Immunotoxicity of Perfluorooctanoic Acid and Perfluorooctane Sulfonate and the Role of Peroxisome Proliferator-Activated Receptor Alpha

DeWitt, Jamie C.; Shnyra, Alexander; Badr, Mostafa Z.; Loveless, Scott E.; Hoban, Denise; Frame, Steven R.; Cunard, Robyn; Anderson, Stacey E.; Meade, B. Jean; Peden‐Adams, Margie M.; Luebke, Robert W.; Luster, Michael I.

doi:10.1080/10408440802209804

Cited by 245 publications

(132 citation statements)

References 88 publications

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“…The observation in the present study, that concentrations of FSH and LH were negatively correlated with additive concentrations of T4 and T3 taken together, suggest that the lesser concentrations of T4 and T3 caused by PTU resulted in greater secretion of FSH and LH, which in turn promoted steroidogenesis. It has previously been reported that several chemicals, such as PCB 126 and PFOA, could decrease concentrations of T4 and T3 and increase concentrations of FSH, LH, T, and E2 (8)(9)(10)(11). Therefore, it was hypothesized that the greater steroidogenesis observed in the present study was due to lesser concentrations of T4 and T3, which in turn promoted secretion of FSH and LH.…”

Section: Discussionmentioning

confidence: 56%

“…For example, concentrations of thyroxine (T4) and triiodothyronine (T3) in the plasma of rats exposed to polychlorinated biphenyl (PCB) 126 decreased, while concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH), and 17 -estradiol (E2) increased (8,9). Exposure to perfluorooctanoic acid (PFOA) resulted in lesser concentrations of T3 and T4 and greater concentrations of testosterone (T), E2, and corticosterone in the plasma of mice and rats (10,11). Fadrozole, an aromatase inhibitor, resulted in lesser concentrations of E2 in the plasma and production of eggs, and modulated thyroid hormone-related gene expression in fathead minnow (Pimephates promelas), Medaka (Oryzias latipes), and Western clawed frog (Silurana tropicalis) (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

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Effects of Prochloraz or Propylthiouracil on the Cross-Talk between the HPG, HPA, and HPT Axes in Zebrafish

Liu

Zhang

Deng

et al. 2010

Environ. Sci. Technol.

120

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The objective of this study was to assess chemical-induced effects on cross-talk among the hypothalamic-pituitary-gonad (HPG), hypothalamic-pituitary-adrenal (HPA), and hypothalamic-pituitary-thyroid (HPT) axes of fish. Adult female zebrafish were exposed to 300 µg/L prochloraz (PCZ) or 100 mg/L propylthiouracil (PTU), and the transcriptional profiles of the HPG, HPA, and HPT axes were examined. Exposure to PCZ decreased plasma testosterone (T) and 17 -estradiol (E2) concentrations and affected HPA and HPT axes by downregulating corticotrophin-releasing hormone (CRH) after 12 and 48 h. By using correlation analyses, it was found that the decrease in E2 plasma concentrations caused by PCZ was correlated with the down-regulation of CRH mRNA expression. Exposure to PTU resulted in lesser concentrations of thyroxine (T4) and triiodothyronine (T3), greater concentrations of follicle stimulating hormone (FSH) and luteinizing hormone (LH) peptides, and increase in steroidogenic gene expression after 12 and 48 h. Concentrations of FSH and LH were negatively correlated with concentrations of T4 and T3. These results are consistent with the hypothesis that increased steroidogenic gene expression after PTU exposure resulted from a reduction in T4 and T3 concentrations, which resulted in greater secretion of FSH and LH.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Effects of Prochloraz or Propylthiouracil on the Cross-Talk between the HPG, HPA, and HPT Axes in Zebrafish

Liu

Zhang

Deng

et al. 2010

Environ. Sci. Technol.

120

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“…7 Due to their structure similarity to fatty acids, early studies focused on the toxicity mechanisms involving liganddependent activation of the hepatic peroxisome proliferator receptor α (PPARα), which induces enzymes responsible for β-oxidation, fatty acid ω-oxidation and cholesterol homeostasis. 8,9 In vitro competitive binding of PFAAs with serum albumin (a transport protein) was also evaluated as a possible route of disruption on fatty acid transport in blood. 10,11 More recently, increasing attention has been paid to the role of estrogenic activity of PFAAs in their hepatocarcinogenesis due to the observation of increased liver cancer incidence by PFAAs in PPARα knockout mice.…”

Section: ■ Introductionmentioning

confidence: 99%

Assessment of Estrogenic Activity of Perfluoroalkyl Acids Based on Ligand-induced Conformation State of Human Estrogen Receptor

Gao

Guo

2012

Environ. Sci. Technol.

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Perfluoroalkyl acids (PFAAs) have been reported to interfere with the endocrine system in vivo by mimicking endogenous hormone activities and causing adverse effects. Some exoestrogens bind to estrogen receptor (ER) and subsequently induce an ERmediated response. The transcriptional activity of ER is regulated by its distinct conformational states that are the results of ligand binding. In this work, a biosensor based on surface plasmon resonance (SPR) technique was developed which can discriminate between agonist and antagonist of human ERα (hERα) by monitoring the conformation state of the protein induced by ligand binding. The biosensor utilized the specific interaction between hERα and conformation-selective peptides. Six PFAAs with different chain lengths and acid groups were tested by the biosensor, and perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were found to be ER agonists. Kinetic analyses of direct interaction between PFAAs and hERα by SPR revealed that PFOS and PFOA were both weak binders of ER with K D values of 2.19 and 107 μM respectively, whereas the other four PFAAs did not bind with ER. To understand the differences in ER binding affinity and estrogenic activity among the six PFAAs, molecular docking based on the crystal structure of hERα ligand binding domain was performed. PFOS and PFOA were efficiently docked with hERα and formed hydrogen bonds with Arg394 in a manner similar to estradiol. Overall, the two 8-carbon PFAAs were assessed as weak agonists of hERα and are of potential concern.

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“…Specifically, PFOA and PFOS bind to peroxisome proliferator-activated receptors (PPARs), a key nuclear hormone receptor with roles in lipid metabolism and inflammation (reviewed in Ref. 6). …”

mentioning

confidence: 99%

Chronic exposure to perfluorinated compounds: Impact on airway hyperresponsiveness and inflammation

Ryu

Jha

Ojo

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Emerging epidemiological evidence reveals a link between lung disease and exposure to indoor pollutants such as perfluorinated compounds (PFCs). PFC exposure during critical developmental stages may increase asthma susceptibility. Thus, in a murine model, we tested the hypothesis that early life and continued exposure to two ubiquitous household PFCs, perfluorooctanoic acid (PFOA) and perflurooctanesulfonic acid (PFOS), can induce lung dysfunction that exacerbates allergen-induced airway hyperresponsiveness (AHR) and inflammation. Balb/c mice were exposed to PFOA or PFOS (4 mg/kg chow) from gestation day 2 to 12 wk of age by feeding pregnant and nursing dams, and weaned pups. Some pups were also sensitized and challenged with ovalbumin (OVA). We assessed lung function and inflammatory cell and cytokine expression in the lung and examined bronchial goblet cell number. PFOA, but not PFOS, without the OVA sensitization/challenge induced AHR concomitant with a 25-fold increase of lung macrophages. PFOA exposure did not affect OVA-induced lung inflammatory cell number. In contrast, PFOS exposure inhibited OVA-induced lung inflammation, decreasing total cell number in lung lavage by 68.7%. Interferon-γ mRNA in the lung was elevated in all PFC-exposed groups. Despite these effects, neither PFOA nor PFOS affected OVA-induced AHR. Our data do not reveal PFOA or PFOS exposure as a risk factor for more severe allergic asthma-like symptoms, but PFOA alone can induce airway inflammation and alter airway function.

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Immunotoxicity of Perfluorooctanoic Acid and Perfluorooctane Sulfonate and the Role of Peroxisome Proliferator-Activated Receptor Alpha

Cited by 245 publications

References 88 publications

Effects of Prochloraz or Propylthiouracil on the Cross-Talk between the HPG, HPA, and HPT Axes in Zebrafish

Effects of Prochloraz or Propylthiouracil on the Cross-Talk between the HPG, HPA, and HPT Axes in Zebrafish

Assessment of Estrogenic Activity of Perfluoroalkyl Acids Based on Ligand-induced Conformation State of Human Estrogen Receptor

Chronic exposure to perfluorinated compounds: Impact on airway hyperresponsiveness and inflammation

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