Mechanistic Pathways Underlying Low-Dose Perfluorooctanoic Acid (PFOA) Effects in Murine Mammary Tissues Public Deposited

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  • March 22, 2019
Creator
  • Macon, Madisa
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • Perfluorooctanoic acid (PFOA) is a synthetic surfactant that is as a prominent environmental toxicant. Previous studies have characterized the morphological effects of prenatal PFOA exposure on the mammary gland at 5mg/kg/day PFOA. The goal of this project was to identify major signaling pathways involved in this effect using a mouse model at dosing exposures that overlap with human serum levels. To minimize the overt developmental toxicity of PFOA, prenatal levels were reduced and/or exposures were abbreviated to a critical window of mammary gland organogenesis, gestational days 10-17. A systems biology approach was utilized to characterize the morphological and molecular changes using microarray, RT-PCR, Western blots, immunohistochemistry, histology, whole mount analysis, mammary epithelial transplant recombination, and serum hormone analysis. Following lowdose (0.01-1.0 mg/kg/day) and abbreviated (GD 10-17) PFOA exposures, mammary glands of treated mice displayed characteristics of delayed development which persisted into adulthood. These adult morphological alterations were characterized by misdirected growth patterns, thicker collagen density, increased active TEBs, and reduced side branching of the ductal tree. Genome-wide microarray analysis of young mammary tissues revealed PFOA altered RNA post-transcriptional modification, lipid metabolism and cholesterol biosynthesis; peroxisome proliferator-activated receptor (Ppar), Wnt, and endocrine related signaling were identified as targeted signaling pathways and confirmed by RT-PCR. The majority of RNA expression changes occurred early in life yet PFOA altered protein levels of candidate gene across multiple time-points. In whole cell lysates, at PND 7 PPARγ and ERα levels were increased; at PND 21 ERα protein levels was reduced; at PND 56 PPARα and PPARγ levels were severely reduced. Results from blots coincided with IHC stained sections for ERα which were reduced at PND 21 and 56 in treated glands. Circulating testosterone levels were reduced at PND 21 and DHEA was reduced at PND 56. Altered steroid levels, differences in steroid receptor populations, and dense breasts in women are associated with increased breast cancer risk, and similar to effects observed in mouse mammary glands following PFOA exposure. Collectively, these data show that prenatal PFOA exposure alters endocrine disruption and steroid receptor expression leading to phenotypic features associated with increased breast cancer risk. Importantly, these effects were observed in mice as PFOA serum concentrations approached background levels and overlapped with reported human serum levels.
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  • In Copyright
Advisor
  • Fenton, Suzanne
Degree
  • Doctor of Philosophy
Graduation year
  • 2014
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