediating the toxic actions of antiandrogens on ovarian function in vertebrates. These studies are expected to provide mechanistic explanations of how xenoestrogens and xenobiotic androgens can interfere with gonadal sex differentiation and reproductive development and induce feminization in fish and wildlife. The mechanisms of toxicity are expected to be similar to those reported in mammals and therefore can be extrapolated to other vertebrate groups. Our findings will be valuable for conducting risk assessments by state and federal agencies, especially for DDT contamination in fish populations in the Southern California Bight.