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Prenatal perfluorooctanoic acid exposure in CD-1 mice: low-dose developmental effects and internal dosimetry.

ABSTRACT: 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.

SUBMITTER: Macon MB

PROVIDER: S-EPMC3143465 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Prenatal perfluorooctanoic acid exposure in CD-1 mice: low-dose developmental effects and internal dosimetry.

Macon Madisa B MB Villanueva LaTonya R LR Tatum-Gibbs Katoria K Zehr Robert D RD Strynar Mark J MJ Stanko Jason P JP White Sally S SS Helfant Laurence L Fenton Suzanne E SE

Toxicological sciences : an official journal of the Society of Toxicology 20110411 1

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 ...[more]

PMID: 21482639

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Project description:BackgroundEpidemiologic studies investigating prenatal exposures in relation to growth typically rely on cumulative growth measures such as weight or BMI. However, less is known about how prenatal exposure may impact other aspects of growth dynamics, including timing and velocity.ObjectivesTo describe and apply a nonlinear growth model previously used in other health science fields to characterize postnatal growth trajectories for use in environmental epidemiology studies.MethodsWe used a double logistic function to model child weight trajectories from birth to 5.5 years using data from the Swedish Environmental Longitudinal Mother and Child, Asthma and Allergy (SELMA) study. From this, we approximated several infant growth metrics: 1) duration of time needed to complete 90% of the infant growth spurt (?t1), 2) the maximum growth rate in infancy or infant peak growth velocity (PGV), 3) the age at infant PGV (?1), a measure of growth tempo, and 4) the weight plateau at the end of the infant growth spurt (?1). We assessed these metrics in relation to prenatal perfluorooctanoic acid (PFOA) exposure among 1334 mother-child pairs, and differences between boys and girls.ResultsAverage estimated infant PGV and its timing (?1) were 0.68 kg/month and 3.4 months, respectively. Mean infant growth spurt duration (?t1) was 13 months, ending at an average weight plateau (?1) of 8.2 kg. Higher prenatal PFOA concentrations were related to a longer duration of infant growth (?t1: 0.06; 95% CI = 0.01, 0.11). PGV was not impacted, but higher prenatal PFOA concentrations were significantly related to delayed infant PGV (?1: 0.58; 95% CI = 0.17, 0.99) and a higher post-spurt weight plateau (?1: 0.81; 95% CI = 0.21, 1.41). After adjusting for false discovery, results were only significant for ?1 and ?1. We observed a significant interaction by sex for the association with ?1, and stratified analyses revealed the association was only significant among girls.ConclusionModel-derived growth metrics were consistent with published growth standards. This novel application of nonlinear growth modeling enabled detection of altered infant growth dynamics in relation to prenatal PFOA exposure. Our results may help describe how PFOA yields lower birthweights, but higher weight later in childhood. Future applications may characterize adolescent growth or additional metrics of biological interest.

Project description:BackgroundPerfluorooctanoic acid (PFOA) is a poly- and perfluoroalkyl substance (PFAS) associated with adverse pregnancy outcomes in mice and humans, but little is known regarding one of its replacements, hexafluoropropylene oxide dimer acid (HFPO-DA, referred to here as GenX), both of which have been reported as contaminants in drinking water.ObjectivesWe compared the toxicity of PFOA and GenX in pregnant mice and their developing embryo-placenta units, with a specific focus on the placenta as a hypothesized target.MethodsPregnant CD-1 mice were exposed daily to PFOA (0, 1, or 5mg/kg) or GenX (0, 2, or 10mg/kg) via oral gavage from embryonic day (E) 1.5 to 11.5 or 17.5 to evaluate exposure effects on the dam and embryo-placenta unit. Gestational weight gain (GWG), maternal clinical chemistry, maternal liver histopathology, placental histopathology, embryo weight, placental weight, internal chemical dosimetry, and placental thyroid hormone levels were determined.ResultsExposure to GenX or PFOA resulted in increased GWG, with increase in weight most prominent and of shortest latency with 10mg/kg/d GenX exposure. Embryo weight was significantly lower after exposure to 5mg/kg/d PFOA (9.4% decrease relative to controls). Effect sizes were similar for higher doses (5mg/kg/d PFOA and 10mg/kg/d GenX) and lower doses (1mg/kg/d PFOA and 2mg/kg/d GenX), including higher maternal liver weights, changes in liver histopathology, higher placental weights and embryo-placenta weight ratios, and greater incidence of placental abnormalities relative to controls. Histopathological features in placentas suggested that PFOA and GenX may exhibit divergent mechanisms of toxicity in the embryo-placenta unit, whereas PFOA- and GenX-exposed livers shared a similar constellation of adverse pathological features.ConclusionsGestational exposure to GenX recapitulated many documented effects of PFOA in CD-1 mice, regardless of its much shorter reported half-life; however, adverse effects toward the placenta appear to have compound-specific signatures. https://doi.org/10.1289/EHP6233.

Dataset Information

Prenatal perfluorooctanoic acid exposure in CD-1 mice: low-dose developmental effects and internal dosimetry.

Publications

Prenatal perfluorooctanoic acid exposure in CD-1 mice: low-dose developmental effects and internal dosimetry.

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