Abstract
Halogenated persistent organic pollutants (POPs) like perfluorinated alkylated substances (PFASs), brominated flame retardants (BFRs), organochlorine pesticides and polychlorinated biphenyls (PCBs) are known to cause cancer, immunotoxicity, neurotoxicity and interfere with reproduction and development. Concerns have been raised about the impact of POPs upon brain development and possibly neurodevelopmental disorders. The developing brain is a particularly vulnerable organ due to dynamic and complex neurodevelopmental processes occurring early in life. However, very few studies have reported on the effects of POP mixtures at human relevant exposures, and their impact on key neurodevelopmental processes using human in vitro test systems. Aiming to reduce this knowledge gap, we exposed mixed neuronal/glial cultures differentiated from neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs) to reconstructed mixtures of 29 different POPs using concentrations comparable to Scandinavian human blood levels. Effects of the POP mixtures on neuronal proliferation, differentiation and synaptogenesis were evaluated using in vitro assays anchored to common key events identified in the existing developmental neurotoxicity (DNT) adverse outcome pathways (AOPs). The present study showed that mixtures of POPs (in particular brominated and chlorinated compounds) at human relevant concentrations increased proliferation of NSCs and decreased synapse number. Based on a mathematical modelling, synaptogenesis and neurite outgrowth seem to be the most sensitive DNT in vitro endpoints. Our results indicate that prenatal exposure to POPs may affect human brain development, potentially contributing to recently observed learning and memory deficits in children.
Highlights
Halogenated persistent organic pollutants (POPs) are long-lived compounds that are present in our daily environment and of concern to human health [1]
Β-III-tu bulin and microtubule-associated protein-2 (MAP2) increased over the time course of neuronal differenti ation, with a progressive increase of neurite length of about 2.3 fold compared to undifferentiated cells (Fig. 1A, C, E)
As described in our previous study [62] and reported in Fig. 1C for ease of reading, SYP and PSD95 co-localization, biomarkers of synapse formation, increased by ~7.7 fold after 28 days in vitro (DIV) of differentiation (Fig. 1C, E, F), whilst BDNF protein levels decreased over time (~65 % reduction compared to un differentiated cells), being more expressed in proliferating neural stem cells (NSCs) (Fig. 1C, E)
Summary
Halogenated persistent organic pollutants (POPs) are long-lived compounds that are present in our daily environment and of concern to human health [1]. Species differences in serum half-lives have been reported for a number of POPs, making it difficult to interpret animal data as a basis for human hazard assessment. Due to their persistent behaviour in the environment, bio-accumulative and toxic properties, some POPs have been banned or are nominated to be banned from production via the Stockholm Convention, and those still on the market are regulated through Registration, Evaluation and Authorization of Chemicals (REACH). Many compounds have not been tested for toxic properties, and banned POPs are still found in both human and animal tissues [14]
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