Transcriptional Effects of Prenatal and Neonatal Exposure to PFOS in Developing Rat Brain

Abstract

Perfluorooctane sulfonate (PFOS), a persistent and bioaccumulative compound, is widely distributed in the environment. To explore the molecular mechanism of neonatal neurotoxic effects, we evaluated the transcriptional effects of prenatal and neonatal exposure to PFOS in developing rat brain by performing gene expression profiling in the cerebral cortex. Dams received 3.2 mg/kg PFOS in their feed from gestational day 1 (GD1) to weaning (PND 21). Pups then had free access to treated feed until PND 35. Six Illumina RatRef-12 Expression BeadChips were used to identify gene expression changes on postnatal days (PNDs) 1, 7, and 35. Significantly affected genes (P < 0.05) were involved in neuroactive ligand-receptor interaction, calcium signaling pathways, cell communication, long-term potentiation/depression, the cell cycle, and peroxisome proliferator-activated receptor (PPAR) signaling. 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 lasting from PND1 to 21. Prenatal and postnatal exposure to PFOS caused potential neurotoxicity as demonstrated by developmentally different global transcriptional changes. 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.

Brain region distribution and patterns of bioaccumulative perfluoroalkyl carboxylates and sulfonates in East Greenland polar bears (Ursus maritimus)

“…Recent studies on PFAAs in rodents have found that neonatal exposure to PFOS or PFOA can cause disruption to the central nervous system, resulting in abnormal development of motor neurons and significant changes in gene expression, including genes responsible for calcium signaling pathways, peroxisome proliferator-activated receptor signaling, cell communication, and the cell cycle [25]. Other symptoms included deranged spontaneous behavior, hyperactivity that worsened with age, changes in exploratory behavior, and reduced muscle strength in males [26].…”

“…Furthermore, exposure concentrations in these studies far surpass concentrations found in free-ranging wildlife. For example, Wang et al [25] administered PFOS both prenatally and neonatally in albino Wistar rats. They showed that at birth (day 1) the PFOS concentration in the brain of pups was 2.085 AE 0.108 mg/g wet weight and over 840 genes were significantly affected.…”

“…In the brain, PFOS has been detected following laboratory animal exposure [25], demonstrating its ability to cross the BBB. Recent studies with rodents have found that neonatal exposure to PFOS or PFOA can cause disruption to the central nervous system, resulting in abnormal development of motor neurons and significant changes in gene expression [25,26]. Furthermore, in vitro PFOS and FOSA exposure in both differentiated and undifferentiated PC12 cells showed that both compounds were disruptive to DNA synthesis [27].…”

Perfluorooctane sulfonate induces neuronal and oligodendrocytic differentiation in neural stem cells and alters the expression of PPARγ in vitro and in vivo

“…PPARs have been shown to be involved in the control of proliferation, differentiation and migration of NSCs (Cimini and Ceru, 2008), and PFOS has been suggested to exert its effects via PPAR signaling (Wang et al, 2010). To clarify the mechanisms of PFOS-induced alterations of differentiation, we examined the mRNA expression of PPARs (PPARα, PPARδ and PPARγ) and their downstream targets; the mitochondrial uncoupling proteins (UPC1, UCP2 and UCP3) controlling the energy conversion in the mitochondria (Villarroya et al, 2007), and the superoxide dismutases (SOD1, SOD2, SOD3) which are important enzymes in the antioxidant defence system of cells (Bordet et al, 2006) (Table 1).…”

“…Takacs and Abbott (2007) have shown that PFOS significantly increased the activation of mouse PPARα and PPARδ isoforms, but not PPARγ, in Cos-1 cells using transient transfection assay. A study on the transcriptional effects of prenatal and neonatal exposure of rat to PFOS using gene expression profiling in the cerebral cortex, showed that PPARs are among the affected signaling pathways (Wang et al, 2010). The effects of PFOS on the three isoforms of PPARs have been shown in marine medaka fish, Oryzias melastigma, where exposure to PFOS first inhibited the expression of PPARα and PPARδ at early developmental stage (dpf 4), and then induced it at later stage (dpf 10), while no changes were observed in PPARγ expression at either stage (Fang et al, 2012).…”