BackgroundNuclear receptor subfamily 1, group I, member 2 (NR1I2), commonly known as steroid and xenobiotic receptor (SXR) in humans, is a key ligand-dependent transcription factor responsible for the regulation of xenobiotic, steroid, and bile acid metabolism. The ligand-binding domain is principally responsible for species-specific activation of NR1I2 in response to xenobiotic exposure.ObjectivesOur objective in this study was to create a common framework for screening NR1I2 orthologs from a variety of model species against environmentally relevant xenobiotics and to evaluate the results in light of using these species as predictors of xenobiotic disposition and for assessment of environmental health risk.MethodsSixteen chimeric fusion plasmid vectors expressing the Gal4 DNA-binding domain and species-specific NR1I2 ligand-binding domain were screened for activation against a spectrum of 27 xenobiotic compounds using a standardized cotransfection receptor activation assay.ResultsNR1I2 orthologs were activated by various ligands in a dose-dependent manner. Closely related species show broadly similar patterns of activation; however, considerable variation to individual compounds exists, even among species varying in only a few amino acid residues.ConclusionsInterspecies variation in NR1I2 activation by various ligands can be screened through the use of in vitro NR1I2 activation assays and should be taken into account when choosing appropriate animal models for assessing environmental health risk.

SYNOPSIS. Many xenobiotic compounds introduced into the environment by human activity have been shownto adversely affect wildlife. Reproductive disorders in wildlife include altered fertility, reduced viability of offspring, impaired hormone secretion or activity and modified reproductive anatomy. It has been hypothesized that many of these alterations in reproductive function are due to the endocrine disruptive effects of various environmental contaminants. The endocrine system exhibits an organizational effect on the developing embryo. Thus, a disruption of the normal hormonal signals can permanently modify the organization and future function of the reproductive system. We have examined the reproductive and developmental endocrinology of several populations of American alligator (Alligator mississippiensis) living in contaminated and reference lakes and used this species as a sentinel species in field studies. We have observed that neonatal and juvenile alligators living in pesticide-contaminated lakes have altered plasma hormone concentrations, reproductive tract anatomy and hepatic functioning. Experimental studies exposing developing embryos to various persistent and nonpersistent pesticides, have produced alterations in gonadal steroidogenesis, secondary sex characteristics and gonadal anatomy. These experimental studies have begun to provide the causal relationships between embryonic pesticide exposure and reproductive abnormalities that have been lacking in pure field studies of wild populations. An understanding of the developmental consequences of endocrine disruption in wildlife can lead to new indicators of exposure and a better understanding of the most sensitive life stages and the consequences of exposure during these periods.

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A previous study from our laboratory examining development in neonatal alligators from polluted Lake Apopka, Florida, found numerous differences relative to neonates from a reference site, Lake Woodruff National Wildlife Refuge. We postulated that the differences were the result of organizational changes derived from embryonic exposure to environmental contaminants and are related to the poor reproductive success reported in alligators from Lake Apopka. In this study we examine differences in alligators collected as eggs from these two populations and raised under similar conditions for 1 yr. Egg hatch rates did not differ between lake populations; however, posthatching mortality was much higher among Lake Apopka hatchlings. Snout-vent length and body mass were greater in Lake Apopka hatchlings, but no differences were detected between lake populations in thyroid, liver, and spleen mass corrected for body size or in plasma concentrations of testosterone and estradiol. Males from Lake Woodruff exhibited greater relative expression of gonadal mRNA for steroidogenic factor 1 (Nr5a1) and steroidogenic acute regulatory protein (Star) than males from Lake Apopka. Alligators from Lake Woodruff also expressed all genes examined in a sexually dimorphic pattern. In contrast, mRNA expression did not differ between males and females from Lake Apopka for Nr5a1, Star, cytochrome P450 11A1 (Cyp11a1), and hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 (Hsd3b1). Our results document persistent differences in development, survivorship, and gene expression in alligators from a contaminated environment. Because these animals were raised under similar laboratory conditions, the differences are most likely of embryonic origin and organizational in nature.