Neurotoxic effects of perfluoroalkylated compounds: mechanisms of action and environmental relevance

Abstract

Perfluoroalkylated compounds (PFCs) are used in fire-fighting foams, treatment of clothes, carpets and leather products, and as lubricants, pesticides, in paints and medicine. Recent developments in chemical analysis have revealed that fluorinated compounds have become ubiquitously spread and are regarded as a potential threats to the environment. Due to the carbon-fluorine bond, which has a very high bond strength, these chemicals are extremely persistent towards degradation and some PFCs have a potential for bioaccumulation in organisms. Of particular concern has been the developmental toxicity of PFOS and PFOA, which has been manifested in rodent studies as high mortality of prenatally exposed newborn rats and mice within 24 h after delivery. The nervous system appears to be one of the most sensitive targets of environmental contaminants. The serious developmental effects of PFCs have lead to the upcoming of studies that have investigated neurotoxic effects of these substances. In this review the major findings of the neurotoxicity of the main PFCs and their suggested mechanisms of action are presented. The neurotoxic effects are discussed in light of other toxic effects of PFCs to indicate the significance of PFCs as neurotoxicants. The main findings are that PFCs may induce neurobehavioral effects, particularly in developmentally exposed animals. The effects are, however, subtle and inconclusive and are often induced at concentrations where other toxic effects also are expected. Mechanistic studies have shown that PFCs may affect the thyroid system, influence the calcium homeostasis, protein kinase C, synaptic plasticity and cellular differentiation. Compared to other environmental toxicants the human blood levels of PFCs are high and of particular concern is that susceptible groups may be exposed to a cocktail of substances that in combination reach harmful concentrations.

Disposition of perfluorododecanoic acid in male rats after oral administration

“…It has been recognized that distribution of PFAAs to the brain is limited (Kudo, 2015;Mariussen, 2012). In adult rats, the levels of PFOA and perfluorononanoic acid (PFNA) in the brain were only 1-3% of those in the liver and serum (Austin et al, 2003;Benskin et al, 2009).…”

Per- and polyfluorinated substances in the Nordic Countries

“…The studies are summarized by Mariussen (2012). Neonatal exposure of PFOS at specific time points, at the period of high neuronal growth, was shown to induce behaviour effects in adult mice.…”

“…This in combination with the longer half-lives and elimination rate of the longer chain PFCs should be recognised as a great health and environmental concern . It has been shown that PFCs may affect the thyroid system (Weiss et al, 2009), influence the calcium homeostasis, protein kinase C, synaptic plasticity, cellular differentiation, induce neurobehavioral effects and induce peroxisome proliferation (Ishibashi et al, 2008;Mariussen, 2012). In vitro assessment of environmental fate and ecotoxicologial effects of individual PFCs in some cases demonstrate that their current environmental levels do not pose a threat to ecosystems (O'Brien et al, 2009).…”

The cytoprotective and the dark side of Nrf2

“…Further influential articles published in the Archives of Toxicology in recent years focus on nanotoxicity (Kim et al 2012;Landsiedel et al 2012;Nunes et al 2012;Trpkovic et al 2012;Gebel 2012;Oesch and Landsiedel 2012), the use of stem cells in toxicology (Wobus and Löser 2011;Krug et al 2013;Seiler et al 2011), carcinogenesis (Bernstein et al 2011Golka et al 2011;Burns and Korach 2012;Pavanello and Lotti 2012;Brambilla et al 2011), metal toxicology (Chasapis et al 2012, neurotoxicity (Soderlund 2012;Carvalho et al 2012;Mariussen 2012), in silico and in vitro methods (Karp and Caspi 2011;Godoy et al 2013;Mehling et al 2012;Geenen et al 2012) and oxidative stress (Matés et al 2012). The editors hope that this choice meets the current needs of our readers, and encourage them to suggest further In 1988, Paul Talalay and colleagues described a protein with highly reactive cysteine residues that protects against chemical carcinogenesis (Talalay et al 1988) This led to the discovery of an elaborate network of highly inducible, cytoprotective proteins that are controlled by the Keap1-Nrf2 pathway (Itoh et al 1999;Dinkova-Kostova et al 2002;Kobayashi et al 2004;Wakabayashi et al 2004;Motohashi and Yamamoto 2004;Zhang and Hannink 2003;Balogun et al 2003;McMahon et al 2003;Zhang et al 2004;Kwak et al 2003).…”