Defense Date

7-28-2011

Graduation Date

2011

Availability

Immediate Access

Submission Type

dissertation

Degree Name

PhD

Department

Pharmacology-Toxicology

School

School of Pharmacy

Committee Chair

Paula Witt-Enderby

Committee Member

Wilson S. Meng

Committee Member

Warren G. Foster

Committee Member

Jane Cavanaugh

Committee Member

Rehana Leak

Keywords

Breast cancer, DDT, DDE, Environmental contaminants, Gene

Abstract

Background: The synthetic insecticide DDT (dichlorodiphenyltrichloroethane) has been speculated to increase breast cancer risk due to its environmental persistence, levels of bioaccumulation in breast adipose tissue, and endocrine disrupting actions. Epidemiological studies have had inconsistent findings, however a study in MMTV-neu mice determined that localized, developmental exposure to the reported anti-androgen p,p' DDE accelerated mammary tumor development. This study tested the potential cancer-promoting actions of p,p' DDE, the most prevalent and persistent DDT metabolite.

Objectives: To identify and characterize the expression of p,p' DDE -regulated genes to determine how developmental exposure may influence mammary tissue to promote tumor formation. Methods: For localized delivery, ELVAX 40P pellets containing various doses of p,p' DDE, hydroxyflutamide (another anti-androgen), and mixtures of p,p' DDE with other congeners like o,p' DDE and p,p' DDT were implanted into the mammary fatpads of prepubertal female mice. p,p' DDE-regulated genes were identified by microarray analysis and analyzed by real time RT-PCR.

Results: Lipid-adjusted levels of p,p' DDE in mammary adipose tissue and serum in young mice were within the ranges of human exposure. p,p' DDE significantly upregulated casein gamma (csn1s2a ), keratin 18 (krt18) and interferon-induced protein 44 (ifi44) genes in mammary tissue. These genes were similarly, but not significantly regulated by hydroxyflutamide. The dose of p,p' DDE that caused early tumor onset in a previous study resulted in unique expression for all three genes and concentrations of p,p' DDE also influenced gene responses for the mixtures. However, no qualitative changes were observed in gland morphology. Significant upregulation of transforming growth factor beta (tgfb1) and downregulation of interleukin 10 (il10) in splenic leukocytes indicated that localized delivery of p,p' DDE to the mammary gland also influences systemic immune responses. Significant upregulation of il10 by p,p' DDE and hydroxyflutamide suggest that some of p,p' DDE actions may be through its anti-androgenic activity.

Conclusions: Relevant human exposure levels of p,p' DDE induce significant increases in expression of csn1s2a, krt18 and ifi44. This activity as well as those induced by other doses, ratios and hydroxyflutamide suggest p,p' DDE actions may involve anti-androgenic activity and influence local and systemic effects in a HER2+ breast cancer mouse model.

Format

PDF

Language

English

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