Neurotoxicology and teratology
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Neurotoxicol Teratol · Nov 2011
Cytoarchitectonic and neurochemical differentiation of the visual system in ethanol-induced cyclopic zebrafish larvae.
Embryonic exposure to ethanol leads to malformations such as cyclopia. Cyclopic embryos present fused eyes and lack of the ventral specification of the brain, with physiological and morphological defects in the visual system, which provides a useful model for teratology and neurotoxicity assessments. We analysed the differentiation of the visual areas in the ethanol-induced cyclopic animals. ⋯ We found that the alterations produced by exposure to ethanol are not only cell-selective, but also tissue-selective. Cyclopia is the most severe phenotype induced by ethanol, although cell differentiation and proliferation can reach normal patterns after a certain period of time, which points to a neural plasticity process. Zebrafish embryos may possess a compensation mechanism against the ethanol effect, which would account for their use for pharmacogenetic and chemical screenings in the analysis of new molecules that could improve visual problems.
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Neurotoxicol Teratol · Nov 2011
Feeding behaviors and ORXR-β-GABA A R subunit interactions in Carassius auratus.
Orexins are one of the most potent orexigenic factors in fish that through their interaction with the GABA(A) receptor system assures the successful execution of feeding, motor and sleep-wake activities. In the present study, the effects of ORX-A (10ng/g BW) very greatly enhanced (p<0.001) the time spent in feeding behaviors while at the same time moderately increased (p<0.05) food intake of the goldfish. It is worthy to note that the great variations of time spent in feeding behaviors induced by β GABA(A)R agonist (muscimol, MUS) and antagonist (bicuculline, BIC) did not result to be correlated to any significant variations of food intake. ⋯ Of all telencephalic regions Dl, considered homologous to the mammalian hippocampus, proved to be a major target for ORX-A effects. Overall, these data suggest that it is mainly the ORXergic system that promotes feeding behaviors via reward pathways in teleost fish as in mammals. Surprisingly, β GABA(A)R drugs did not modify such behaviors when given alone while the inhibitory effect on cognitive/reward processes was evoked when given together with ORX-A, suggesting that more than β subunits other GABA(A)R subunits could be promoting mnemonically guided motor behaviors.
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Neurotoxicol Teratol · Sep 2011
Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey.
The combination of nitrous oxide gas (N(2)O) and isoflurane (ISO) vapor is commonly used in pediatric surgical procedures for human infants and children to produce unconsciousness and analgesia. Because of obvious limitations it is difficult to thoroughly explore the effects of pediatric anesthetic agents on neurons in human infants or children. Due to the complexity of the primate brain, the monkey is often the animal model of choice for developmental neurotoxicology experiments, and it is in the rhesus monkey that the phenomenon of interest (anesthetic-induced neuronal cell death in the brain) has been previously reported. ⋯ However, neuronal damage was apparent when N(2)O was combined with ISO as indicated by increased numbers of caspase-3-, Silver staining- and Fluoro-Jade C-positive cells in the frontal cortex, temporal gyrus and hippocampus. Electron micrographs indicated typical swelling of the cytoplasm and nuclear condensation in the frontal cortex. These data suggest that prolonged exposure to inhaled anesthetics (a combination of N(2)O and ISO) in the developing rhesus monkey results in neuronal damage, and that the cell death observed is apoptotic and necrotic in nature.
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Neurotoxicol Teratol · Jul 2011
Developmental thyroid hormone insufficiency reduces expression of brain-derived neurotrophic factor (BDNF) in adults but not in neonates.
Brain-derived neurotrophic factor (BDNF) is a neurotrophin critical for many developmental and physiological aspects of CNS function. Severe hypothyroidism in the early neonatal period results in developmental and cognitive impairments and reductions in mRNA and protein expression of BDNF in a number of brain regions. The present study examined the impact of modest levels of developmental thyroid hormone insufficiency on BDNF protein expression in the hippocampus, cortex and cerebellum in the neonatal and adult offspring of rat dams treated throughout pregnancy and lactation. ⋯ However, no differences in BDNF expression were detected in the preweanling animals as a function of PTU exposure; yet dose-dependent alterations emerged in adulthood despite the return of thyroid hormone levels to control values. Males were more affected by PTU than females, BDNF levels in hippocampus and cortex were altered but not those in cerebellum, and biphasic dose-response functions were detected in both sexes. These findings indicate that BDNF may mediate some of the adverse effects accompanying developmental thyroid hormone insufficiency, and reflect the potential for delayed impact of modest reductions in thyroid hormones during critical periods of brain development on a protein important for normal synaptic function.
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Neurotoxicol Teratol · Mar 2011
Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys.
Previously our laboratory has shown that ketamine exposure (24h of clinically relevant anesthesia) causes significant increases in neuronal cell death in perinatal rhesus monkeys. Sensitivity to this ketamine-induced neurotoxicity was observed on gestational days 120-123 (in utero exposure via maternal anesthesia) and on postnatal days (PNDs) 5-6, but not on PNDs 35-37. In the present study, six monkeys were exposed on PND 5 or 6 to intravenous ketamine anesthesia to maintain a light surgical plane for 24h and six control animals were unexposed. ⋯ There are also apparent differences in the motivation of these animals which may be impacting OTB performance. These observations demonstrate that a single 24-h episode of ketamine anesthesia, occurring during a sensitive period of brain development, results in very long-lasting deficits in brain function in primates and provide proof-of-concept that general anesthesia during critical periods of brain development can result in subsequent functional deficits. Supported by NICHD, CDER/FDA and NCTR/FDA.