Neonatal Exposure to PFOS and PFOA in Mice Results in Changes in Proteins which are Important for Neuronal Growth and Synaptogenesis in the Developing Brain

Abstract

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) belong to the family of perfluorinated compounds. They are used in industrial and consumer applications, e.g., clothing fabrics, carpets, and food packaging. PFOS and PFOA are present in the environment and are found in dust and human milk, which implies that newborns and toddlers can be directly exposed to these agents during brain development. Recently, we reported that PFOS and PFOA can cause neurobehavioral defects and changes in the cholinergic system, in the adult animal, when given directly to neonatal mice, and thereby showing similarities with other investigated persistent organic pollutants, such as dichloro-diphenyl-trichloroethan, polychlorinated biphenyls, and polybrominated diphenyl ethers (PBDEs). In recent studies, we have also seen that highly brominated PBDEs can affect the levels of proteins that are important for neuronal growth and synaptogenesis in the neonatal mouse brain. The present study shows that a single oral dose of either 21 micromol PFOS or PFOA/kg body weight (11.3 or 8.70 mg), given directly to the neonatal mice on postnatal day 10, significantly increased the levels of CaMKII, GAP-43, and synaptophysin in the hippocampus of the neonatal mouse. Both compounds significantly increased the levels of synaptophysin and tau in cerebral cortex, and PFOA also increased the levels of tau in hippocampus. These proteins are important for normal brain development, and altered levels of these proteins during a critical period of the brain growth spurts could be one of the mechanisms behind earlier reported behavioral defects.

A single neonatal exposure to perfluorohexane sulfonate (PFHxS) affects the levels of important neuroproteins in the developing mouse brain

“…This supports our present results, and previous studies on PFOS, PFOA and PBDEs (Viberg et al, 2006b, Johansson et al, 2008a, Johansson et al, 2008b, Johansson et al, 2009, Viberg, 2009a, showing that disturbed synaptophysin levels may affect the brain development and…”

“…An overexpression of CaMKII may favor hippocampal long-term depression (LTD), instead of LTP, which is more associated with forgetting (Bach et al, 1995). Similar neurotoxic effects, with increased CaMKII levels in hippocampus and deranged adult behavior manifested as lack of habituation and hyperactivity, have also been seen in our previous studies where neonatal male mice were exposed to PFOS, PFOA, PBDEs or ketamine (Johansson et al, 2008a, Viberg et al, 2008a, Johansson et al, 2009, Viberg, 2009a. This supports the results from our present study and the suggestion that changes in CaMKII levels may be one of the mechanisms behind the adult behavioral and cognitive impairments seen after neonatal exposure to PFHxS.…”

“…The NFTs are mainly present in brain regions involved in learning and memory. The present study showed that there was an increase of tau in the hippocampus of the neonates, which is similar to the effects seen in the study by Johansson et al (2009). This was only seen after exposure to PFOA in male mice; however Johansson et al also measured an increase of tau in the cerebral cortex of the neonatal mice for both PFOS and PFOA 24h after exposure.…”

“…It is suggested that the altered cholinergic system could be one possible mechanism behind the disturbed adult behavior. In addition, PFOS and PFOA also affected neuroproteins important for the normal brain development after a single neonatal exposure on PND 10 (Johansson et al, 2009). Johansson et al (2009) showed that the neonatal exposure to PFOS or PFOA on PND 10 caused an up regulation of calcium/calmodulin-dependent kinase II (CaMKII), growthassociated protein-43 (GAP-43) and synaptophysin protein levels in the hippocampus of male mice 24h after exposure.…”

“…The brain growth spurt (BGS) is a recognized stage, where many critical developmental changes occur (Davison and Dobbing, 1968), and that the period is sensitive to insults by xenobiotics e.g. DDT, bioalltherin, nicotine, PCBs, PBDEs, PFCs, ketamine, bisphenol A (Eriksson, 1992, Ahlbom et al, 1994, Eriksson et al, 2000, Eriksson et al, 2001, Eriksson et al, 2002, Eriksson and Fredriksson, 2004, Viberg et al, 2006a, Johansson et al, 2008a, Johansson et al, 2009, Viberg, 2009a, Viberg et al, 2011, Viberg and Lee, 2012. During the BGS the establishment of neuronal connections, the maturation of axonal and dendritic outgrowth, synaptogenesis and glial multiplication and myelination take place (Dobbing andSands, 1979, Kolb andWhishaw, 1989).…”