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.

Perfluorooctanoic acid (PFOA) is an environmental contaminant that causes adverse developmental effects in laboratory animals. To investigate the low-dose effects of PFOA on offspring, timed-pregnant CD-1 mice were gavage dosed with PFOA for all or half of gestation. In the full-gestation study, mice were administered 0, 0.3, 1.0, and 3.0 mg PFOA/kg body weight (BW)/day from gestation days (GD) 1-17. In the late-gestation study, mice were administered 0, 0.01, 0.1, and 1.0 mg PFOA/kg BW/day from GD 10-17. Exposure to PFOA significantly (p < 0.05) increased offspring relative liver weights in all treatment groups in the full-gestation study and in the 1.0 mg PFOA/kg group in the late-gestation study. In both studies, the offspring of all PFOA-treated dams exhibited significantly stunted mammary epithelial growth as assessed by developmental scoring. At postnatal day 21, mammary glands from the 1.0 mg/kg GD 10-17 group had significantly less longitudinal epithelial growth and fewer terminal end buds compared with controls (p < 0.05). Evaluation of internal dosimetry in offspring revealed that PFOA concentrations remained elevated in liver and serum for up to 6 weeks and that brain concentrations were low and undetectable after 4 weeks. These data indicate that PFOA-induced effects on mammary tissue (1) occur at lower doses than effects on liver weight in CD-1 mice, an observation that may be strain specific, and (2) persist until 12 weeks of age following full-gestational exposure. Due to the low-dose sensitivity of mammary glands to PFOA in CD-1 mice, a no observable adverse effect level for mammary developmental delays was not identified in these studies.

Background: Prenatal exposure to perfluorooctanoic acid (PFOA), a ubiquitous industrial surfactant, has been reported to delay mammary gland development in female mouse offspring (F1) and the treated lactating dam (P0) after gestational treatments at 3 and 5 mg PFOA/kg/day.Objective: We investigated the consequences of gestational and chronic PFOA exposure on F1 lactational function and subsequent development of F2 offspring.Methods: We treated P0 dams with 0, 1, or 5 mg PFOA/kg/day on gestation days 1–17. In addition, a second group of P0 dams treated with 0 or 1 mg/kg/day during gestation and their F1 and F2 offspring received continuous PFOA exposure (5 ppb) in drinking water. Resulting adult F1 females were bred to generate F2 offspring, whose development was monitored over postnatal days (PNDs) 1–63. F1 gland function was assessed on PND10 by timed-lactation experiments. Mammary tissue was isolated from P0, F1, and F2 females throughout the study and histologically assessed for age-appropriate development.Results: PFOA-exposed F1 dams exhibited diminished lactational morphology, although F1 maternal behavior and F2 offspring body weights were not significantly affected by P0 treatment. In addition to reduced gland development in F1 females under all exposures, F2 females with chronic low-dose drinking-water exposures exhibited visibly slowed mammary gland differentiation from weaning onward. F2 females derived from 5 mg/kg PFOA-treated P0 dams displayed gland morphology similar to F2 chronic water exposure groups on PNDs 22–63.Conclusions: Gestational PFOA exposure induced delays in mammary gland development and/or lactational differentiation across three generations. Chronic, low-dose PFOA exposure in drinking water was also sufficient to alter mammary morphological development in mice, at concentrations approximating those found in contaminated human water supplies.