TY - JOUR
T1 - Modulation of endocrine pathways by 4,4'-DDE in the deer mouse Peromyscus maniculatus
AU - Dickerson, R. L.
AU - McMurry, C. S.
AU - Smith, E. E.
AU - Taylor, M. D.
AU - Nowell, S. A.
AU - Frame, L. T.
N1 - Funding Information:
The authors gratefully acknowledge ECORISK, Inc., the Chlorine Chemistry Council of the Chemical Manufacturers Association, and the National Institutes of Environmental Health Sciences for funding the research described herein. We also wish to thank Dr Charles Crespi of Gentest for providing the antibodies used in these studies. The authors gratefully acknowledge the assistance of Sherry Skipper of Clemson University and Tracy Gatlin of University of Arkansas for Medical Sciences for their technical assistance. We also wish to acknowledge Dr Nick Lang, John McClellan Veteran’s Administration Hospital, Little Rock Arkansas for his support and assistance with this project.
PY - 1999/8/15
Y1 - 1999/8/15
N2 - 4,4'-DDT and 4,4'-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 4,4'-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 4,4'-DDE elicited a corresponding increase in CYP1A protein expression but not CYP2B using Western blotting and immunoprecipitation. 4,4'-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 4,4'-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-dependent 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 mg/kg dose. Dose-dependent increases in CYP1A1 and UGT-specific immunoreactive proteins were observed, suggesting de novo synthesis as a consequence of 4,4'-DDE exposure. We also measured Phase I and II enzymes in deer mouse platelets. Preliminary results indicate that the 4,4'-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 4,4'-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. Copyright (C) 1999 Elsevier Science B.V.
AB - 4,4'-DDT and 4,4'-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 4,4'-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 4,4'-DDE elicited a corresponding increase in CYP1A protein expression but not CYP2B using Western blotting and immunoprecipitation. 4,4'-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 4,4'-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-dependent 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 mg/kg dose. Dose-dependent increases in CYP1A1 and UGT-specific immunoreactive proteins were observed, suggesting de novo synthesis as a consequence of 4,4'-DDE exposure. We also measured Phase I and II enzymes in deer mouse platelets. Preliminary results indicate that the 4,4'-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 4,4'-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. Copyright (C) 1999 Elsevier Science B.V.
KW - 4,4'-DDE
KW - CYP1A1
KW - CYP2B
KW - Endocrine disruption
KW - Platelet
KW - Sulfotransferase
KW - UDP-glucuronosyltransferase
UR - http://www.scopus.com/inward/record.url?scp=0032775374&partnerID=8YFLogxK
U2 - 10.1016/S0048-9697(99)00183-7
DO - 10.1016/S0048-9697(99)00183-7
M3 - Article
C2 - 10492900
AN - SCOPUS:0032775374
SN - 0048-9697
VL - 233
SP - 97
EP - 108
JO - Science of the Total Environment
JF - Science of the Total Environment
IS - 1-3
ER -