Dataset Information

Hepatic Mitochondrial Alteration in CD-1 Mice Associated with Prenatal Exposures to Low Doses of Perfluorooctanoic Acid (PFOA).

ABSTRACT: Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid primarily used as an industrial surfactant. It persists in the environment and has been linked to potentially toxic and/or carcinogenic effects in animals and people. As a known activator of peroxisome proliferator-activated receptors (PPARs), PFOA exposure can induce defects in fatty acid oxidation, lipid transport, and inflammation. Here, pregnant CD-1 mice were orally gavaged with 0, 0.01, 0.1, 0.3, and 1 mg/kg of PFOA from gestation days (GD) 1 through 17. On postnatal day (PND) 21, histopathologic changes in the livers of offspring included hepatocellular hypertrophy and periportal inflammation that increased in severity by PND 91 in an apparent dose-dependent response. Transmission electron microscopy (TEM) of selected liver sections from PND 91 mice revealed PFOA-induced cellular damage and mitochondrial abnormalities with no evidence of peroxisome proliferation. Within hypertrophied hepatocytes, mitochondria were not only increased in number but also exhibited altered morphologies suggestive of increased and/or uncontrolled fission and fusion reactions. These findings suggest that peroxisome proliferation is not a component of PFOA-induced hepatic toxicity in animals that are prenatally exposed to low doses of PFOA.

SUBMITTER: Quist EM

PROVIDER: S-EPMC4400180 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Hepatic Mitochondrial Alteration in CD-1 Mice Associated with Prenatal Exposures to Low Doses of Perfluorooctanoic Acid (PFOA).

Quist Erin M EM Filgo Adam J AJ Cummings Connie A CA Kissling Grace E GE Hoenerhoff Mark J MJ Fenton Suzanne E SE

Toxicologic pathology 20141016 4

Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid primarily used as an industrial surfactant. It persists in the environment and has been linked to potentially toxic and/or carcinogenic effects in animals and people. As a known activator of peroxisome proliferator-activated receptors (PPARs), PFOA exposure can induce defects in fatty acid oxidation, lipid transport, and inflammation. Here, pregnant CD-1 mice were orally gavaged with 0, 0.01, 0.1, 0.3, and 1 mg/kg of PFOA from gestation days ...[more]

PMID: 25326589

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Project description:Per- and polyfluoroalkyl substances (PFAS) comprise a diverse class of chemicals used in industrial processes, consumer products, and fire-fighting foams which have become environmental pollutants of concern due to their persistence, ubiquity, and associations with adverse human health outcomes, including in pregnant persons and their offspring. Multiple PFAS are associated with adverse liver outcomes in adult humans and toxicological models, but effects on the developing liver are not fully described. Here we performed transcriptomic analyses in the mouse to investigate the molecular mechanisms of hepatic toxicity in the dam and its fetus after exposure to two different PFAS, perfluorooctanoic acid (PFOA) and its replacement, hexafluoropropylene oxide-dimer acid (HFPO-DA, known as GenX). Pregnant CD-1 mice were exposed via oral gavage from embryonic day (E) 1.5-17.5 to PFOA (0, 1, or 5 mg/kg-d) or GenX (0, 2, or 10 mg/kg-d). Maternal and fetal liver RNA was isolated (N = 5 per dose/group) and the transcriptome analyzed by Affymetrix Array. Differentially expressed genes (DEG) and differentially enriched pathways (DEP) were obtained. DEG patterns were similar in maternal liver for 5 mg/kg PFOA, 2 mg/kg GenX, and 10 mg/kg GenX (R2: 0.46-0.66). DEG patterns were similar across all 4 dose groups in fetal liver (R2: 0.59-0.81). There were more DEGs in fetal liver compared to maternal liver at the low doses for both PFOA (fetal = 69, maternal = 8) and GenX (fetal = 154, maternal = 93). Upregulated DEPs identified across all groups included Fatty Acid Metabolism, Peroxisome, Oxidative Phosphorylation, Adipogenesis, and Bile Acid Metabolism. Transcriptome-phenotype correlation analyses demonstrated > 1000 maternal liver DEGs were significantly correlated with maternal relative liver weight (R2 >0.92). These findings show shared biological pathways of liver toxicity for PFOA and GenX in maternal and fetal livers in CD-1 mice. The limited overlap in specific DEGs between the dam and fetus suggests the developing liver responds differently than the adult liver to these chemical stressors. This work helps define mechanisms of hepatic toxicity of two structurally unique PFAS and may help predict latent consequences of developmental exposure.

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:BACKGROUND:Perfluorooctanoic 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. OBJECTIVES:We 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. METHODS:Pregnant 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. RESULTS:Exposure 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. CONCLUSIONS:Gestational 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

Hepatic Mitochondrial Alteration in CD-1 Mice Associated with Prenatal Exposures to Low Doses of Perfluorooctanoic Acid (PFOA).

Publications

Hepatic Mitochondrial Alteration in CD-1 Mice Associated with Prenatal Exposures to Low Doses of Perfluorooctanoic Acid (PFOA).

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