Perfluorooctane sulfonate (PFOS) is a perfluoroalkyl acid (PFAA) and a persistent environmental contaminant found in the tissues of humans and wildlife. Although blood levels of PFOS have begun to decline, health concerns remain because of the long half-life of PFOS in humans. Like other PFAAs, such as, perfluorooctanoic acid (PFOA), PFOS is an activator of peroxisome proliferator-activated receptor-alpha (PPAR
Perfluoroalkyl acids (PFAAs) are stable man-made perfluorinated organic molecules that have been utilized since the 1950s in the manufacture of a variety of industrial and commercial products suchas fire fighting foams, fluoropolymers for the automobile and aerospace industry, paper food packaging, stain-resistant coatings for carpet and fabric, cosmetics, insecticides, lubricants, and nonstick coatings for cookware. One such PFAA, perfluorooctane sulfonate (PFOS), was identified nearly a decade ago as a persistent organic pollutant which could also be found in the tissues of wildlife throughout the globe [
PFOS and PFOA are associated with toxicity in laboratory animals at blood levels that are approximately 2-3 orders of magnitude above those normally observed in humans. This includes hepatomegaly and liver tumors in rats and mice as well as pancreatic and testicular tumors in rats (for review see [
The mode of action related to PFAA toxicity in rodents is not fully understood. As a class of chemicals, PFAAs activate peroxisome proliferator-activated receptor alpha (PPAR
In the current study, we used global gene expression profiling to assess the transcriptional changes induced by PFOS in the liver of wild-type and PPAR
Studies were approved by the U.S. EPA ORD/NHEERL Institutional Animal Care and Use Committee. The facilities and procedures used followed the recommendations of the 1996 NRC “Guide for the Care and Use of Laboratory Animals,” the Animal Welfare Act, and the Public Health Service Policy on the Humane Care and Use of Laboratory Animals.
PPAR
Collected tissue (≤50 mg) was immediately placed in 1 mL RNA
Following overnight fixation in Bouins fixative, collected tissue was washed three times in PBS, dehydrated to 70% ethanol, and stored at 4°C until use. On the day of embedding, the tissue was dehydrated through an ethanol gradient to 100% ethanol and paraffin embedded using standard techniques. Five micron sections were then prepared using a rotary microtome prior to routine staining with hematoxylin and eosin.
Microarray analysis was conducted at the U.S. EPA NHEERL Toxicogenomics Core Facility using Affymetrix GeneChip 430_2 mouse genome arrays according to the protocols recommended by the manufacturer (Affymetrix, Santa Clara, CA). Biotin-labeled cRNA was produced from 5 ug total RNA using Enzo Single-Round RNA Amplification and Biotin Labeling System (Cat. no. 42420-10, Enzo Life Sciences Inc, Farmingdale, NY), quantified using an ND-1000 spectrophotometer, and evaluated on a 2100 Bioanalyzer after fragmentation. To minimize technical day to day variation, labeling and hybridization for all samples were conducted as a single block. Following overnight hybridization at 45°C in an Affymetrix Model 640 GeneChip hybridization oven, the arrays were washed and stained using an Affymetrix 450 fluidics station and scanned on an Affymetrix Model 3000 scanner. Raw data (Affymetrix Cel files) were obtained using Affymetrix GeneChip Operating Software (version 1.4). This software also provided summary reports by which array QA metrics were evaluated including average background, average signal, and 3′/5′ expression ratios for spike-in controls,
Real-time PCR analysis of selected genes was conducted using 2 micrograms of total RNA. All samples were initially digested using 2 units DNaseI (no. M6101, Promega Corporation, Madison, WI) for 30 min at 37°C followed by 10 min at 65°C in a buffer containing 40 mM Tris (pH 8.0), 10 mM
Body and liver weight data were analyzed by strain using a one-way ANOVA. Individual treatment contrasts were assessed using a Tukey Kramer HSD test (
Liver weight increased at the highest dose of PFOS in both WT and Null animals (Table
Average body weight and liver weight of control and PFOS-treated mice on the day of tissue collection
Dose group | WT | Null | ||||
Body weight | Total liver weight | Relative liver weight | Body weight | Total liver weight | Relative liver weight | |
0 mg/kg | 28.3 ± .0 | 1.21 ± 0.17 | 0.043 ± 0.014 | 30.3 ± 1.3 | 1.04 ± 0.06 | 0.034 ± 0.003 |
3 mg/kg | 26.2 ± 1.5 | 1.12 ± 0.18 | 0.043 ± 0.002 | 28.0 ± 1.2 | 1.20 ± 0.05 | 0.043 ± 0.001 |
10 mg/kg | 31.4 ± 1.5 | 1.98 ± 0.11* | 0.062 ± 0.003* | 30.2 ± 1.7 | 1.48 ± 0.16* | 0.049 ± 0.012* |
1Data are mean ± SE, *Significantly different than control (
Hematoxylin-and eosin-stained tissue sections from control and PFOS treated mice. Control WT and Null mice are shown in panels (a) and (b), respectively. WT and null mice treated with 10 mg/kg/day PFOS are shown in panels (c) and (d), respectively. Vacuole formation was observed in sections from treated WT mice, and in sections from control and treated Null mice. Mice exposed to 3 mg/kg/day PFOS were similar to controls (data not shown). Bar = 50
Based on the number of genes significantly altered by PFOS (
Number of fully annotated genes altered by PFOS, PFOA1, or Wy-14,64
PFOS | PFOA | Wy 14,643 | ||
3 mg/kg/day | 10 mg/kg/day | 3 mg/kg | 50 mg/kg/day | |
Wild-type | 81 | 906 | 879 | 902 |
PPAR | 630 | 808 | 176 | 10 |
1From Rosen et al. (2008), 2 Based on Ingenuity Pathways Analysis database.
Expression of a group of well characterized markers of PPAR
In WT mice, PFOS modified the expression of genes related to a variety of PPAR
Average fold change for genes related to lipid metabolism in wild-type and PPAR
WT | Null | ||||||||
Symbol | Gene name | Entrez no. | Wy14,643 50 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg |
ACAA1 | acetyl-CoA | 113868 | 1.89 | 2.92 | 1.61 | 2.10** | 1.22 | 1.37 | 1.53* |
ACAA1B | acetyl-CoA | 235674 | 2.38 | 2.70 | 1.49 | 1.40** | 3.00 | 1.09 | 1.19* |
ACAD10 | acyl-CoA dehydrogenase, | 71985 | 1.51 | 2.39 | −1.18 | 1.38** | −1.01 | 1.05 | 1.20* |
ACADL | acyl-CoA dehydrogenase, | 11363 | 3.03 | 2.86 | 1.40 | 1.68** | 2.50 | 1.34 | 1.59** |
ACADM | acyl-CoA dehydrogenase, | 11364 | 1.70 | 1.30 | 1.21 | 1.31** | 1.06 | 1.11 | 1.10 |
ACADS | acyl-CoA dehydrogenase, | 66885 | 1.03 | 1.52 | 1.22 | 1.31* | −1.13 | −1.12 | −1.08 |
ACADSB | acyl-CoA dehydrogenase, | 66885 | −1.56 | −1.64 | −1.04 | −1.39** | −1.26 | 1.00 | −1.23 |
ACADVL | acyl-CoA dehydrogenase, | 11370 | 1.92 | 1.80 | 1.44 | 1.49** | 1.16 | 1.04 | 1.12 |
ACAT1 | acetyl-CoA | 101446 | −1.01 | 1.10 | 1.45 | 1.36* | −1.55 | −1.05 | −1.17 |
ACAT2 | acetyl-CoA | 110460 | 2.59 | 1.68 | 1.14 | 1.34* | 1.26 | 1.58 | 1.69** |
ACOT1 | acyl-CoA thioesterase 1 | 26897 | 19.48 | 73.06 | 3.27 | 6.82** | 2.95 | 1.53 | 2.02 |
ACOT3 | acyl-CoA thioesterase 3 | 171281 | 2.55 | 32.83 | 2.42 | 6.41** | −1.59 | 1.46 | 1.86 |
ACOT2 | acyl-CoA thioesterase 2 | 171210 | 3.83 | 19.29 | 1.91 | 7.32** | 1.78 | 1.25 | 1.52 |
ACOX1 | acyl-CoA oxidase 1 | 11430 | 5.65 | 7.17 | 1.23 | 1.49** | 1.51 | 1.30 | 1.29** |
ACSL1 | acyl-CoA synthetase long- | 14081 | 1.34 | 2.36 | 1.28 | 1.36** | 1.01 | 1.31 | 1.30 |
ACSL3 | acyl-CoA synthetase long- | 74205 | 2.25 | 1.90 | 1.28 | 1.69** | 1.11 | 1.77 | 1.63 |
ACSL4 | acyl-CoA synthetase long- | 50790 | 1.95 | 2.00 | 1.03 | 1.42* | 1.51 | 1.34 | 1.29 |
ACSL5 | acyl-CoA synthetase long- | 433256 | 3.06 | 2.76 | 1.24 | 1.31** | 1.38 | 1.23 | 1.28 |
ALDH1A1 | aldehyde dehydrogenase 1, | 11668 | 1.56 | 1.59 | 1.07 | 1.12** | 1.22 | 1.16 | 1.17 |
ALDH1A7 | aldehyde dehydrogenase 1, A7 | 26358 | 1.83 | 1.86 | 1.12 | 1.24* | 1.55 | 1.26 | 1.35 |
ALDH3A2 | aldehyde dehydrogenase 3, | 11671 | 3.65 | 7.72 | 2.10 | 3.80** | 2.30 | 1.73 | 2.20** |
ALDH9A1 | aldehyde dehydrogenase 9, | 56752 | 1.80 | 1.91 | 1.27 | 1.50** | 1.21 | 1.05 | 1.11* |
CPT1B | carnitine palmitoyltransferase | 12896 | 2.29 | 1.50 | 1.23 | 2.69** | −1.00 | 1.13 | 1.11 |
CPT2 | carnitine palmitoyltransferase II | 12896 | 1.33 | 2.54 | 1.58 | 2.03** | 1.44 | 1.15 | 1.34 |
CYP4A14 | cytochrome P450, 4, a, | 13119 | 75.38 | 103.48 | 11.26 | 12.28** | 12.75 | −1.09 | 2.22 |
DCI | dodecenoyl-CoA | 13177 | 2.91 | 4.55 | 1.90 | 2.38** | 1.99 | 1.04 | 1.38* |
ECH1 | enoyl CoA hydratase 1, | 51798 | 3.27 | 5.23 | 1.93 | 2.49** | 2.10 | 1.16 | 1.39 |
EHHADH | enoyl-CoA, hydratase | 74147 | 27.89 | 22.11 | 2.37 | 4.34** | 1.37 | 1.32 | 1.52* |
FABP1 | fatty acid binding protein 1, liver | 14080 | −1.27 | 1.02 | 1.11 | 1.24** | 1.25 | −1.09 | −1.23 |
HADHA | Trifunctional protein, alpha unit | 97212 | 2.13 | 2.95 | 1.37 | 1.65** | 1.01 | 1.06 | 1.02 |
HADHB | Trifunctional protein, beta unit | 231086 | 2.33 | 3.43 | 1.37 | 1.60** | 1.08 | −1.15 | −1.28* |
HSD17B4 | hydroxysteroid (17-beta) | 15488 | 2.03 | 2.56 | 1.34 | 1.45** | −1.13 | 1.12 | 1.20* |
SLC27A1 | solute carrier 27, member 1 | 26457 | 9.14 | 8.22 | −1.02 | 1.14* | −1.57 | 1.04 | 1.04 |
SLC27A2 | solute carrier 27, | 26458 | 1.48 | 1.80 | 1.19 | 1.16** | 1.33 | 1.10 | 1.05 |
SLC27A4 | solute carrier 27, | 26569 | 1.87 | 1.91 | 1.04 | 1.31** | −1.03 | 1.09 | 1.07 |
1From Rosen et al. (2008),
*Significantly different than control (
**Significantly different than control (
Average fold change for genes related to proteasome biogenesis in wild-type and PPAR
WT | Null | ||||||||
Symbol | Gene name | Entrez no. | Wy14,643 50 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg |
PSMA1 | proteasome unit, | 26440 | 1.61 | 1.38 | 1.15 | 1.31* | 1.17 | −1.29 | −1.34 |
PSMA2 | proteasome unit, | 19166 | −1.46 | −1.15 | 1.09 | 1.23** | −1.34 | −1.20 | −1.07 |
PSMA3 | proteasome unit, | 19167 | 1.33 | 1.22 | 1.12 | 1.14 | 1.28 | −1.13 | −1.17 |
PSMA4 | proteasome unit, | 26441 | 1.19 | 1.32 | 1.10 | 1.19* | 1.01 | −1.04 | 1.05 |
PSMA5 | proteasome unit, | 26442 | 1.67 | 1.59 | 1.12 | 1.26** | 1.15 | −1.12 | 1.09 |
PSMA6 | proteasome unit, | 26443 | 1.20 | 1.29 | 1.14 | 1.24** | 1.06 | −1.14 | −1.06 |
PSMA7 | proteasome unit, | 26444 | 1.47 | 1.60 | 1.23 | 1.53** | 1.23 | −1.12 | 1.11 |
PSMB1 | proteasome unit, | 19170 | 1.09 | 1.29 | 1.07 | 1.28* | 1.04 | −1.17 | 1.13* |
PSMB10 | proteasome unit, | 19171 | −1.42 | −1.48 | −1.25 | −1.19 | −1.57 | −1.14 | −1.21** |
PSMB2 | proteasome unit, | 26445 | 1.33 | 1.48 | 1.05 | 1.31** | 1.02 | −1.20 | 1.05 |
PSMB3 | proteasome unit, | 26446 | 1.22 | 1.47 | 1.21 | 1.36** | 1.04 | −1.37 | −1.20 |
PSMB4 | proteasome unit, | 19172 | 1.59 | 1.65 | 1.27 | 1.55** | 1.22 | −1.12 | 1.09 |
PSMB5 | proteasome unit, | 19173 | 1.34 | 1.74 | 1.04 | 1.24** | 1.02 | −1.15 | 1.03 |
PSMB6 | proteasome unit, | 19175 | 1.54 | 1.83 | 1.08 | 1.24* | 1.19 | −1.23 | −1.09 |
PSMB7 | proteasome unit, | 19177 | 1.46 | 1.33 | 1.07 | 1.15** | 1.13 | −1.17 | −1.09 |
PSMB8 | proteasome unit, | 16913 | −1.61 | −2.00 | −1.44 | −1.51 | −1.38 | −1.23 | −1.45** |
PSMB9 | proteasome unit, | 16912 | 1.24 | −1.12 | −1.31 | −1.09 | −1.10 | −1.11 | −1.30** |
PSMC1 | proteasome 26S unit, | 19179 | 1.44 | 1.00 | 1.19 | 1.15* | 1.11 | −1.06 | 1.01 |
PSMC6 | proteasome 26S unit, | 67089 | 1.18 | 1.21 | 1.09 | −1.02 | 1.07 | 1.14 | −1.16 |
PSMD1 | proteasome 26S unit, | 70247 | 1.20 | 1.22 | 1.15 | 1.25** | 1.09 | 1.03 | 1.15 |
PSMD11 | proteasome 26S unit, | 69077 | 1.56 | 1.38 | 1.09 | 1.26* | −1.17 | 1.16 | 1.32 |
PSMD12 | proteasome 26S unit, | 66997 | 1.34 | 1.27 | 1.10 | 1.14 | 1.20 | −1.03 | 1.04 |
PSMD13 | proteasome 26S unit, | 23997 | 1.21 | 1.38 | 1.14 | 1.26* | −1.03 | −1.38 | −1.42** |
PSMD14 | proteasome 26S unit, | 59029 | −1.39 | −1.42 | 1.17 | 1.31* | 1.31 | 1.01 | 1.17 |
PSMD2 | proteasome 26S unit, | 21762 | 1.34 | 1.32 | 1.14 | 1.24* | 1.10 | 1.09 | 1.30** |
PSMD3 | proteasome 26S unit, | 22123 | −1.35 | −1.19 | 1.17 | 1.29* | 1.08 | 1.04 | 1.22* |
PSMD4 | proteasome 26S unit, | 19185 | 1.31 | 1.92 | 1.19 | 1.38** | 1.03 | −1.07 | 1.17* |
PSMD6 | proteasome 26S unit, | 66413 | 1.17 | 1.33 | 1.10 | 1.14* | 1.07 | −1.06 | 1.04 |
PSMD7 | proteasome 26S unit, | 17463 | 1.13 | 1.27 | 1.13 | 1.24* | 1.02 | −1.19 | −1.22* |
PSMD8 | proteasome 26S unit, | 57296 | 1.68 | 1.24 | 1.03 | 1.30** | 1.16 | −1.15 | −1.00 |
PSME1 | proteasome activator | 19186 | 1.22 | −1.00 | −1.05 | 1.32** | 1.27 | −1.10 | −1.09 |
VCP | valosin−containing | 269523 | 1.40 | 1.49 | 1.04 | 1.12 | 1.07 | 1.13 | 1.21** |
1From Rosen et al. (2008),
*Significantly different than control (
**Significantly different than control (
Average fold change for genes related to peroxisome biogenesis in wild-type and PPAR
WT | Null | ||||||||
Symbol | Gene name | Entrez no. | Wy14,643 50 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg |
PECI | peroxisome D3, D2-enoyl- | 23986 | 1.73 | 3.15 | 1.61 | 1.87** | 1.96 | 1.42 | 1.57** |
PEX1 | peroxisomal biogenesis | 71382 | 1.25 | 1.84 | 1.07 | 1.21** | −1.02 | 1.10 | 1.14* |
PEX11A | peroxisomal biogenesis | 18631 | 1.80 | 6.71 | 1.70 | 2.99** | 1.04 | −1.09 | −1.11 |
PEX12 | peroxisomal biogenesis | 103737 | 1.07 | 1.36 | 1.11 | 1.17* | 1.09 | 1.17 | 1.30* |
PEX13 | peroxisomal biogenesis | 72129 | 1.04 | 1.58 | 1.01 | 1.09 | 1.02 | 1.09 | 1.16* |
PEX14 | peroxisomal biogenesis | 56273 | 1.06 | 1.24 | 1.03 | 1.25* | 1.03 | 1.05 | 1.13 |
PEX16 | peroxisomal biogenesis | 18633 | 1.51 | 1.44 | 1.13 | 1.33** | −1.00 | −1.12 | −1.03 |
PEX19 | peroxisomal biogenesis | 19298 | 1.61 | 2.25 | 1.19 | 1.36** | 1.12 | 1.15 | 1.32** |
PEX26 | peroxisomal biogenesis | 74043 | −1.32 | −1.86 | 1.01 | 1.26 | 1.01 | 1.29 | 1.10 |
PEX3 | peroxisomal biogenesis | 56535 | 1.50 | 1.77 | 1.13 | 1.37** | −1.05 | 1.09 | 1.20* |
PEX6 | peroxisomal biogenesis | 224824 | 1.08 | −1.06 | 1.12 | 1.16 | 1.30 | −1.08 | 1.09 |
PXMP2 | peroxisomal membrane | 19301 | −1.22 | −1.29 | −1.08 | −1.20* | −1.28 | −1.13 | −1.06 |
PXMP4 | peroxisomal membrane | 59038 | 1.62 | 2.09 | 1.61 | 1.62* | 1.99 | −1.03 | 1.01 |
1From Rosen et al. [
*Significantly different than control (
**Significantly different than control (
Average fold change for genes related to the inflammatory response in wild-type and PPAR
WT | Null | ||||||||
Symbol | Gene name | Entrez no. | Wy14,643 50 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg |
APCS | amyloid P component, | 20219 | −1.50 | −2.33 | −1.23 | −1.28 | −1.19 | 1.41 | 1.13 |
C1QA | complement component | 12259 | −1.75 | −1.40 | −1.13 | −1.17 | −1.31 | −1.24 | −1.34** |
C1R | complement component 1r | 50909 | −2.67 | −1.78 | −1.15 | −1.23* | −1.22 | 1.16 | −1.17* |
C1S | complement component 1s | 317677 | −3.73 | −2.53 | −1.14 | −1.62** | −1.52 | 1.06 | −1.11 |
C2 | complement component 2 | 12263 | −2.56 | −1.91 | −1.37 | −1.32* | −1.18 | 1.10 | 1.11 |
C3 | complement component 3 | 12266 | −1.41 | −1.41 | −1.04 | −1.04 | −1.22 | 1.13 | 1.08* |
C4B | complement component 4B | 12268 | −2.35 | −2.15 | −1.08 | −1.28 | −1.91 | 1.15 | −1.13 |
C4BP | complement component | 12269 | −1.86 | −1.82 | −1.11 | −1.19 | 1.02 | 1.39 | 1.13 |
C6 | complement component 6 | 12274 | −2.66 | −1.27 | −1.35 | −1.08 | 1.90 | 1.12 | 1.06 |
C8A | complement | 230558 | −3.62 | −1.94 | −1.17 | −1.31* | −1.17 | 1.19 | 1.04 |
C8B | complement | 110382 | −5.25 | −2.99 | −1.20 | −1.60** | −1.12 | 1.11 | 1.02 |
C8G | complement | 69379 | −1.59 | −1.35 | −1.05 | −1.17* | −1.34 | −1.10 | −1.17** |
C9 | complement | 12279 | −2.12 | −2.64 | −1.35 | −1.58** | −1.46 | 1.08 | −1.19* |
CFB | complement | 14962 | −1.81 | −1.77 | −1.07 | −1.26 | −1.39 | 1.07 | −1.11 |
CFH | complement | 12628 | −2.39 | −2.30 | −1.19 | −1.62 | −1.76 | 1.45 | −1.35 |
CFI | complement | 12630 | −1.63 | −1.77 | −1.06 | −1.15 | −1.06 | 1.12 | 1.04 |
CRP | C−reactive | 12944 | −1.33 | −1.39 | −1.01 | −1.15* | 1.32 | 1.14 | 1.13 |
CTSC | cathepsin C | 13032 | −1.56 | −2.52 | 1.01 | −1.36 | −1.96 | 1.04 | −1.35 |
F10 | coagulation | 14058 | −1.62 | −1.42 | −1.09 | −1.13 | −1.00 | 1.07 | −1.07 |
F11 | coagulation | 109821 | −2.17 | −2.68 | −1.41 | −2.08** | −1.08 | −1.08 | −1.34* |
F12 | coagulation | 58992 | −1.22 | −1.35 | −1.05 | −1.14 | −1.21 | −1.07 | −1.12* |
F13B | coagulation | 14060 | −1.41 | −1.54 | −1.11 | −1.22** | 1.02 | 1.02 | −1.12 |
F2 | coagulation | 14061 | −1.19 | −1.20 | −1.02 | −1.13* | −1.10 | 1.02 | −1.02 |
F5 | coagulation | 14067 | −1.78 | −1.53 | −1.09 | −1.44* | −1.41 | 1.08 | −1.34* |
F7 | coagulation | 14068 | −2.68 | −2.15 | −1.09 | −1.46** | −1.23 | 1.03 | −1.03 |
F9 | coagulation | 14071 | −1.42 | −1.43 | −1.02 | −1.39* | −1.33 | 1.07 | −1.19 |
FGA | fibrinogen | 14161 | −1.27 | −1.75 | 1.00 | −1.12 | −1.07 | 1.05 | −1.07 |
FGB | fibrinogen | 110135 | −1.32 | −1.97 | 1.03 | −1.15 | −1.25 | 1.08 | −1.07 |
FGG | fibrinogen gamma | 99571 | −1.14 | −1.68 | 1.02 | −1.15* | −1.08 | 1.04 | −1.06 |
KLKB1 | kallikrein B, | 16621 | −1.58 | −1.76 | −1.09 | −1.39* | −1.05 | −1.03 | −1.18* |
LUM | lumican | 17022 | −1.34 | −1.27 | 1.02 | −1.20* | −1.66 | 1.03 | −1.27 |
MASP1 | Mannan- | 17174 | −1.23 | −1.62 | −1.19 | −1.18* | 1.11 | 1.18 | 1.17* |
MBL2 | Mannose-binding | 17195 | −1.77 | −2.18 | −1.12 | −1.23* | −1.36 | −1.20 | −1.28** |
ORM2 | orosomucoid 2 | 18405 | −1.96 | −2.04 | −1.26 | −1.21 | −1.16 | 1.30 | 1.05 |
PROC | protein C | 19123 | −1.49 | −1.50 | −1.02 | −1.13* | −1.09 | −1.01 | −1.09* |
SAA1 | serum amyloid | 20209 | −3.71 | −3.98 | −2.75 | 1.04 | −2.76 | 6.51 | 2.55 |
SAA2 | serum amyloid | 20210 | −1.75 | −1.30 | −1.79 | −1.29 | 3.05 | 1.44 | 1.22 |
SAA4 | serum amyloid | 20211 | −2.19 | −1.45 | −1.06 | −1.27 | −1.02 | 1.47 | −1.05 |
SERPINA1 | serpin peptidase | 20701 | −3.43 | −2.07 | −1.03 | −1.05** | −1.16 | 1.11 | −1.33 |
SERPINC1 | serpin peptidase | 11905 | −1.19 | −1.21 | −1.03 | −1.08* | −1.02 | −1.04 | −1.06* |
SERPIND1 | serpin peptidase | 15160 | −1.62 | −1.70 | −1.08 | −1.25** | −1.05 | 1.09 | 1.05 |
SERPINE1 | serpin peptidase | 18787 | 1.44 | 9.75 | 1.03 | 1.85** | 2.95 | 1.03 | 1.26* |
SERPINF2 | serpin peptidase | 18816 | −1.15 | −1.87 | 1.01 | −1.13* | 1.02 | 1.12 | 1.05 |
SERPING1 | serpin peptidase | 12258 | −1.23 | −1.37 | −1.12 | −1.13 | −1.07 | 1.12 | 1.02 |
VWF | von Willebrand | 22371 | 1.06 | 1.12 | −1.25 | 1.07 | −1.51 | 1.22 | 1.14 |
1From Rosen et al. [
*Significantly different than control (
**Significantly different than control (
Average fold change for genes related to xenobiotic metabolism in wild-type and PPAR
WT | Null | ||||||||
Symbol | Gene name | Entrez no. | Wy14,643 50 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg |
ADH1C | alcohol dehydrogenase 1C | 11522 | 1.27 | 1.02 | −1.00 | 1.02 | −1.09 | −1.02 | −1.04 |
ADH5 | alcohol dehydrogenase 5 | 11532 | −1.18 | 1.10 | 1.09 | −1.04 | −1.02 | 1.11 | 1.14 |
ADH7 | alcohol dehydrogenase 7 | 11529 | −1.51 | 1.06 | −1.01 | −1.06 | −1.71 | −1.01 | −1.01 |
ALDH1L1 | aldehyde dehydrogenase 1L1 | 107747 | −1.29 | −1.85 | −1.08 | −1.18* | −1.41 | 1.76 | 1.68** |
ALDH3B1 | aldehyde dehydrogenase | 67689 | 1.12 | 1.04 | −1.11 | 1.04 | 1.48 | −1.03 | −1.11 |
CES1 | carboxylesterase 1 | 12623 | 1.43 | 2.29 | 1.61 | 2.62** | 3.15 | 4.80 | 4.84** |
CES2 | carboxylesterase 2 | 234671 | 3.37 | 5.75 | 1.03 | 2.29 | 4.25 | 1.41 | 1.74* |
CYP1A1 | cytochrome | 13076 | 1.25 | −1.93 | −1.05 | 1.08 | −1.02 | 1.34 | 1.49** |
CYP1A2 | cytochrome | 13077 | −1.67 | −1.24 | −1.13 | 1.10 | 1.26 | 1.15 | 1.25* |
CYP2A4 | cytochrome | 13087 | −4.26 | 1.33 | 1.08 | 2.01 | 5.82 | 1.28 | 1.57** |
CYP2B10 | cytochrome | 13088 | 1.31 | 4.39 | 3.50 | 5.92* | 24.20 | 11.34 | 21.66** |
CYP2C55 | cytochrome | 72082 | 1.58 | 21.72 | 1.54 | 8.37* | 110.35 | 10.57 | 25.18** |
CYP2C37 | cytochrome | 13096 | −2.42 | 1.57 | 1.39 | 1.48 | 4.09 | 1.53 | 1.68 |
CYP2C38 | cytochrome | 13097 | 1.62 | 1.12 | 1.78 | 2.30** | −1.42 | −1.26 | 1.03 |
CYP2C39 | cytochrome | 13098 | 2.45 | 1.51 | 1.65 | 1.51 | −1.42 | 1.11 | −1.01 |
CYP2C50 | cytochrome | 107141 | −2.63 | 1.31 | 1.11 | 1.19 | 1.71 | 1.34 | 1.26 |
CYP2C54 | cytochrome | 404195 | −2.98 | 1.44 | 1.16 | 1.14 | 1.87 | 1.29 | 1.35** |
CYP2C70 | cytochrome | 226105 | −2.75 | −4.22 | −1.23 | −1.68* | −1.05 | −1.05 | 1.04 |
CYP2C65 | cytochrome | 72303 | 1.44 | 1.63 | −1.93 | 1.98 | 46.78 | 2.28 | 8.63** |
CYP2D10 | cytochrome | 13101 | −1.47 | −1.09 | −1.02 | −1.03 | 1.33 | −1.00 | 1.02 |
CYP2D26 | cytochrome | 76279 | −1.17 | −1.21 | 1.06 | −1.01 | −1.12 | −1.03 | −1.08 |
CYP3A11 | cytochrome | 13112 | −1.23 | 1.40 | 1.03 | 1.06 | 4.61 | 1.12 | 1.20 |
CYP3A41A | cytochrome | 53973 | −2.08 | 1.11 | 1.24 | 1.58* | 2.01 | 1.39 | 1.25 |
CYP3A25 | cytochrome | 56388 | −1.94 | −1.70 | 1.01 | −1.01 | 1.04 | 1.13 | 1.12 |
CYP3A13 | cytochrome | 13113 | −1.54 | 1.19 | 1.22 | 1.38* | 1.52 | 1.75 | 1.62** |
EPHX1 | epoxide hydrolase 1, | 13849 | 1.22 | 1.78 | 1.16 | 1.60* | 1.82 | 1.33 | 1.59* |
EPHX2 | epoxide hydrolase 2, | 13850 | 2.25 | 2.34 | 1.45 | 1.67** | 1.04 | 1.05 | 1.07 |
GSTA3 | glutathione | 14859 | 1.08 | −1.04 | 1.05 | 1.26 | 1.11 | 1.11 | 1.13 |
GSTA4 | glutathione | 14860 | −2.01 | −1.10 | −1.02 | 1.52 | 1.37 | −1.20 | 1.36 |
GSTA5 | glutathione | 14857 | −1.12 | 1.44 | 1.19 | 2.76* | 2.26 | 1.15 | 2.13 |
GSTK1 | glutathione | 76263 | 1.85 | 1.43 | 1.02 | −1.04 | −1.30 | −1.26 | −1.27 |
GSTM1 | glutathione | 14863 | −2.12 | −1.56 | −1.51 | 1.77 | 2.54 | 1.18 | 1.97 |
GSTM3 | glutathione | 14864 | −1.32 | 1.50 | 1.16 | 2.44* | 1.83 | 1.57 | 2.59* |
GSTM4 | glutathione | 14865 | 2.07 | 3.13 | 1.30 | 2.40* | 2.48 | 1.40 | 2.63* |
GSTP1 | glutathione | 14870 | −2.79 | 4.14 | −1.16 | 1.00 | 2.87 | −1.06 | −1.03 |
GSTT2 | glutathione | 14872 | 1.64 | 2.74 | 1.42 | 1.83** | 1.13 | 1.16 | 1.43** |
GSTT3 | glutathione | 103140 | 2.10 | 1.13 | 1.41 | 1.61 | 1.77 | 1.30 | 1.85** |
GSTZ1 | glutathione | 14874 | −1.36 | −1.14 | −1.03 | −1.08 | 1.01 | 1.03 | 1.01 |
MGST1 | microsomal | 56615 | 1.28 | 1.24 | −1.02 | 1.01 | 1.21 | 1.04 | 1.01 |
MGST3 | microsomal | 66447 | 1.73 | 1.60 | 1.24 | 1.80* | −1.54 | −1.31 | −1.06 |
POR | P450 (cytochrome) | 18984 | −1.26 | 2.63 | 1.27 | 1.94 | 2.04 | 2.91 | 3.30** |
UGT2B17 | UDP glucuronosyltransferase | 71773 | −3.90 | −1.13 | −1.03 | 1.02 | 1.24 | 1.03 | −1.01 |
UGT2B4 | UDP glucuronosyltransferase | 552899 | −1.37 | −1.93 | −1.26 | −1.23* | 1.35 | 1.01 | 1.03 |
UGT2B7 | UDP glucuronosyltransferase | 231396 | −1.19 | −1.20 | −1.05 | −1.05 | 1.16 | 1.04 | −1.00 |
1From Rosen et al. (2008),
*Significantly different than control (
**Significantly different than control (
Average fold change for genes related to cholesterol biosynthesis in wild-type and PPAR
WT | Null | ||||||||
Symbol | Gene name | Entrez no. | Wy14,643 50 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg |
CYP51 | cytochrome P450, | 13121 | 2.85 | 1.37 | 1.27 | 2.10* | 1.37 | 2.99 | 1.93** |
FDFT1 | farnesyl-diphosphate | 14137 | 2.30 | 1.28 | 1.29 | 1.73* | 1.09 | 2.00 | 1.92** |
FDPS | farnesyl diphosphate | 110196 | 3.19 | 1.79 | 1.16 | 1.38 | 1.83 | 1.84 | 1.96** |
HMGCR | 3-hydroxy-3-methylglutaryl | 15357 | 1.79 | −1.08 | 1.19 | 1.97** | 1.20 | 1.85 | 1.80* |
HMGCS1 | 3-hydroxy-3-methylglutaryl | 208715 | 6.67 | 1.79 | 1.15 | 1.61 | −1.06 | 3.11 | 1.86* |
HMGCS2 | 3-hydroxy-3-methylglutaryl | 15360 | 1.17 | 1.54 | 1.28 | 1.34* | 1.25 | −1.08 | −1.28* |
IDI1 | isopentenyl-diphosphate | 319554 | 3.14 | 1.61 | 1.35 | 1.62 | 1.40 | 1.96 | 1.57* |
LSS | lanosterol synthase | 16987 | 1.73 | 1.08 | 1.12 | 1.41 | −1.26 | 1.98 | 2.13** |
MVK | mevalonate kinase | 17855 | 1.45 | −1.24 | 1.12 | 1.22 | −1.02 | 1.57 | 1.52** |
PMVK | phosphomevalonate kinase | 68603 | 3.23 | 2.04 | 1.36 | 1.51* | 1.20 | 1.58 | 1.53** |
SQLE | squalene epoxidase | 20775 | 3.10 | 1.05 | 1.17 | 1.46 | 1.26 | 2.25 | 1.98** |
1From Rosen et al. (2008), *Significantly different than control (
**Significantly different than control (
Average fold change for genes related to oxidative phosphorylation/electron transport in wild-type and PPAR
WT | Null | ||||||||
Symbol | Gene name | Entrez no. | Wy14,643 50 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg |
ATP5D | ATP synthase H+ | 66043 | 1.03 | 1.10 | 1.04 | 1.09 | −1.17 | −1.22 | −1.13* |
ATP5E | ATP synthase H+ | 67126 | −1.10 | 1.21 | −1.00 | 1.03 | −1.17 | −1.32 | −1.38** |
ATP5G2 | ATP synthase H+ | 67942 | −1.09 | −1.03 | 1.10 | −1.10 | −1.10 | −1.33 | −1.26** |
ATP5G3 | ATP synthase H+ | 228033 | 1.62 | 1.48 | −1.01 | 1.05 | −1.10 | −1.12 | −1.10** |
ATP5H | ATP synthase H+ | 71679 | 1.18 | 1.10 | 1.05 | 1.06 | −1.01 | −1.30 | −1.38** |
ATP5I | ATP synthase H+ | 11958 | −1.01 | −1.45 | −1.03 | 1.10 | 1.17 | −1.38 | −1.50** |
ATP5J | ATP synthase H+ | 11957 | −1.20 | 1.44 | −1.04 | −1.07 | −1.14 | −1.25 | −1.35** |
ATP5J2 | ATP synthase H+ | 57423 | 2.38 | −1.56 | −1.05 | −1.09 | 1.03 | −1.29 | −1.35** |
ATP5L | ATP synthase H+ transporting, | 27425 | 1.58 | 1.21 | −1.02 | 1.00 | −1.05 | −1.33 | −1.30** |
ATP5O | ATP synthase H+ | 28080 | 1.12 | 1.16 | 1.06 | 1.22 | −1.03 | −1.33 | −1.31** |
ATP6V0B | ATPase, H+ | 114143 | −1.37 | −1.25 | 1.03 | −1.09 | 1.05 | −1.22 | −1.20** |
ATP6V1F | ATPase, H+ | 66144 | −1.18 | 1.23 | 1.00 | 1.05 | 1.01 | −1.33 | −1.28** |
COX4I1 | cytochrome c | 12857 | 1.14 | 1.15 | 1.02 | 1.03 | −1.15 | −1.19 | −1.16** |
COX5A | cytochrome c | 12858 | 1.25 | 1.12 | −1.02 | 1.09 | −1.13 | −1.26 | −1.33** |
COX5B | cytochrome c | 12859 | 1.19 | 1.33 | 1.09 | 1.08 | −1.27 | −1.27 | −1.35** |
COX6B1 | cytochrome c | 110323 | 1.32 | 1.39 | −1.01 | 1.10* | −1.12 | −1.25 | −1.19* |
COX6C | cytochrome c | 12864 | 1.62 | −1.23 | 1.03 | −1.05 | 1.21 | −1.22 | −1.25** |
COX7A2 | cytochrome c | 12866 | −1.68 | −1.08 | −1.04 | −1.04 | −1.57 | −1.39 | −1.37** |
COX7C | cytochrome c | 12867 | 1.22 | 1.32 | −1.03 | −1.28* | −1.05 | −1.23 | −1.19** |
COX8A | cytochrome c | 12868 | 1.34 | 1.34 | 1.02 | 1.04 | 1.07 | −1.23 | −1.13* |
NDUFA1 | NADH dehydrogenase 1 | 54405 | −1.19 | 1.13 | −1.03 | −1.11 | −1.25 | −1.31 | −1.49** |
NDUFA2 | NADH dehydrogenase 1 | 17991 | 1.06 | 1.18 | 1.04 | 1.04 | −1.06 | −1.26 | −1.33** |
NDUFA3 | NADH dehydrogenase 1 | 66091 | 1.60 | 1.60 | 1.06 | 1.16* | −1.06 | −1.37 | −1.30** |
NDUFA4 | NADH dehydrogenase 1 | 17992 | 1.02 | 2.46 | −1.00 | 1.01 | 3.16 | −1.12 | −1.11** |
NDUFA5 | NADH dehydrogenase 1 | 68202 | 1.41 | 1.26 | 1.10 | 1.11 | −1.07 | −1.55 | −1.73** |
NDUFA6 | NADH dehydrogenase 1 | 67130 | 1.10 | 1.06 | 1.02 | −1.04 | −1.02 | −1.34 | −1.29** |
NDUFA7 | NADH dehydrogenase 1 | 66416 | −1.14 | −1.01 | 1.09 | 1.12 | −1.17 | −1.45 | −1.38** |
NDUFA8 | NADH dehydrogenase 1 | 68375 | 1.14 | 1.33 | 1.00 | 1.09 | 1.05 | −1.29 | −1.18* |
NDUFA12 | NADH dehydrogenase 1 | 66414 | 1.47 | 1.16 | −1.03 | 1.06 | 1.06 | −1.51 | −1.40** |
NDUFA13 | NADH dehydrogenase 1 | 67184 | −1.12 | −1.16 | −1.03 | −1.03 | −1.08 | −1.26 | −1.28** |
NDUFA9 | NADH dehydrogenase 1 | 66108 | 1.18 | 1.07 | 1.02 | −1.01 | −1.09 | −1.20 | −1.19** |
NDUFAB1 | NADH dehydrogenase 1, | 70316 | 1.56 | 1.19 | 1.05 | 1.23* | −1.07 | −1.31 | −1.44* |
NDUFB2 | NADH dehydrogenase 1 | 68198 | −2.31 | −3.32 | 1.04 | 1.11 | 1.49 | −1.31 | −1.35** |
NDUFB3 | NADH dehydrogenase 1 | 66495 | 1.55 | 1.93 | 1.09 | 1.19 | 1.05 | −1.41 | −1.32** |
NDUFB4 | NADH dehydrogenase 1 | 68194 | −1.03 | 1.17 | −1.01 | 1.06 | −1.13 | −1.45 | −1.46** |
NDUFB5 | NADH dehydrogenase 1 | 66046 | 1.21 | 1.13 | 1.08 | 1.03 | 1.05 | −1.28 | −1.41** |
NDUFB6 | NADH dehydrogenase 1 | 230075 | 1.32 | −1.03 | 1.04 | 1.19 | −1.02 | −1.38 | −1.36** |
NDUFB7 | NADH dehydrogenase 1 | 66916 | 1.02 | 1.14 | 1.04 | 1.11 | −1.11 | −1.40 | −1.29** |
NDUFB9 | NADH dehydrogenase 1 | 66218 | 1.19 | 1.01 | 1.05 | 1.01 | −1.08 | −1.22 | −1.25** |
NDUFB11 | NADH dehydrogenase 1 | 104130 | −1.29 | 1.05 | 1.05 | 1.06 | −1.00 | −1.26 | −1.23** |
NDUFC1 | NADH dehydrogenase 1 | 66377 | −1.28 | 1.84 | 1.07 | 1.21* | 1.17 | −1.28 | −1.37** |
NDUFC2 | NADH dehydrogenase 1 | 68197 | −1.02 | 1.13 | 1.06 | 1.06 | −1.13 | −1.37 | −1.33** |
NDUFS4 | NADH dehydrogenase | 17993 | 1.51 | 1.21 | 1.12 | −1.12 | 1.07 | −1.41 | −1.40** |
NDUFS5 | NADH dehydrogenase | 595136 | 1.16 | 1.13 | −1.01 | 1.08 | 1.02 | −1.37 | −1.44** |
NDUFS7 | NADH dehydrogenase | 75406 | 1.09 | 1.40 | 1.09 | 1.13* | 1.07 | −1.28 | −1.15 |
NDUFS6 | NADH dehydrogenase | 407785 | −1.32 | 1.06 | −1.01 | 1.02 | −1.14 | −1.30 | −1.32** |
NDUFV2 | NADH dehydrogenase | 72900 | 1.38 | 1.09 | 1.06 | 1.07 | −1.02 | −1.24 | −1.24** |
NDUFV3 | NADH dehydrogenase | 78330 | 1.12 | 1.16 | −1.03 | −1.01 | −1.14 | −1.35 | −1.39** |
UCRC | ubiquinol-cytochrome c | 66152 | 1.58 | 1.26 | 1.10 | 1.27 | 1.07 | −1.40 | −1.27** |
UHRF1BP1 | UHRF1 binding | 224648 | −1.03 | 1.36 | −1.08 | 1.06 | 1.15 | 1.23 | 1.15** |
UQCR | ubiquinol-cytochrome | 66594 | 1.26 | 1.40 | 1.04 | 1.14* | 1.09 | −1.28 | −1.19* |
UQCRC2 | ubiquinol-cytochrome | 67003 | 1.09 | 1.17 | 1.07 | 1.13 | −1.04 | −1.11 | −1.27* |
UQCRQ | ubiquinol-cytochrome | 22272 | 1.01 | 1.08 | 1.07 | 1.12* | −1.07 | −1.18 | −1.21** |
1From Rosen et al. [
Average fold change for genes related to ribosome biogenesis following a seven-day exposure to Wy-14,64
WT | Null | ||||||||
Symbol | Gene name | Entrez no. | Wy14,643 50 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg | PFOA 3 mg/kg | PFOS 3 mg/kg | PFOS 10 mg/kg |
MRPL12 | mitochondrial | 56282 | −1.16 | 1.25 | 1.07 | 1.14* | −1.16 | −1.18 | −1.12* |
MRPL13 | mitochondrial | 68537 | 1.32 | 1.33 | 1.12 | 1.35* | 1.01 | −1.21 | −1.42** |
MRPL17 | mitochondrial | 27397 | 1.68 | 1.76 | 1.10 | 1.43** | 1.13 | −1.13 | 1.09 |
MRPL23 | mitochondrial | 19935 | −1.14 | −1.04 | −1.00 | 1.10 | 1.09 | −1.38 | −1.20* |
MRPL33 | mitochondrial | 66845 | 1.22 | 1.26 | 1.07 | 1.05 | 1.04 | −1.29 | −1.28** |
MRPS12 | mitochondrial | 24030 | −1.24 | 1.18 | 1.05 | 1.12 | 1.02 | −1.27 | −1.15 |
MRPS18A | mitochondrial | 68565 | −1.46 | 1.34 | 1.04 | 1.28* | 1.60 | −1.19 | −1.06 |
RPL10 | ribosomal protein | 110954 | −1.15 | −1.21 | 1.02 | 1.03 | 1.07 | −1.10 | −1.02 |
RPL10A | ribosomal protein | 19896 | −1.11 | 1.10 | 1.03 | 1.05 | 1.00 | −1.07 | 1.01 |
RPL11 | ribosomal protein | 67025 | 1.14 | 1.12 | 1.10 | 1.11* | 1.15 | −1.15 | −1.09 |
RPL12 | ribosomal protein | 269261 | 1.01 | 1.37 | 1.08 | 1.15* | 1.11 | −1.08 | 1.05 |
RPL13A | ribosomal protein | 22121 | −1.14 | 1.03 | 1.07 | 1.12* | −1.17 | −1.15 | −1.10 |
RPL14 | ribosomal protein | 67115 | −1.28 | −1.06 | 1.15 | 1.23** | −1.13 | −1.18 | −1.22* |
RPL17 | ribosomal protein | 319195 | −1.27 | 1.15 | 1.03 | 1.12 | −1.52 | −1.10 | −1.09 |
RPL18 | ribosomal protein | 19899 | −1.11 | 1.28 | 1.04 | 1.07* | 1.19 | −1.27 | −1.09* |
RPL18A | ribosomal protein | 76808 | 1.65 | −1.37 | 1.04 | 1.11* | 1.08 | −1.15 | −1.02 |
RPL19 | ribosomal protein | 19921 | 1.22 | 1.23 | 1.01 | 1.05 | 1.07 | −1.11 | −1.03 |
RPL21 | ribosomal protein | 19933 | 2.00 | 1.55 | 1.03 | 1.09 | 1.18 | −1.20 | −1.18 |
RPL22 | ribosomal protein | 19934 | 1.17 | 1.45 | 1.06 | 1.29** | 1.08 | −1.25 | −1.14* |
RPL23 | ribosomal protein | 65019 | −1.07 | 1.35 | 1.06 | 1.06 | 1.22 | −1.24 | −1.16 |
RPL24 | ribosomal protein | 68193 | −1.13 | 1.07 | 1.06 | 1.09* | −1.00 | −1.19 | −1.11* |
RPL26 | ribosomal protein | 19941 | 1.04 | 1.22 | 1.03 | 1.03 | 1.07 | −1.22 | −1.18** |
RPL27 | ribosomal protein | 19942 | 1.04 | −1.01 | 1.08 | 1.38** | 1.06 | −1.25 | −1.40* |
RPL27A | ribosomal protein | 26451 | −1.07 | 1.07 | −1.00 | 1.17 | 1.26 | −1.17 | −1.09 |
RPL28 | ribosomal protein | 19943 | 1.29 | 1.04 | 1.01 | 1.11* | 1.67 | −1.22 | −1.10 |
RPL29 | ribosomal protein | 19944 | 1.16 | −1.30 | 1.04 | 1.09 | 1.08 | −1.23 | −1.17 |
RPL3 | ribosomal protein | 27367 | −1.00 | −1.14 | 1.01 | 1.09 | −1.01 | −1.03 | 1.06 |
RPL30 | ribosomal protein | 19946 | −1.15 | −1.07 | 1.02 | −1.21 | −1.04 | −1.29 | −1.23** |
RPL31 | ribosomal protein | 114641 | 1.11 | 1.37 | 1.09 | 1.05 | 1.29 | −1.18 | −1.12* |
RPL32 | ribosomal protein | 19951 | 1.06 | 1.11 | 1.02 | 1.12* | 1.08 | −1.16 | −1.03 |
RPL34 | ribosomal protein | 68436 | −1.26 | 1.16 | −1.07 | 1.05 | −1.04 | −1.22 | −1.31** |
RPL35 | ribosomal protein | 66489 | −1.03 | 1.15 | 1.13 | 1.26** | 1.04 | −1.17 | −1.11 |
RPL36 | ribosomal protein | 54217 | −1.07 | 1.12 | 1.09 | 1.23* | 1.07 | −1.27 | −1.20* |
RPL37 | ribosomal protein | 67281 | −1.16 | −1.18 | 1.04 | 1.27* | 1.17 | −1.19 | −1.10** |
RPL37A | ribosomal protein | 19981 | −1.15 | −1.09 | 1.03 | 1.16 | −1.12 | −1.22 | −1.19* |
RPL38 | ribosomal protein | 67671 | −1.17 | 1.14 | −1.01 | 1.06 | −1.03 | −1.18 | −1.10 |
RPL39 | ribosomal protein | 67248 | 1.04 | 1.02 | 1.06 | 1.13* | 1.07 | −1.18 | −1.16** |
RPL4 | ribosomal protein | 67891 | 1.16 | 1.43 | 1.03 | 1.03 | 1.32 | 1.03 | 1.04 |
RPL41 | ribosomal protein | 67945 | −1.06 | 1.14 | 1.05 | 1.06 | −1.13 | −1.20 | −1.26* |
RPL5 | ribosomal protein | 19983 | −1.21 | 1.02 | 1.24 | 1.09* | −1.05 | −1.05 | −1.11 |
RPL6 | ribosomal protein | 19988 | 1.01 | −1.08 | 1.00 | 1.05 | 1.15 | −1.05 | 1.03 |
RPL7A | ribosomal protein | 27176 | −1.02 | −1.11 | 1.01 | 1.01 | −1.02 | −1.07 | 1.01 |
RPL9 | ribosomal protein | 20005 | −1.35 | −1.08 | 1.03 | 1.07 | −1.11 | −1.19 | −1.12* |
RPS10 | ribosomal protein | 67097 | −1.02 | 1.02 | 1.05 | 1.07 | 1.00 | −1.17 | −1.12* |
RPS11 | ribosomal protein | 27207 | 1.05 | −1.74 | −1.01 | 1.11 | 1.06 | −1.24 | −1.14* |
RPS12 | ribosomal protein | 20042 | 1.16 | 1.22 | 1.11 | 1.19 | 1.22 | −1.21 | −1.12 |
RPS13 | ribosomal protein | 68052 | −1.03 | 1.10 | 1.07 | 1.22* | 1.11 | −1.27 | −1.22* |
RPS14 | ribosomal protein | 20044 | −1.03 | 1.19 | 1.05 | 1.11* | 1.01 | −1.17 | −1.11** |
RPS15A | ribosomal protein | 267019 | −1.05 | 1.05 | 1.02 | 1.12 | 1.02 | −1.14 | −1.20 |
RPS16 | ribosomal protein | 20055 | −1.09 | 1.05 | 1.05 | 1.07 | −1.02 | −1.12 | −1.07 |
RPS17 | ribosomal protein | 20068 | 1.00 | 1.16 | 1.04 | −1.19* | 1.01 | −1.19 | −1.15* |
RPS19 | ribosomal protein | 20085 | −1.07 | 1.23 | 1.08 | 1.19** | −1.00 | −1.14 | −1.05 |
RPS2 | ribosomal protein | 16898 | −1.09 | 1.02 | 1.04 | 1.02 | −1.16 | −1.03 | 1.04 |
RPS20 | ribosomal protein | 67427 | −1.40 | 1.21 | 1.04 | 1.15 | 1.25 | −1.11 | −1.13 |
RPS21 | ribosomal protein | 66481 | 1.11 | −1.32 | 1.15 | 1.38 | 1.39 | −1.32 | −1.25** |
RPS23 | ribosomal protein | 66475 | 1.01 | 1.04 | −1.00 | 1.04 | 1.09 | −1.21 | −1.10* |
RPS24 | ribosomal protein | 20088 | 1.58 | 1.62 | 1.11 | −1.29* | 1.75 | −1.16 | −1.19** |
RPS25 | ribosomal protein | 75617 | −1.23 | 1.01 | 1.09 | 1.13* | −1.02 | −1.30 | −1.17* |
RPS26 | ribosomal protein | 27370 | 1.32 | 1.30 | 1.04 | 1.16* | 1.14 | −1.20 | −1.08 |
RPS27A | ribosomal protein | 78294 | 1.05 | −1.05 | −1.00 | 1.02 | 1.09 | −1.08 | −1.05 |
RPS27L | ribosomal protein | 67941 | 1.72 | 1.28 | 1.07 | 1.14* | 1.19 | −1.18 | −1.17* |
RPS28 | ribosomal protein | 54127 | −1.19 | −1.03 | 1.03 | 1.06 | −1.05 | −1.28 | −1.17* |
RPS29 | ribosomal protein | 20090 | −1.26 | −1.05 | −1.02 | 1.01 | −1.03 | −1.19 | −1.20** |
RPS3 | ribosomal protein | 27050 | −1.04 | 1.29 | 1.03 | 1.20* | −2.88 | −1.11 | −1.06 |
RPS3A | ribosomal protein | 544977 | −1.18 | −1.07 | 1.02 | −1.01 | −1.05 | −1.10 | −1.03 |
RPS5 | ribosomal protein | 20103 | −1.16 | 1.18 | 1.06 | 1.09* | −1.02 | −1.13 | −1.00 |
RPS6 | ribosomal protein | 20104 | −1.20 | −1.02 | −1.20 | 1.06 | −1.02 | −1.14 | −1.06* |
RPS8 | ribosomal protein | 20116 | 1.19 | −1.05 | 1.07 | 1.13* | 1.04 | −1.29 | −1.13 |
RPS9 | ribosomal protein | 76846 | −1.39 | 1.30 | 1.05 | 1.07 | 1.05 | −1.08 | −1.04 |
1From Rosen et al. (2008), *Significantly different than control (
**Significantly different from control (
Functional categories of genes modified by PFOS in WT and Null mice. In WT mice, PFOS altered the expression of genes related to a variety of PPAR
The results from real-time RT-PCR analysis of selected genes are summarized, along with the corresponding results from the microarray analysis, in Figure
Microarray and Real-time PCR analysis of selected genes. Data from both assays were in close agreement. Small changes in
In the current study, exposure to PFOS induced both PPAR
Recognition that PPAR ligands can induce “off-target” effects is not new (for review, see [
Additional signaling pathways that may contribute to the effects observed in Null mice include pathways regulated by Srebf2 (Srebp2) and PPARGC1
Because certain effects were found only in Null mice, their relevance to the toxicity of PFOS is not clear. Although the developmental toxicity of PFOS has been shown to be independent of PPAR
In summary, PFOS is a PPAR
The authors would like to thank Dr. Hongzu Ren for conducting the microarray analysis and Drs. Jennifer Seed and Neil Chernoff for their critical review of this manuscript.