The goal of this application is to characterize the molecular changes that underlie the development of estrogen-induced uterine lesions, including cancer. Neonatal exposure of hamsters to diethylstilbestrol (DES) or natural estrogen produces uterine tumors. Our preliminary studies revealed that exposure of neonatal hamsters to DES leads to induction of myeloperoxidase and hyperproduction of proinflammatory cytokines, TNF-alfa and IL-1B in the uteri of the pubertal animals. Compared to unexposed controls, the pubertal hamsters that had been exposed to DES neonatally exhibited a several-fold increase in 8-OH-dG levels and mutations in the uterine DNA. These findings led us to postulate that estrogen exposure of neonates results in imprinting that predisposes the pubertal animal to develop uterine cancer. The objectives of this application are: (1) to further elucidate the molecular consequences of estrogen exposure, with a focus on identifying whether hyperproduction of proinflammatory cytokine lL-1B and TNF-alfa in the uterus due to neonatal imprinting by estrogen exposure is involved in the etiopathology of uterine lesions; and (2) to examine whether hyperproduction of IL-1 J3 as a consequence of alterations in susceptibility genes in the uterus is involved in estrogen-induced uterine cancer.
The specific aims are: 1. To determine how perinatal estrogen exposure leads to persistent hyperproduction of proinflammatory cytokines IL-1B and TNF-alfa in the pubertal period in the organ in which cancer develops, the uterus. 2. To determine whether the sensitivity of the uterus to neonatal estrogen that results in persistent hyperproduction of IL-1 f3 and TNF-alfa in the uteri of pubertal animals is controlled genetically. 3. To determine if persistent hyperproduction of IL-1B and TNF-alfa resulting from neonatal exposure produces instability in the uterine genome. 4.To determine whether persistent hyperproduction of IL-1B and TNF-alfa associated with neonatal exposure triggers oxidative damage to the genome through reactive oxidants leading to the development of uterine lesions, particularly cancer. These studies will provide key information concerning the mechanistic basis for the association of neonatal imprinting of the uterus in response to estrogen with subsequent persistent inflammatory responses and their role in damage to the genome through the formation of mutations in uterine susceptibility genes. They also will provide a new paradigm for analyzing how exposure of the uterus to synthetic and natural estrogens during the perinatal period might alter the uterine genome during development, which, in turn, may predispose an individual to the development of adverse effects, including cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES010851-01
Application #
6229487
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Heindel, Jerrold
Project Start
2001-01-08
Project End
2005-11-30
Budget Start
2001-01-08
Budget End
2001-11-30
Support Year
1
Fiscal Year
2001
Total Cost
$312,000
Indirect Cost
Name
University of Alabama Birmingham
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Roy, Deodutta; Cai, Qiuyin; Felty, Quentin et al. (2007) Estrogen-induced generation of reactive oxygen and nitrogen species, gene damage, and estrogen-dependent cancers. J Toxicol Environ Health B Crit Rev 10:235-57
Roy, Deodutta; Felty, Quentin; Narayan, Satya et al. (2007) Signature of mitochondria of steroidal hormones-dependent normal and cancer cells: potential molecular targets for cancer therapy. Front Biosci 12:154-73
Roy, Deodutta; Sarkar, Shubhashish; Felty, Quentin (2006) Levels of IL-1 beta control stimulatory/inhibitory growth of cancer cells. Front Biosci 11:889-98
Parkash, Jai; Felty, Quentin; Roy, Deodutta (2006) Estrogen exerts a spatial and temporal influence on reactive oxygen species generation that precedes calcium uptake in high-capacity mitochondria: implications for rapid nongenomic signaling of cell growth. Biochemistry 45:2872-81
Singh, K P; Roy, D (2006) SKCG-1: a new candidate growth regulatory gene at chromosome 11q23.2 in human sporadic Wilms tumours. Br J Cancer 94:1524-32
Felty, Quentin; Singh, Kamaleshwar P; Roy, Deodutta (2005) Estrogen-induced G1/S transition of G0-arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling. Oncogene 24:4883-93
Felty, Quentin; Xiong, Wen-Cheng; Sun, Dongmei et al. (2005) Estrogen-induced mitochondrial reactive oxygen species as signal-transducing messengers. Biochemistry 44:6900-9
Du Mond Jr, J W; Singh, K P; Roy, D (2001) The biphasic stimulation of proliferation of Leydig cells by estrogen exposure. Int J Oncol 18:623-8