2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most toxic environmental pollutants. In the present study, we examined c-Fos expression in the central nervous system (CNS) after administration of a lethal dose of TCDD to the adult Long-Evans rat to clarify if the CNS participates in TCDD-induced intoxication. A single dose of TCDD (dissolved in olive oil, 50 microg/kg) or olive oil alone was administered to the rats by gavage. Animals were allowed to survive for 1 day to 5 weeks. Three days after the administration, a significantly large number of Fos-immunopositive cells were found in the hypothalamus (i.e. dorsomedial hypothalamic nucleus, paraventricular hypothalamic nucleus, medial preoptic nucleus), central amygdaloid nucleus and bed nucleus of the stria terminalis. These results suggest that some TCDD toxicity may be induced by its direct action on the CNS.
"eciWcally , c - Fos is expressed rapidly and transiently when neuronal activity changes rapidly , and it is induced by transynaptic activity and neuronal stress . Altered c - Fos expression is associated with a stress response and related to neuronal survival , short term memory , and locomotory behaviors in many vertebrates ( Bosch et al . 2001 ; Cheng et al . 2002 ; Sadananda and Bischof 2002 ; Espana et al . 2003 ) . The goal of the present study was to demonstrate potential alterations in mummichog brain activity in vivo resulting from P . shumwayae and C . concavicornis exposure , visu - alized through changes in c - Fos expression . In addition to general changes in brain activity , knowledge"
[Show abstract][Hide abstract] ABSTRACT: To better understand sublethal effects of harmful algal blooms (HABs) on fish, mummichog, Fundulus heteroclitus (L.), were exposed in the laboratory to varying, environmentally relevant densities of Pfiesteria shumwayae (Glasgow et Burkholder, CCMP 2089, dinoflagellate) and Chaetoceros concavicornis (Mangin, CCMP 169, diatom). Two experiments were conducted during the spring of 2003 and 2004 to quantitatively examine the
effects of acute (2h) P. shumwayae and C. concavicornis algal exposure on mummichog brain activity using c-Fos expression as a marker of altered neuronal activity. Brains from HAB-exposed
fish were removed, sectioned, and stained using immunocytochemistry prior to quantifying neuronal c-Fos expression. Fish exposed
to P. shumwayae and C. concavicornis showed increased c-Fos expression compared to unexposed control fish. A significant dose-response relationship was observed,
with increased labeling in brains of fish exposed to higher cell densities for both HAB species tested (P≤0.01). Increased labeling was found in the telencephalon, optic lobes, midbrain, and portions of the medulla. The greatest
increases in expression were observed in the telencephalon of P. shumwayae-exposed fish, and in the telencephalon and optic lobes of C. concavicornis-exposed fish (P≤0.01). These increases in c-Fos expression are consistent with other physical and chemical stress exposures observed in
fish. Neuronal stress, evidenced by c-Fos expression, demonstrates a sublethal effect of exposure and changes in brain activity
in fish exposed to HAB species.
"In rats, it has been demonstrated that c-Fos expression mediates neuronal excitation and enhances survival (Zhang et al., 2002). c-fos can be induced in rats through glutamate receptor agonists, ion channel flux, dioxins, and the mind altering drugs haloperidol and clozapine (Morgan and Curran, 1986; Sonnenberg et al., 1989; Murphy and Feldon, 2001; Cheng et al., 2002). Further, it appears that drug-induced patterns of Fos expression are dependent on the animals' concurrent behavioral status (Murphy and Feldon, 2001). "
[Show abstract][Hide abstract] ABSTRACT: The immediate early gene c-fos, and its protein product c-Fos, are known to be induced in neurons of mammals and fish as a result of neuronal stimulation. The purpose of this study was to quantitatively examine CNS alterations in killifish, Fundulus heteroclitus, in relation to harmful algal bloom (HAB) toxin exposure. c-Fos expression was visualized using immunocytochemistry in the brains of killifish exposed to the excitatory neurotoxins domoic acid (DA) and brevetoxin (PbTx-2), and a paralytic neurotoxin, saxitoxin (STX), released from HABs. In addition, a simulated transport stress experiment was conducted to investigate effects of physical stress on c-Fos induction. Groups of fish were exposed to the different stress agents, brain sections were processed for c-Fos staining, and expression was quantified by brain region. Fish exposed to DA, STX, and transport stress displayed significant alterations in neuronal c-Fos expression when compared to control fish (p< or = 0.05). DA, PbTx-2, and transport stress increased c-Fos expression in the optic tecta regions of the brain, whereas STX significantly decreased expression. This is the first study to quantify c-Fos protein expression in fish exposed to HAB toxins. General alterations in brain activity, as well as knowledge of specific regions within the brain activated in association with HABs or other stressors, provides valuable insights into the neural control of fish behavior as well as sublethal effects of specific stressors in the CNS.
"Statistically significant differences (P < 0.05) vs. control (a) or vs. the corresponding group in the other strain (b) are indicated. exposure triggers c-Fos expression in hypothalamic nuclei (Cheng et al., 2002) and that TCDD modulates hypothalamic neuropeptide concentrations (Fetissov et al., 2004). Our laboratory has demonstrated a striking difference in TCDD toxicity between two rat strains, inbred L–E and outbred H/W (Pohjanvirta et al., 1993; Unkila et al., 1998). "
[Show abstract][Hide abstract] ABSTRACT: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) brings about a wide variety of toxic and biochemical effects via an AH receptor (AHR)-mediated signalling pathway. Wasting syndrome and acute lethality are TCDD-induced endpoints showing a striking sensitivity difference between two rat strains, TCDD-sensitive Long-Evans (Turku/AB) (L-E) and TCDD-resistant Han/Wistar (Kuopio) (H/W). These rat strains were used to study hypothalamic effects of TCDD on expression of genes encoding AHR-regulated bHLH/PAS proteins potentially involved in molecular pathogenesis of the wasting syndrome. In addition, two well-established target genes of TCDD, CYP1A1 and CYP1A2 were also examined. Quantitative RT-PCR was used to measure mRNA levels in hypothalamus, which is a major center of food intake and body weight regulation. At both 6 and 96 h after a single dose of 50 microg/kg TCDD, significant elevations were found in mRNA levels of AHR repressor (AHRR), CYP1A1 and CYP1A2, but not those of AHR, ARNT or ARNT2. Likewise, TCDD (100 microg/kg) did not alter the expression of SIM1, implicated in the suppressive impact of TCDD on food intake, nor that of PER2, involved in regulation of circadian rhythms. Differences between H/W and L-E rats appeared in constitutive levels of AHR and ARNT and in TCDD-induced levels of CYP1A2, AHRR, AHR and ARNT, which all were about two- to four-fold lower in H/W rats. Thus, although the changes found do not account for the wasting syndrome, expression of all principal genes of the AHR-signalling pathway in rat hypothalamus make it a candidate target for TCDD.
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