_- 14
5ft Twenty-Fourth Annual
##wggwH :3 ii E .. " Symp03ium on
9:00 am. Registration and Coffee - Room 137, terizing AhR-mediated antiestrogenicity in the rodent uterus and g g, .3
Chemistry-Physics Building mammary and in human breast cancer cells. The mechanisms of g g . u..
AhR-mediated antiestrogenicity are complex; however, studies on 5 8 -' j-. .
9:30 am. Welcome by Dr. Fitzgerald Bramwell, Vice the molecular biology of crosstalk between the AhR and estro- E D: :1 7i g Chemlstry
President for Research and Graduate Studies, gen-receptor (ER) signaling pathways have been initiated using 9 1 ;;
University of Kentucky - Room 139, Chemis- several E2-regulated genes as models. The results indicate that D.- D x 1"" &
try-Physics Building the nuclear AhR complex targets specific genomic core inhibitory S I 3
dioxin responsive elements (iDREs) in promoter regions of E2- Z... / 
9:35 am. Introductory Remarks - Dr. Sylvia Daunert, responsive target genes to inhibit hormone-induced transactivation. ' Molecular
University of Kentucky Research has also focused on development of AhR-based
antiestrogens which inhibit mammary tumor development and .
9:40 am. Dr. Louis J. Guillette, Jr., University of Florida growth butdo not exhibit prototypical AhR-induced toxic responses. BlOlogy
EcoEstrogens and Embryos The antitumorigenic activities of these new drugs will be discussed.
Since the onset of the industrial age, environmental contami- 11 :20 am. Discussion
nants have posed a threat to wildlife health. The focus of our
concern on the health consequences of environmental pollution 11:30 am. Dr. Kenneth S. Korach, National Institute of
have, in the last three decades, been on lethal, carcinogenic and/ Environmental Health Sciences . .
or extreme teratogenic manifestations. Evidence from a number Molecular and Functional Phenotypes in
of sources suggests that another mechanism, endocrine-disrup- Estrogen Receptor Knock-Out Mice
tion must also be examined. There is excellent laboratory and _
field evidence that man-made chemicals - xenochemicals - re- The estrogen receptor (ER) is thoughtto playacrucial role in
leased 'into the enwronmentact as hormones or antihormones - the regulation of many [ife processes, including development, . Q .
endocrine disrupting contaminants (EDCs). The release of EDCs reproduction, and normal physiology. We have produced a line Of -
occurred in the past and continues today. We have used reptiles transgenic mice possessing a disrupted ER gene (ERKO).
- primarily the alligator - as an ecosystem monitor for it exhibits Comparable levels of ER-B mRNA were detected in tissues of
limited mobility and feeds at the top of the food chain. Qur recent ERKO mice, suggesting that ER'B expression is not dependent
Stud? show that reptiles Wg ' contaminated enVironments on ER. Estrogen insensitivity was confirmed using estradiol,
GXh'b't (1) population declines due to lethal _and reproductive ef- hydroxy tamoxifen, and diethylstilbestrol treatment. Estradiol- established in the memory of
fects 0f the contaminants on embryos, Juveniles or adults, (2) d? treated wild type mice showed a 350-fold induction in lactoferrin A S N ff
velopmental abnormalities of embryos, including subtle effects in mRNA, an estrogen-responsive gene in the uterus, while ERKO 3 - a
the reproductive system 0f alligators,and (3) abnormalities 0f the females showed no detectable response. Progesterone receptor
endocrine system. A hYPOthGSIS W' be presented suggesting mRNA was detected but not stimulated by estrogen in the uterus,
that any compound that disrupts the normal ster0id milieu of the mammary gland, and ovary, indicating an estrogen-dependent and '_
developcing 6mm?) Wyniatge Sign'f'9anti, life Icnfg censeqfiiences -independent regulation. Both male and female animals survive Toxicology of Environmental
on sex _e ermina '0 e organiza '0 an 0 '0 0 e '9' to adulthood with normal ross external henot pes. ERKO -
productive system. females have elevated ovarigan gonadotropirF: recepor levels (6-8 Chemicals that AC]. as Hormones
fold) as well as elevated serum estrogen (10-15x) and LH (8x), ___________
10:25 am. Discussion compared to wild type. The influence of ER activity on mammary
tumorgenicity was evaluated by crossing WNT-1 transgenic mice In
10:35 am. Dr. Stephen H. Safe, Texas A&M University having an increased incidence of mammary tumors onto the ERKO in SPEAKERS
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) background. Mice exhibiting wild type ER and WNT-1 transgene > 8 . .
as an Antiestrogen: Crosstalk Between Two show 98% tumor incidence at 26 weeks of age. ERKONVNT-1 a A? I: LOUIS J. GUlllette, Jr.
Endocrine Pathways mice show a reduced tumor incidence (58%) and delayed onset '
(54 weeks). Both sexes show an effect on the skeleton and E E "07 Kenneth 8 KoraCh
2,3,7,8-Tetrachlorodibenzo-pdioxin (TCDD) and related ha- shortened bone length supporting a direct role for ER action in .i: E 8 Stephen H. Safe
logenated aromatics (HAs) are industrial compounds or by-prod- bone. 8 {:4 >4
ucts, which have been identified as contaminants in air, water, 0 H M
fish, wildlife and humans. HAs induce a broad spectrum of bio 12:15 pm. Discussion E O - Monday April 13 1998
chemical and toxic responses and their effects on laboratory ani- a) 3 C  
mals are species-, strain-, tissue-, age-, and sex~specific. The 12:30 pm. Buffet Lunch, Faculty Club (Please return 5 '5 8
mechanism of action of HAs has been extensively investigated registration form by April 6, 1998 for reserva- g B a
and results indicate that the aryl hydrocarbon receptor (AhR) pro- tions. Cost $10.00 to be paid at registration.) Q, .2 Q ,
tein is the initial intracellular target for TCDD. The bound AhR CD 3 0 Department Of Chemistry
complex functions as a ligand-induced nuclear transcription fac- 2:30 pm. Discussion with Graduate Students, Room Q D 4 University Of Kentucky
tor and also modulates phosphorylation of critical regulatory pro- 137, Chemistry-Physics Building .
teins. TCDD and related compounds disrupt multiple endocrine Lexmgton, Kentucky 40506'0055
pathways, and research in this laboratory has focused on charac- .