PFOS prenatal exposure induce mitochondrial injury and gene expression change in hearts of weaned SD rats

Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Toxicology (Impact Factor: 3.62). 03/2011; 282(1-2):23-9. DOI: 10.1016/j.tox.2011.01.011
Source: PubMed


Xenobiotics exposure in early life may have adverse effects on animals' development through mitochondrial injury or dysfunction. The current study demonstrated the possibility of cardiac mitochondrial injury in prenatal PFOS-exposed weaned rat heart. Pregnant Sprague-Dawley (SD) rats were exposed to perfluorooctane sulfonate (PFOS) at doses of 0.1, 0.6 and 2.0 mg/kg/d and 0.05% Tween 80 as control by gavage from gestation days 2-21. The dams were allowed to give nature delivery and then heart tissues from weaned (postnatal day 21) offspring rats were analyzed for mitochondrial injury through ultrastructure observation by electron microscope, global gene expression profile by microarray, as well as related mRNA and proteins expression levels by quantitative PCR and western blot. Ultrastructural analysis revealed significant vacuolization and inner membrane injury occurred at the mitochondria of heart tissues from 2.0 mg/kg/d dosage group. Meanwhile, the global gene expression profile showed significant difference in level of some mRNA expression associated with mitochondrial function at 2.0 mg/kg/d dosage group, compared to the control. Furthermore, dose-response trends for the expression of selected genes were analyzed by quantitative PCR and western blot analysis. The selected genes were mainly focused on those encoding for proteins involved in energy production, control of ion levels, and maintenance of heart function. The down-regulation of mitochondrial ATP synthetase (ATP5E, ATP5I and ATP5O) implicated a decrease in energy supply. This was accompanied by down-regulation of gene transcripts involved in energy consumption such as ion transporting ATPase (ATP1A3 and ATP2B2) and inner membrane protein synthesis (SLC25A3, SLC25A4, SLC25A10, SLC25A29). The up-regulation of gene transcripts encoding for uncoupling proteins (UCP1 and UCP3), epidermal growth factor receptor (EGFR) and connective tissue growth factor (CTGF), was probably a protective process to maintain heart function. The results indicate PFOS prenatal exposure can induce cardiac mitochondrial injury and gene transcript change, which may be a significant mechanism of the developmental toxicity of PFOS to rat.

6 Reads
  • Source
    • "Recent studies found that perfluorinated fatty acids (PFFAs) induced mitochondrial dysfunction and thus resulted in PFFAs toxicity effect. Xia et al. reported that PFOS prenatal exposure induced cardiac mitochondrial injury and gene expression change associated with mitochondrial function in rat [30]. Some studies documented that PFOS could uncouple mitochondrial respiration, increase nonspecific membrane permeability , and induce calcium-dependent mitochondrial swelling [15,31], and thus mitochondria-mediated apoptosis might occur. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Perfluorooctane sulfonate (PFOS) was listed as one of the persistent organic pollutants (POPs) in Stockholm Convention in 2009. Recent evidence showed that PFOS could induce apoptosis both in vivo and in vitro. However, the apoptotic mechanisms induced by PFOS as well as the possible relationship between apoptosis and other PFOS-induced endpoints, remain unclear. In the present study, normal human-hamster hybrid (AL) cells and mtDNA-depleted (ρ(0) AL) cells were exposed to PFOS, and assayed for cytotoxicity, mutagenicity, and apoptosis (caspase-3/7, -9 activities). Our results showed that PFOS decreased cell viability in a time- and concentration-dependent manner in AL cells, but not in ρ(0) AL cells. However, long-term exposure to PFOS failed to induce the mutagenic effects at the CD59 locus in AL cells. Exposure to 200 (M PFOS significantly increased the activities of caspase-3/7 and caspase-9 in AL cells, but the activities of these caspases were not affected in ρ(0) AL cells. In addition, PFOS increased the levels of reactive oxygen species (ROS), superoxide anion (O2(.-)), as well as nitric oxide (NO), and decreased mitochondrial membrane potential (MMP) at the concentrations of 100 and 200μM in AL cells. On the other hand, exposure to PFOS had no effect on intracellular ROS, O2(.-), and NO production in ρ(0) AL cells. Caspase-3/7 activity, which was increased by 200 (M PFOS, could be suppressed by ROS/O2(.-) scavengers and nitric oxide synthases (NOSs) inhibitors in AL cells. These results implicate that PFOS-induced apoptosis and oxidative stress is mediated by a mitochondria-dependent pathway and that the induction of apoptosis might be a protective function against mutagenesis in AL cells exposed to PFOS.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 04/2013; 754(1-2). DOI:10.1016/j.mrgentox.2013.04.004 · 3.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Oryzias melastigma is a newly emerging marine fish model. However, the application of this model has been restricted because of the lack of genomic information. Perfluorooctane sulfonate (PFOS), a persistent organic pollutant, is widely distributed in the estuarine/marine environment. The toxicological effects of PFOS on organisms, especially on marine fish species, remain largely unknown. In this study, the transcriptome of O. melastigma was sequenced using newly developed sequencing technology (Illumina RNA-seq). A total of 145,394 unigenes were obtained with 565 bp of unigene N50. These genes were further enriched in various molecular pathways involved in the toxicological response. We also investigated the transcriptional response of O. melastigma embryos after PFOS exposure from 2 days post fertilization (dpf) to 6 dpf by digital gene expression (DGE) technology. The differentially expressed genes were related to neurobehavioral defects, mitochondrial dysfunction and the metabolism of proteins and fats. A further quantitative RT-PCR study showed the down-regulation of ATP synthase and the up-regulation of uncoupling protein 2 (UCP2), which indicated mitochondrial dysfunction. In all, the transcriptome data represent the most comprehensive expressed gene catalog for O. melastigma and will serve as an important reference for various marine fish that are yet to be sequenced. The transcriptome profiling of O. melastigma embryos after exposure to PFOS are also expected to improve our current understanding of the molecular toxicology of PFOS.
    Aquatic toxicology (Amsterdam, Netherlands) 04/2012; 120-121:54-8. DOI:10.1016/j.aquatox.2012.04.013 · 3.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Perfluorooctane sulfonate (PFOS) is a widespread environmental contaminant that is detected in the lung of mammals. The mechanisms underlying PFOS-induced lung cytotoxicity remain unclear. The main purpose of this study was to evaluate the cytotoxic effects of PFOS on human lung cancer A549 cells and its possible molecular mechanism. A549 cells were treated with PFOS (0, 25, 50, 100 and 200 μ m) and the cellular apoptosis, mitochondrial membrane potential as well as intracellular reactive oxygen species were determined. In this study, PFOS induced a dose-dependent increase in A549 cell toxicity via an apoptosis pathway as characterized by increased percentage of sub-G1, activation of caspase-3 and -9, and increased ratio of Bax/bcl-2 mRNA expression. In addition, there was obvious oxidative stress, represented by decreased glutathione level, increased malondialdehyde level and superoxide dismutase activity. N-Acetylcysteine, as an antioxidant that is a direct reactive oxygen species scavenger, can effectively block PFOS-induced reactive oxygen species generation, mitochondrial membrane potential loss and cell apoptosis. These data indicate that PFOS induces apoptosis in A549 cells through a reactive oxygen species-mediated mitochondrial dysfunction pathway mechanism. Copyright © 2012 John Wiley & Sons, Ltd.
    Journal of Applied Toxicology 09/2012; 33(11). DOI:10.1002/jat.2785 · 2.98 Impact Factor
Show more