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Extramural Research

Final Report: Environmental Endocrine Disruption in Avian Wildlife

EPA Grant Number: R826298
Title: Environmental Endocrine Disruption in Avian Wildlife
Investigators: Lasley, Bill L. , Conley, Alan J. , Enan, Essam E. , Fry, D. Michael , Overstreet, James W.
Institution: University of California - Davis
EPA Project Officer: Reese, David H.
Project Period: February 1, 1998 through January 31, 2001
Project Amount: $437,544
RFA: Endocrine Disruptors (1997)
Research Category: Economics and Decision Sciences , Endocrine Disruptors

Description:

Objective:

The overall objective of this research project was to characterize the mechanisms by which halogenated aromatic hydrocarbons (HAHs) cause disruption of growth factor and steroid hormone signal transduction in the cells of avian wildlife species. Our general hypothesis was that the primary mechanism of toxic action of HAHs involves the activation of cytoplasmic signal transduction, which interferes with steroid hormone and growth factor functions. This hypothesis was based on results from laboratory mammals, which had demonstrated not only an interaction of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with sex steroids, but also a protective effect of estrogen in terms of the adverse effects of TCDD on most cell types in vivo and in vitro. The first 2 years of this study clearly demonstrated that while an interaction of TCDD and estrogen also was found in avian species, estrogen was not protective; rather, it increased the adverse effects of TCDD in avian species. Therefore, funding in the third year was directed towards gaining a better understanding of gender differences in toxicity in avian species, and specifically on the mechanism(s) of actions of HAHs and their interaction with estrogen.

Summary/Accomplishments (Outputs/Outcomes):

The results of wildlife studies suggest that the bioaccumulation of environmental toxicants leads to endocrine disruption, developmental abnormalities, and reproductive failure. Because the lipophilic nature of putative toxicants, such as organochlorines, promotes the concentration of these toxicants in the food chain, they have become prime candidates for the cause of reproductive failure and developmental defects in birds, reptiles, and amphibians. Parallel laboratory experiments have not replicated these adverse effects in rodent models; consequently, the field observations were interpreted to indicate that: (1) the types of exposures common in situ may be poorly replicated ex situ; (2) lower vertebrates are more sensitive to HAHs than the higher vertebrates commonly used in the laboratory; and/or (3) different mechanisms of toxicity operate in different genders and species. Despite the growing evidence that birds, reptiles, and amphibians are adversely affected by environmental hazards, there are few unifying concepts to explain the cellular mechanisms that link confirmed environmental exposures to the increased developmental defects and decline in populations that are observed.

We previously have shown that there are important similarities between the mechanisms that mediate the physiologic actions of sex steroid hormones and those which mediate the toxic actions of chlorinated hydrocarbons in mammals. Some HAHs have mechanisms of action, which are similar to sex steroid, or they used the same cytosolic signal transduction pathways as the growth factors. This recognition permits a novel approach to gaining a better understanding of how many xenobiotics exert their adverse effects. Though the xenobiotics may not act directly with the hormone/growth factor receptors, understanding how they interact downstream from these receptor-mediated events may provide new and important insights regarding the cellular basis for gender-specific toxicity differences in diverse wildlife species.

We hypothesized that interactions between specific xenobiotics and endogenous factors that control cell function and differentiation can explain both the similar and disparate toxic responses observed in birds compared to laboratory mammals. Results from a series of studies support this hypothesis and demonstrate that the response of tissues from chickens (used here as a model for avian wildlife), respond differently to dioxin (used here as a model HAH) than do tissues from mammals. Furthermore, these studies indicate that the differences are largely attributable to the interaction between dioxin growth factors and circulating hormones, including sex steroids.

Our previous studies have shown that in rodents, males show a greater sensitivity to dioxin-induced decreases in body weight than females. This difference can be reduced by exogenous estrogen. In contrast, immature female chickens are more sensitive than males; estrogen treatment of immature male chickens replicates this increased sensitivity of females. In addition, dioxin treatment of hen-laying chickens reduces egg production and delays onset of lay, suggesting that HAHs directly or indirectly affect the normal initiation and continuation of this estrogen-induced process. These studies suggest that potent HAHs and estrogen act as the modulators for changes such as body weight, energy homeostasis, and lipid metabolism in both mammalian and avian species. More importantly, the mechanism by which estrogen and dioxin interact with hepatic lipid synthesis and metabolism appears to be both gender- and species-specific.

Because avian, reptilian, and amphibian species utilize lipids more than other vertebrate classes for migration and reproduction, these species would be expected to be more sensitive to HAH's toxic effects energy balance than mammals. Specifically, the adverse effects resulting from the interaction of dioxin and estrogen may be magnified for females undergoing the physiological changes in lipid synthesis and metabolism necessary for egg production. Therefore, the interaction of dioxin and estrogen with hepatic lipid synthesis and metabolism became the focus of our more recent investigations.

Estrogen treatment of male birds resulted in qualitatively similar lipid profiles to mature laying hens and estrogen-treated immature hens, thus providing a model by which to study dioxin-estrogen effects on lipid metabolism in the absences of the energetic needs of egg production. In general, estrogen treatment decreased comb height (24 percent), comb length (26 percent), and adipose tissue (AT) lipoprotein lipase activity relative to AT mass (51 percent), while liver mass and body weight gain were each increased by 28 percent compared to controls. Dioxin treatment resulted in increased liver mass (62 percent), reduced comb length (17 percent), and reduced AT lipoprotein lipase (LPL) activity indexed to AT mass (70 percent) compared with controls. The combined treatment (estrogen and dioxin) had 37 percent lower body weight gain and 30 percent larger livers relative to body mass, compared with the estrogen treatment, but these alone were not significantly different from the dioxin treatment. These data show that dioxin antagonized several effects of exogenous estrogen in male chickens, while estrogen enhanced TCDD toxicity in a tissue-specific manner. Birds treated with estrogen alone had increased total triacylglyceride concentrations with specific increases in the D9-desaturase products 16:1n7, 18:1n7, 18:1n9, and 20:1n9. However, these increases did not occur for birds treated with TCDD alone or in combination with estrogen. TCDD and estrogen plus TCDD treatments increased phospholipid concentrations of the diet?derived polyunsaturated fatty acids 18:2n6, 18:3n6, 20:3n6, 18:3n3, and 20:5n3, although only the estrogen plus TCDD group had significantly increased total phospholipids. All three treatments decreased the total cholesterol ester concentrations compared to the control group. However, TCDD and estrogen plus TCDD treatments decreased total concentrations of 9-desaturase products and saturated fatty acids, while estrogen treatment alone more specifically decreased concentrations of several saturated and polyunsaturated fatty acids.

These findings support our hypotheses that profound differences exist in the response of different species, age-stage, and genders of animals to the same HAHs. The interaction of dioxin with estrogen was common to both mammals and birds; however, the nature of the interaction in mammals and birds was quite different. The protective effect of estrogen that is observed in mammals is not found in the chicken model, and estrogen treatment augments the adverse effects of dioxin in some avian tissues. The augmenting effect of estrogen on the metabolic effects of dioxin in chickens is consistent with a more severe effect of these compounds on reproduction in lower vertebrates compared to mammals, and may explain the failure of laboratory experiments to fully replicate the adverse effects that have been observed in the field. More importantly, the specific adverse effects of dioxin on key lipid mobilization may explain the wide range of developmental defects that are observed in egg-laying species compared to placental mammals. The results of these studies underscore the importance of selecting similar and appropriate models for laboratory investigations, and demonstrate the wide differences that can be expected in terms of adverse effects resulting from similar exposures with different species and genders.


Journal Articles on this Report : 4 Displayed | Download in RIS Format

Other project views: All 7 publications 4 publications in selected types All 4 journal articles

Type Citation Project Document Sources
Journal Article El-Sabeawy F, Enan E, Lasley B. Biochemical and toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in immature male and female chickens. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 2001;129(4):317-327.
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R826298 (Final)
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  • Journal Article Stanton BJ, Watkins SM, German JB, Lasley BL. Effect of estrogen and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on plasma fatty acids of immature male chickens (Gallus domesticus). Comparative Biochemistry and Physiology Part C:Toxicology & Pharmacology 2002;132(2):129-142.
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    R826298 (Final)
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  • Other: ScienceDirect-PDF
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  • Journal Article Stanton B, Watkins S, German JB, Lasley B. Interaction of estrogen and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with hepatic fatty acid synthesis and metabolism of male chickens (Gallus domesticus). Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 2001;129(2):137-150.
    abstract available   full text available
    R826298 (2000)
    R826298 (Final)
    R825433 (Final)
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  • Journal Article Stanton B, DeWitt J, Henshel D, Watkins S, Lasley B. Fatty acid metabolism in neonatal chickens (Gallus domesticus) treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3 ',4,4 ',5-pentachlorobiphenyl (PCB-126) in ovo. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 2003;136(1):73-84.
    abstract available  
    R826298 (Final)
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  • Supplemental Keywords:

    avian, toxicology, environmental hazard, cellular, toxics, biochemistry, biology, children's health, endocrine disruptors, human health, environmental chemistry, pesticides, 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD, adverse outcomes, animal models, avian development, biological effects, endocrine disrupting chemicals, exposure studies, gulls, halogenated aromatic hydrocarbon, HAH, hormone production, steroid, RFA, Health, Scientific Discipline, Toxics, Environmental Chemistry, Health Risk Assessment, pesticides, Endocrine Disruptors - Environmental Exposure & Risk, endocrine disruptors, Children's Health, Molecular Biology/Genetics, Biology, Endocrine Disruptors - Human Health, adverse outcomes, natural hormones, avian development, wildlife, TCDD, endocrine disrupting chemicals, exposure studies, steroid, 2, 3, 7, 8-Tetrachloro-dibenzo-p-dioxin (TCDD), HAH, animal models, developmental processes, halogenated aromatic hydrocarbons (HAH), reproductive processes, biological effects, hormone production, halogenated aromatic hydrocarbons, chickens

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