Phenotypic dichotomy following developmental exposure to perfluorooctanoic acid (PFOA) in female CD-1 mice: Low doses induce elevated serum leptin and insulin, and overweight in mid-life☆

Abstract

a b s t r a c tThe synthetic surfactant, perfluorooctanoic acid (PFOA) is a proven developmental toxicant in mice, causing 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 and tissues of wildlife and humans throughout the world, but is especially high in the sera of children compared to adults. These studies in CD-1 mice aim to determine the latent health effects of PFOA following: (1) an in utero exposure, (2) an in utero exposure followed by ovariectomy (ovx), or (3) 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 young adults. 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) significantly increased body weight, and serum insulin and leptin (0.01-0.1 mg/kg) in mid-life after developmental exposure. PFOA exposure combined with ovx caused no additional increase in mid-life body weight. At 18 months of age, the effects of in utero PFOA exposure on body weight were no longer detected. White adipose tissue and spleen weights were decreased at high doses of PFOA in intact developmentally exposed mice, and spleen weight was reduced in PFOA-exposed ovx mice. Brown adipose tissue weight was significantly increased in both ovx and intact mice at high PFOA doses. Liver weight was unaffected in late life by these exposure paradigms. Finally, there was no effect of adult exposure to PFOA on body weight. These studies demonstrate an important window of exposure for low-dose effects of PFOA on body weight gain, as well as leptin and insulin concentrations in mid-life, at a lowest observed effect level of 0.01 mg PFOA/kg BW. The mode of action of these effects and its relevance to human health remain to be explored.Published by Elsevier Ireland Ltd.

Association between prenatal exposure to perfluorinated compounds and symptoms of infections at age 1–4years among 359 children in the Odense Child Cohort

“…In pregnant mice exposure to PFOS resulted in a decrease in natural killer cell activity, specific IgM response, and a decrease in lymphocyte subpopulations (Keil et al 2008) in the offspring. Similar studies of mice have found a reduced spleen weight and affected PPARs after prenatal exposure to PFOA (Abbott et al 2012;Hines et al 2009). In addition, PFOS exposure has been shown to suppress immunity to influenza A in adult mice (Guruge et al 2009).…”

In utero exposure to perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS) did not increase body weight or intestinal tumorigenesis in multiple intestinal neoplasia (Min/+) mice

“…The doses were reported in published literature to affect body weight without having major effects on pup development or survival. The doses of 0.01 and 0.1 mg/kg of PFOA given on GD 1-17 increased body weight observed from age 10-19 weeks and increased serum leptin and serum insulin at age 21-33 weeks in female CD-1 mice, whereas 0.1 mg/kg PFOA gave a nearly significant increase in blood glucose over control (P=0.06) at 20 min post-glucose challenge in 15-16 weeks old mice (Hines et al, 2009 12 although 3 mg/kg was reported to give some developmental effect (ossifications of limbs) (Lau et al, 2006). Higher doses than 3.0 mg/kg PFOA were not used in our experiment, since 5 mg/kg PFOA on GD 1-17 gave significantly increased number of dams with full litter resorptions in CD-1 mice (Lau et al, 2006).…”

“…Discussion PFOA or PFOS did not increase body weight in any of the doses tested (0.01, 0.1 or 3.0 mg/kg bw/day) up to 20 weeks. Exposure of CD-1 mice on GD1-17 to 0.01, 0.1 and 3.0 mg/kg PFOA significantly increased body weight, and 0.01 and 0.1 mg/kg affected serum insulin and leptin levels in female offspring (Hines et al, 2009). Associations between maternal PFOA, but not PFOS, serum concentration and overweight/obesity and waist circumference in their daughters, and with serum insulin and leptin levels, were also reported in a prospective cohort study (Halldorsson et al, 2012).…”

“…Thus both animal and human data indicate that PFOA may be obesogenic. Comparable doses were used in our study and by Hines et al (2009). However, we used C57BL/6J mice, whereas Hines et al used CD-1 mice.…”

“…The levels in the pups were approximately 1.3-4 times lower than the levels in the dams shortly after weaning. It has been shown in CD-1 mice that substantial amounts of these substances were transferred from the dams to their pups during lactation (Fenton et al, 2009). Therefore, the exposure of the pups continued via the milk after the in utero exposure through po gavage of the dams had finished on GD17.…”