Mechanisms Underlying Low-Dose Perfluorooctanoic Acid Developmental Effects in Mouse Mammary TissuesEPA Grant Number: FP917481
Title: Mechanisms Underlying Low-Dose Perfluorooctanoic Acid Developmental Effects in Mouse Mammary Tissues
Investigators: Macon, Madisa B
Institution: University of North Carolina at Chapel Hill
EPA Project Officer: Cobbs-Green, Gladys M.
Project Period: August 1, 2012 through July 31, 2015
Project Amount: $126,000
RFA: STAR Graduate Fellowships (2012) RFA Text | Recipients Lists
Research Category: Fellowship - Toxicology , Academic Fellowships
PFOA is a synthetic surfactant that has been shown to delay mammary gland development of prenatally exposed mice resulting in persistent aberrations. Although PFOA toxicity in other tissues (e.g., liver) is mediated by the peroxisome proliferator activated receptor alpha (PPARα), the mode of action for PFOA-induced mammary gland delays has yet to be fully characterized. The overarching goal of this research project is to characterize the major molecular pathways involved in the persistent perturbation of mammary gland development following prenatal PFOA exposure, at dose levels that overlap with reported human exposures, so that the human relevance of these mechanisms can be determined.
Using mice as a model for humans, pregnant mice will be dosed with low levels of PFOA that are relevant to human exposures. The mammary glands of the female offspring will be examined during various ages spanning from neonatal time points to late adolescence. Activation of peroxisome proliferator activated-receptor alpha (PPARα) and its signaling pathways has been implicated to mediate the effects of PFOA in the liver, yet the role of PPARα in PFOA-induced mammary gland toxicity is unclear due to limited studies and conflicting results. Using 129S1/SvImJ PPARα wild-type (WT) and knock-out (KO) mice, timepregnant mice will be orally dosed with 0, 0.01, 0.1, or 1.0 mg PFOA/ kg B/day from gestation days 10-17. Mammary glands from the female offspring treated with PFOA will be compared to determine the role of PPARα in PFOA-induced mammary gland delays. In other experiments following the same dosing paradigms, time-pregnant CD-1 mice will be orally dosed with PFOA to characterize the changes in the mammary glands of the female offspring. Mammary glands of PFOA-treated animals will be compared to controls based on morphology, histology, protein and RNA. Data analyses will include mammary gland whole mount analysis, immunohistochemistry, serum PFOA and steroid hormone measurements, fluorescent activated cell sorting and microarray analysis.
Through the use of 129S1/SvImJ PPARα WT and KO mice, the role of PPARα activation in PFOA-induced mammary gland delays will be determined. Although the limited PPARα WT/KO studies with PFOA exposures have produced conflicting results, it is expected that PPARα activation does not play a major role in PFOA-induced mammary gland delays. Utilizing RNA microarray analysis from the CD-1 mice experiments, candidate signaling pathways will be identified and validated through various protein analyses.
Potential to Further Environmental/Human Health Protection
Although epidemiology studies have found positive associations between PFOA levels in human serum and adverse health effects, determination of a causal link relies on data produced from animal studies. Characterization of the major signaling pathways involved in PFOAinduced mammary gland delays at blood levels that overlap with known human exposures would further the understanding of PFOA toxicity and its heightened effects in children, and will help to determine the human relevance of this outcome. Therefore, data produced from this research project are expected to inform regulatory agencies at the state and federal levels in their risk assessment of PFOA so that intervention schemes can be developed.