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RETINOID METABOLISM IN FISH EMBRYOS FROM SENSITIVE AND RESISTANT POPULATIONS EXPOSED TO DIOXIN-LIKE COMPOUNDS
Citation:
Nacci, D E. AND J. Specker. RETINOID METABOLISM IN FISH EMBRYOS FROM SENSITIVE AND RESISTANT POPULATIONS EXPOSED TO DIOXIN-LIKE COMPOUNDS. Presented at 26th Northeast Endocrinology Conference, U.R.I.,Narragansett RI, November 13, 1999.
Description:
Early developmental stages of fish are extremely sensitive to a class of toxic and persistent environmental contaminants known as dioxin-like compounds (DLCs). Most of the toxicological actions of DLCs are mediated via the Aryl hydrocarbon Receptor (AhR) that regulates transcriptionally phase I and II metabolizing enzymes. While these enzymes are conceptualized as components of contaminant detoxifying systems, they can also affect the processing of endogenous signaling molecules, including metabolites of vitamin A, the retinoids. We propose that DLCs disrupt development through interference with embryonic metabolism and homeostasis ofretinoic acid (RA), a critical developmental regulator. These changes result in local excesses or depletions of RA via: A) induction of phase I-type enzymes, including those of the cytochrome P450 family, increasing the production ofRA from retinal, the primary yolk retinoid in fishes; and/or, B) induction of phase II-type enzymes, i.e., uridine diphosphate glucuronyl transferase that increases RA elimination as RA-glucuronide. We studied mechanisms of DLC developmental toxicity using the oviparous estuarine fish, Fundulus heteroclitus, because in addition to its usefulness as a laboratory model, we have characterized populations of F. heteroclitus indigenous to a highly contaminated site that are resistant to DLC effects. We have shown that embryonic exposure to increasing concentrations of a prototypical DLC (the co-planar PCB congener 126, CB126) produces increases in the activities of certain enzymes, characteristic lesions and death. Effects produced by CB 126 exposures were similar in sensitive and resistant fish populations, but were produced at exposure concentrations two orders of magnitude greater in the latter group. Enzyme changes were measured initially as changes in cytochrome P450 lA-associated production of resorufin by ethoxyresorufin-o-deethylase (EROD) in living embryos. Of the lesions produced by CB126 exposure, severe heart anomalies including pericardial edema were prominent. Exogenous RA produced developmental anomalies that were similar to those observed following CB 126 exposure but also included unique responses, i.e., fin duplication. To test whether CB 126 developmental toxicity was associated with excessive production of RA (hypothesis A), we used disulfiram (DSFM), an enzyme inhibitor that blocked RA formation. While preliminary results were encouraging, rescue ofCB126-exposed embryos by DSFM was not consistently successful. To test hypothesis B, we measured metabolism of radioactively-labeled RA in sensitive and resistant embryos exposed to CB126. These results showed high basal levels ofRA-glucuronide in resistant embryos and increased production of this conjugation product of RA in CB126-treated sensitive embryos, supporting hypothesis B. Comparisons between specific retinoid- and DLC-induced changes in these sensitive and resistant embryos have contributed to our understanding of environmental toxicants and biological protective mechanisms.