Article

Effects of perfluoroalkyl compounds on mRNA expression levels of thyroid hormone-responsive genes in primary cultures of avian neuronal cells.

Department of Biology, Centre for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5.
Toxicological Sciences (Impact Factor: 4.48). 03/2011; 120(2):392-402. DOI: 10.1093/toxsci/kfq395
Source: PubMed

ABSTRACT There is growing interest in assessing the neurotoxic and endocrine disrupting potential of perfluoroalkyl compounds (PFCs). Several studies have reported in vitro and in vivo effects related to neuronal development, neural cell differentiation, prenatal and postnatal development and behavior. PFC exposure altered hormone levels and the expression of hormone-responsive genes in mammalian and aquatic species. This study is the first to assess the effects of PFCs on messenger RNA (mRNA) expression in primary cultures of neuronal cells in two avian species: the domestic chicken (Gallus domesticus) and herring gull (Larus argentatus). The following thyroid hormone (TH)-responsive genes were examined using real-time reverse transcription-PCR: type II iodothyronine 5'-deiodinase (D2), D3, transthyretin (TTR), neurogranin (RC3), octamer motif-binding factor (Oct-1), and myelin basic protein. Several PFCs altered the mRNA expression levels of genes associated with the TH pathway in avian neuronal cells. Short-chained PFCs (less than eight carbons) altered the expression of TH-responsive genes (D2, D3, TTR, and RC3) in chicken embryonic neuronal cells to a greater extent than long-chained PFCs (more than or equal to eight carbons). Variable transcriptional changes were observed in herring gull embryonic neuronal cells exposed to short-chained PFCs; mRNA levels of Oct-1 and RC3 were upregulated. This is the first study to report that PFC exposure alters mRNA expression in primary cultures of avian neuronal cells and may provide insight into the possible mechanisms of action of PFCs in the avian brain.

0 Followers
 · 
90 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Perfluoroalkyl compounds (PFCs) have been shown to disrupt thyroid functions through thyroid hormone receptor (TR)-mediated pathways, but direct binding of PFCs with TR has not been demonstrated. We investigated the binding interactions of 16 structurally diverse PFCs with human TR, their activities on TR in cells, and the activity of perfluorooctane sulfonate (PFOS) in vivo. In fluorescence competitive binding assays, most of the 16 PFCs were found to bind to TR with relative binding potency in the range of 0.0003-0.05 compared with triiodothyronine (T3). A structure-binding relationship for PFCs was observed, where fluorinated alkyl chain length longer than ten, and an acid end group were optimal for TR binding. In thyroid hormone (TH)-responsive cell proliferation assays, PFOS, perfluorohexadecanoic acid, and perfluorooctadecanoic acid exhibited agonistic activity by promoting cell growth. Furthermore, similar to T3, PFOS exposure promoted expression of three TH upregulated genes and inhibited three TH downregulated genes in amphibians. Molecular docking analysis revealed that most of the tested PFCs efficiently fit into the T3-binding pocket in TR and formed a hydrogen bond with arginine 228 in a manner similar to T3. The combined in vitro, in vivo, and computational data strongly suggest that some PFCs disrupt the normal activity of TR pathways by directly binding to TR.
    Archives of Toxicology 05/2014; 89(2). DOI:10.1007/s00204-014-1258-y · 5.08 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tests with vertebrates are an integral part of environmental hazard identification and risk assessment of chemicals, plant protection products, pharmaceuticals, biocides, feed additives and effluents. These tests raise ethical and economic concerns and are considered as inappropriate for assessing all of the substances and effluents that require regulatory testing. Hence, there is a strong demand for replacement, reduction and refinement strategies and methods. However, until now alternative approaches have only rarely been used in regulatory settings. This review provides an overview on current regulations of chemicals and the requirements for animal tests in environmental hazard and risk assessment. It aims to highlight the potential areas for alternative approaches in environmental hazard identification and risk assessment. Perspectives and limitations of alternative approaches to animal tests using vertebrates in environmental toxicology, i.e., mainly fish and amphibians, are discussed. Free access to existing (proprietary) animal test data, availability of validated alternative methods and a practical implementation of conceptual approaches such as the Adverse Outcome Pathways and Integrated Testing Strategies were identified as major requirements towards the successful development and implementation of alternative approaches. Although this article focusses on European regulations, its considerations and conclusions are of global relevance.
    Regulatory Toxicology and Pharmacology 10/2013; DOI:10.1016/j.yrtph.2013.10.003 · 2.14 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Several environmental contaminants, such as polychlorinated biphenyls, dioxins, bisphenol A and phthalates, have been linked to diabetes. We therefore investigated whether other kinds of contaminants, perfluoroalkyl substances (PFAS), also called perfluorinated compounds (PFCs), are also associated with diabetes. The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study investigated 1,016 men and women aged 70 years. Seven PFAS were detected in almost all participant sera by ultra-high performance liquid chromatograph/tandem mass spectrometry. Diabetes was defined as use of hypoglycaemic agents or fasting glucose >7.0 mmol/l. 114 people had diabetes. In the linear analysis, no significant relationships were seen between the seven PFAS and prevalent diabetes. However, inclusion of the quadratic terms of the PFAS revealed a significant non-linear relationship between perfluorononanoic acid (PFNA) and diabetes, even after adjusting for multiple confounders (OR 1.96, 95% CI 1.19, 3.22, p = 0.008 for the linear term and OR 1.25, 95% CI 1.08, 1.44, p = 0.002 for the quadratic term). Perfluorooctanoic acid (PFOA) also showed such a relationship (p = 0.01). PFOA was related to the proinsulin/insulin ratio (a marker of insulin secretion), but none of the PFAS was related to the HOMA-IR (a marker of insulin resistance) following adjustment for multiple confounders. PFNA was related to prevalent diabetes in a non-monotonic fashion in this cross-sectional study, supporting the view that this perfluoroalkyl substance might influence glucose metabolism in humans at the level of exposure seen in the general elderly population.
    Diabetologia 12/2013; 57(3). DOI:10.1007/s00125-013-3126-3 · 6.88 Impact Factor

Full-text (3 Sources)

Download
2 Downloads
Available from
Feb 12, 2015