Comparative hepatic gene expression profiling of rats treated with 1H,1H,2H,2H-heptadecafluorodecan-1-ol or with pentadecafluorooctanoic acid.

Pentadecafluorooctanoic acid is an established peroxisome proliferator. Little is known about effects of treatment with 1H,1H,2H,2H-heptadecafluorodecan-1-ol, which is metabolized to pentadecafluorooctanoic acid. We compared effects of various dosages (3, 10, or 25 mg/kg body wt) of each of these compounds on hepatic gene expression in rats with microarrays. Microarray data were validated by real-time RT-PCR. Expression data were also correlated with hepatic activities of selected enzymes and with hepatic levels of pentadecafluorooctanoic acid and 1H,1H,2H,2H-heptadecafluorodecan-1-ol. Pentadecafluorooctanoic acid caused the more powerful change in gene expression, in terms of both number of genes affected and extent of change in expression. Across the dosages used pentadecafluorooctanoic acid and 1H,1H,2H,2H-heptadecafluorodecan-1-ol caused significant (P < or = 0.05) changes in expression for 441 and 105 genes, respectively. With 1H,1H,2H,2H-heptadecafluorodecan-1-ol approximately 38% of the 105 genes exhibited decreased expression with a dose of 25 mg/kg body wt, these genes also appearing less responsive to treatment at the lower dosages. Bioinformatic analysis suggested that these genes are associated with regulatory functions. With pentadecafluorooctanoic acid, increasing dosage up to 10 mg/kg body wt brought about progressive increase in expression of affected genes. Pathways analysis suggested similar effects of the two compounds on lipid and amino acid metabolism. Marked differences were also found, particularly with respect to effects on genes related to oxidative phosphorylation, oxidative metabolism, free radical scavenging, xenobiotic metabolism, and complement and coagulation cascades.

Distinct changes in neuronal and astrocytic amino acid neurotransmitter metabolism in mice with reduced numbers of synaptic vesicles.

The relations between glutamate and GABA concentrations and synaptic vesicle density in nerve terminals were examined in an animal model with 40-50% reduction in synaptic vesicle numbers caused by inactivation of the genes encoding synapsin I and II. Concentrations and synthesis of amino acids were measured in extracts from cerebrum and a crude synaptosomal fraction by HPLC and (13)C nuclear magnetic resonance spectroscopy (NMRS), respectively. Analysis of cerebrum extracts, comprising both neurotransmitter and metabolic pools, showed decreased concentration of GABA, increased concentration of glutamine and unchanged concentration of glutamate in synapsin I and II double knockout (DKO) mice. In contrast, both glutamate and GABA concentrations were decreased in crude synaptosomes isolated from synapsin DKO mice, suggesting that the large metabolic pool of glutamate in the cerebral extracts may overshadow minor changes in the transmitter pool. (13)C NMRS studies showed that the changes in amino acid concentrations in the synapsin DKO mice were caused by decreased synthesis of GABA (20-24%) in cerebral neurons and increased synthesis of glutamine (36%) in astrocytes. In a crude synaptosomal fraction, the glutamate synthesis was reduced (24%), but this reduction could not be detected in cerebrum extracts. We suggest that lack of synaptic vesicles causes down-regulation of neuronal GABA and glutamate synthesis, with a concomitant increase in astrocytic synthesis of glutamine, in order to maintain normal neurotransmitter concentrations in the nerve terminal cytosol.