DIFFERENCES IN SENSITIVITY BUT NOT SELECTIVITY OF XENOESTROGEN BINDING TO ALLIGATOR VERSUS HUMAN ESTROGEN RECEPTOR ALPHA

Reproductive abnormalities in alligators exposed to contaminants in Lake Apopka, Florida, USA represent a clear example of endocrine disruption in wildlife. Several of these contaminants that are not able to bind to mammalian estrogen receptors (such as atrazine and cyanazine) have previously been reported to bind to the alligator estrogen receptor from oviductal tissue. Binding of known Lake Apopka contaminants to full length estrogen receptors alpha from human (hER alpha) and alligator (aER alpha) was assessed in a side-by-side comparison within the same assay system. Baculovirus-expressed recombinant hER alpha and aERa were used in a competitive binding assay. Atrazine and cyanazine were not able to bind to either receptor. p,p'-Dicofol was able to bind to aERa with a concentration inhibiting 50% of binding (IC50) of 4 mu M, while only partially displacing 17 beta-estradiol (E2) from hERa and yielding a projected IC50 of 45 mu M. Chemicals that only partially displaced E2 from either receptor, including some dichlorodiphenyltrichloroethane (DDT) metabolites and trans-nonachlor, appeared to have higher affinity for aER alpha than hER alpha. p,p'-Dicofol-mediated transcriptional activation through aERa and hERa was assessed to further explore the preferential binding of p,p'-dicofol to aER alpha over hER alpha. p,p'-Dicofol was able to stimulate transcriptional activation in a similar manner with both receptors. However, the in vitro results obtained with p,p'-dicofol were not reflected in an in vivo mammalian model, where Kelthane (TM) (mixed o,p'- and p,p'-dicofol isomers) did not elicit estrogenic effects. In conclusion, although there was no evidence of exclusively species-specific estrogen receptor binders, some xenoestrogens, especially p,p'-dicofol, had a higher affinity for aERa than for hERa. Environ. Toxicol. Chem. 2010;29:2064-2071. (C) 2010 SETAC