Developmental Neurotoxicity of Environmental Pollutants : Effects on neuronal protein markers after neonatal exposure

Sammanfattning: This thesis focused on investigations of the developmental neurotoxic effects of bisphenol A (BPA) or perfluorohexane sulfonate (PFHxS), after a single neonatal exposure, during a critical period of the brain development in mice.BPA is a well-known industrial chemical used in the production of polymer products and PFHxS is used as an industrial additive as a surfactant. Commonly, these two compounds have been found in the environment, wild-life and in humans. They are a cause of concern as BPA is known to be an endocrine disrupter and PFHxS is presently unregulated; although similar compounds have been phased-out of production. Additionally, humans may be exposed to these compounds throughout their life time starting already before birth. Infants and children are especially vulnerable as they are not yet fully developed and therefore can be more sensitive to toxic insults. The brain growth spurt (BGS), is a critical period of the mammalian brain development, and is characterized by a rapid growth as well as biochemical changes. Toxic insults during this period have shown to cause persistent and irreversible behavioral and cognitive dysfunctions in mice. The onset and duration of the BGS varies between species, and in mice it is postnatal starting from birth and spans up to 3-4 weeks of life. In humans, it starts from around the third trimester and extends up to the first two years of life. For both species the BGS coincide with the period of lactation. The BGS process involves several important neuroproteins, such as BDNF, CaMKII, GAP-43, synaptophysin and tau. These neuroproteins are essential for maintaining normal neuronal growth and synaptogenesis. Additionally, these proteins display specific ontogenic patterns and peak during the BGS in the neonatal mouse brain.This thesis has shown that BPA and PFHxS can cause developmental neurotoxic effects when administered directly during the peak of the BGS. BPA induced altered levels of CaMKII and synaptophysin in adult mice, whereas PFHxS induced altered levels of CaMKII, GAP-43, synaptophysin and tau in neonatal mice. These effects are similar to previously studied persistent organic pollutants such as polybrominated diphenyl ethers (PBDEs) and other perfluorinated compounds (PFCs). The altered neuroprotein levels may be a plausible explanation to recently seen disarranged behavior in adult mice neonatally exposed to BPA or PFHxS. As the two compounds are seemingly different, but produce similar neurotoxic effect, it further supports the notion that the developing brain is sensitive to toxic insults when exposed during a sensitive period of brain development. Also, further investigations on finding mechanisms of action and biomarkers for toxic insult of environmental pollutants are important in order to be able to foresee and prevent future consequences of existing and new emerging substances.