Modulation of endocrine pathways by 4,49-DDE in the deer mouse Peromyscus maniculatus

4,49-DDT and 4,49-DDE are widespread environmental contaminants that cause eggshell thinning in birds, altered sex ratios in the American alligator, and changes in the anal]genital distance in rodents. These contaminants are known to cause some of their toxicity by altering steroid receptor-mediated mechanisms. However, chemical-specific alterations in the expression of hormone-metabolizing enzymes may also be a mechanism for endocrine disruption, by altering the half-life of hormones in critical tissues. Previously, we showed that 4,49-DDE causes a dose-dependent increase in ethoxyresorufin-O-deethylase EROD. activity, but not pentoxyresorufin-O-dealkylase PROD. activity, in the deer mouse. In this study, we demonstrated that 4,49-DDE elicited a corresponding increase in CYP1A protein expression but not CYP2B using Western blotting and immunoprecipitation. 4,49-DDE-mediated changes in phase II conjugating enzymes; UDP-glucuronosyltransferase UGT. and phenolsulfotransferase ST., were also investigated for the first time. Prepubescent female deer mice were dosed with 4,49-DDE by gavage on days 1 and 2, then euthanized on day 4. As anticipated, dose-dependent increases in hepatic EROD and MROD activities, but not PROD or BROD, were observed. UGT activity was monitored by incubating liver microsomes and 14C-UDP-GA with potential substrates and measuring incorporation of radioactivity into TLC-resolved glucuronides. Dose-depen- dent increases in conjugation were observed with p-nitrophenol a general UGT substrate. but not testosterone. Interestingly, a biphasic dose]response curve was observed for ST activity, with a peak at the 3 mgrkg dose. Dose-dependent increases in CYP1A1 and UGT-specific immunoreactive proteins were observed, suggesting de novo synthesis as a consequence of 4,49-DDE exposure. We also measured Phase I and II enzymes in deer mouse platelets. Preliminary results indicate that the 4,49-DDE-induced changes in liver Phase I and II enzyme activity were similar, but not identical, to those found in platelets. These results indicate that environmentally-relevant levels of 4,49-DDE modulate the activity and expression of CYP1A1 and phase II enzymes in the deer mouse and that certain changes may be measured non-lethally.