Exploration Of Molecular Mechanisms Of PFOS-induced Developmental Neurotoxicity

PFOS is considered as an emerging persistent organic pollutant in2009. Although the developmental neurotoxicity of PFOS exposure has been widely studied, little is known about how PFOS perturbs the developing central nervous system (CNS) at the molecular level. To investigate and compare the potential molecular effects of prenatal and neonatal exposure to PFOS in the developing nervous system, figure out the relationship of PFOS with neuroendocrine system, and predict the potentially interrupted neuro-dysfunction and nervous system impairment by PFOS exposure, we carried out this study containing that:(1) We evaluate the transcriptional effects of prenatal and neonatal exposure to PFOS in developing rat brain by performing gene expression profiling in the cerebral cortex. Six Illumina RatRef-12Expression BeadChips were used to identify gene expression changes on postnatal days (PNDs)1,7, and35. To compare prenatal and lactational exposure contributions to transcriptional effects, a subset of altered genes obtained from the gene-profile study that represented neurobiological functions was analyzed using RT-PCR in a follow-up cross-foster study from PND1to21. It was observed that prenatal and postnatal exposure to PFOS caused potential neurotoxicity as demonstrated by developmentally different global transcriptional changes.842and634genes were significantly affected by PFOS at PND1and PND7, respectively (P<0.05), whereas only13genes were significantly affected at PND35. Significantly affected genes (P<0.05) were involved in central nervous system development, neurogenesis, long-term potentiation/depression, learning and memory, neurotransmission and synaptic plasticity. These results suggest that prenatal exposure was more effective in altering expression of several genes. Also, transcriptional effects of PFOS exposure on neurodevelopment occurred primarily by disrupting the neuroendocrine system.(2) We used eight miRNA arrays to profile the expression of brain miRNAs in neonatal rats on postnatal days (PND)1and7with0mg/kg (Control) and3.2mg/kg of PFOS feed treatment, and subsequently examined six potentially altered synapse-associated proteins to evaluate presumptive PFOS-responsive functions. A complex TH-mediated gene and protein response to BDE-47and/or PFOS exposure that depends on the region, time and chemical characteristics was observed. The results revealed that1) a significant accumulation difference occurred between the two chemicals;2) On a equimolar basis, BDE-47and PFOS affected serum TT3and TT4differently in adults and offspring;3) there were region-specific and exposure-and time-dependent alterations in TH concentrations and tested gene and protein expression levels; and4) interaction for the combined chemicals was only observed for BDNF, which exhibited a synergistic effect on PND1in the cortex and an antagonistic effect on PND14in the hippocampus. Our results suggest that little combined interaction of co-exposures was observed except on BDNF. The underlying mechanisms remain uncertain but seem to involve more actions than just TH-regulated pathway.(3) To investigate whether an interaction existed between PFOS and BDE-47on TH-mediated pathways, adult female Wistar rats were exposed to3.2and32mg/kg of PFOS or BDE-47in their diet, and co-exposed to a combination of each chemical (3.2mg/kg) from gestational day (GD)1to postnatal day (PND)14. Serum and brain tissues from both male and female neonates were collected on PND1,7, and14to examine TH-regulated gene and protein expression. Twenty-four brain miRNAs on PND1and seventeen on PND7were significantly altered with PFOS exposure (P<0.05), of which, miR-466b,-672, and-297that are critical in neurodevelopment and synapse transmission showed high reduction by more than five fold. Protein levels of p75, TrkC, and VGLUT2were significantly decreased and no protein level increased with PFOS exposure during PND1to7. Our findings indicate that PFOS has the potential to effect the formation of glutamate excitatory pre-synaptic terminals, which may involve the functional regulation of miR-297,-214and-1. Negative regulation of miRNA was rarely observed in the present study, suggesting a possible fail-safe mechanism for the interaction of miRNA and its targets. These data identify the role of miRNAs in PFOS-responsive neurobiological processes, especially the synaptic pathway.(4) Based on the GO and Pathway results associated with differentially expressed mRNAs and miRNAs, and results of neuro-functional protein changes, we further explored the common associated neurological pathways by these miRNAs, mRNAs and proteins with attempt to find out the most potential neurological diseases and neuro-dysfunctions involved in PFOS exposure. It was found that PFOS has the potential of affecting the initiation, development and lasting process of LTP to make a toxic action. Moreover, the underlying mechanism of PFOS-induced potential LTP is likely related to the induction of changes in mRNA and miRNA levels, and alteration of LTP-associated gene and protein expressions. As cell LTP is important in brain functions such as learning and memory, the potential toxicity of PFOS exposure on LTP processes may translate into other neuro-disorders such as interruption of synaptic plasticity and threaten to impair the learning and memory ability, suggesting that protection of offspring from PFOS prenatal and postnatal exposure is very critical for the healthy development of brain.