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Phenotypic Dichotomy Following Developmental Exposure to Perfluorooctanic Acid (PFOA) Exposure in CD-1 Mice: Low Doses Induce Elevated Serum, Leptin, Insulin, and Overweight in Mid-Life.
Citation:
STANKO, J, S WHITE, E P. HINES, E A. GIBBS-FLOURNOY, C LAU, AND S E. FENTON. Phenotypic Dichotomy Following Developmental Exposure to Perfluorooctanic Acid (PFOA) Exposure in CD-1 Mice: Low Doses Induce Elevated Serum, Leptin, Insulin, and Overweight in Mid-Life. Molecular and Cellular Endocrinology. ELSEVIER, AMSTERDAM, Holland, 304(1-2):97-105, (2009).
Impact/Purpose:
This study addresses health concerns that are also under study in the human population of C8 contaminated areas of West Virginia and Ohio. A NOAEL for body weight gain and serum leptin concentrations was not determined in this study; the LOAEL of 0.01 mg PFOA/kg on these sensitive end points was the lowest reported so far in the literature for any health effect in rodents. Our data are being used to guide the search for health effects in highly exposed human populations (work of Ted Emmett, U Penn; Susan Pinney, U Cinn; and the C8 Science Panel). These data are of interest to the OPPT, CalEPA, and the Office of Water, who are actually interested in performing some sort of formal risk assessment or guidance on PFOA concentrations in public water sources. The MN and NJ risk assessment teams have cited our work in their efforts to rederive a MCL for PFOA.
Description:
The synthetic surfactant, perfluorooctanoic acid (PFOA) is a proven developmental toxicant in mice, causing prenatal pregnancy loss, increased neonatal mortality, delayed eye opening, and abnormal mammary gland growth in animals exposed during fetal life. PFOA is found in the sera of wildlife and humans throughout the world, but is especially high in the sera of children. These studies in CD-1 mice aim to determine the latent health effects of PFOA following an in utero exposure, a developmental exposure followed by ovariectomy (ovx), or exposure as an adult. Mice were exposed to 0, 0.01, 0.1, 0.3, 1, 3, or 5 mg PFOA/kg BW for 17 days of pregnancy or as an adult. Body weight was reduced in the highest doses on postnatal day (PND) 1 and at weaning. However, the lowest exposures (0.01-0.3 mg/kg) induced excessive weight gain between 20-40 weeks, as well as a significant increase in serum leptin (0.01-0.1 mg/kg). Although body weight was significantly increased due to ovx, there was no longer a body weight effect of PFOA in ovx animals. Further, there was no effect of adult exposure to PFOA on body weight gain. At 18 months of age, the effects of PFOA on body weight were no longer detected. The white adipose tissue and spleen weights were decreased at high doses of PFOA in intact developmentally exposed mice, and spleen weight was reduced in ovx mice. But, brown adipose tissue weight was significantly increased in both ovx and intact mice at high doses. Liver weight, historically affected by acute high-dose PFOA exposure, was unaffected in late life by these exposure paradigms. These studies demonstrate low dose effects of PFOA on excessive body weight gain and leptin concentrations in mid life, at a lowest observed effect level of 0.01 mg PFOA/kg BW. The mode of action and its relevance to human health for these effects is currently unknown.
