Lesions In Male Rats Research Articles

Stimulation of medial amygdala GABA neurons with kinetically different channelrhodopsins yields opposite behavioral outcomes.

The medial amygdala (MeA) receives pheromone information about conspecifics and has crucial functions in social behaviors. A previous study showed that activation of GABA neurons in the postero-dorsal MeA (MeApd) with channelrhodopsin-2H134R (ChR2) stimulates inter-male aggression. When performing these experiments using the faster channelrhodopsinH134R,E123T (ChETA), we find the opposite behavioral outcome. A systematic comparison between the two channelrhodopsin variants reveals that optogenetic activation of MeApd GABA neurons with ChETA suppresses aggression, whereas activation under ChR2 increases aggression. Although the mechanism for this paradoxical difference is not understood, we observe that activation of MeApd GABA neurons with ChR2 causes larger plateau depolarizations, smaller action potentials, and larger local inhibition than with ChETA. Thus, the channelrhodopsin variant used for invivo optogenetic experiments can radically influence the behavioral outcome. Future work should continue to study the role of specific sub-populations of MeApd GABA neurons in aggression control.

Anterior Thalamic Inputs Are Required for Subiculum Spatial Coding, with Associated Consequences for Hippocampal Spatial Memory.

Just as hippocampal lesions are principally responsible for “temporal lobe” amnesia, lesions affecting the anterior thalamic nuclei seem principally responsible for a similar loss of memory, “diencephalic” amnesia. Compared with the former, the causes of diencephalic amnesia have remained elusive. A potential clue comes from how the two sites are interconnected, as within the hippocampal formation, only the subiculum has direct, reciprocal connections with the anterior thalamic nuclei. We found that both permanent and reversible anterior thalamic nuclei lesions in male rats cause a cessation of subicular spatial signaling, reduce spatial memory performance to chance, but leave hippocampal CA1 place cells largely unaffected. We suggest that a core element of diencephalic amnesia stems from the information loss in hippocampal output regions following anterior thalamic pathology.SIGNIFICANCE STATEMENT At present, we know little about interactions between temporal lobe and diencephalic memory systems. Here, we focused on the subiculum, as the sole hippocampal formation region directly interconnected with the anterior thalamic nuclei. We combined reversible and permanent lesions of the anterior thalamic nuclei, electrophysiological recordings of the subiculum, and behavioral analyses. Our results were striking and clear: following permanent thalamic lesions, the diverse spatial signals normally found in the subiculum (including place cells, grid cells, and head-direction cells) all disappeared. Anterior thalamic lesions had no discernible impact on hippocampal CA1 place fields. Thus, spatial firing activity within the subiculum requires anterior thalamic function, as does successful spatial memory performance. Our findings provide a key missing part of the much bigger puzzle concerning why anterior thalamic damage is so catastrophic for spatial memory in rodents and episodic memory in humans.

Transneuronal Downregulation of the Premotor Cholinergic System After Corticospinal Tract Loss.

Injury to the supraspinal motor systems, especially the corticospinal tract, leads to movement impairments. In addition to direct disruption of descending motor pathways, spinal motor circuits that are distant to and not directly damaged by the lesion undergo remodeling that contributes significantly to the impairments. Knowing which spinal circuits are remodeled and the underlying mechanisms are critical for understanding the functional changes in the motor pathway and for developing repair strategies. Here, we target spinal premotor cholinergic interneurons (IN) that directly modulate motoneuron excitability via their cholinergic C-bouton terminals. Using a model of unilateral medullary corticospinal tract lesion in male rats, we found transneuronal downregulation of the premotor cholinergic pathway. Phagocytic microglial cells were upregulated in parallel with cholinergic pathway downregulation and both were blocked by minocycline, a microglia activation inhibitor. Additionally, we found a transient increase in interneuronal complement protein C1q expression that preceded cell loss. 3D reconstructions showed ongoing phagocytosis of C1q-expressing cholinergic INs by microglia 3 d after injury, which was complete by 10 d after injury. Unilateral motor cortex inactivation using the GABAA receptor agonist muscimol replicated the changes detected at 3 d after lesion, indicating activity dependence. The neuronal loss after the lesion was rescued by increasing spinal activity using cathodal trans-spinal direct current stimulation. Our finding of activity-dependent modulation of cholinergic premotor INs after CST injury provides the mechanistic insight that maintaining activity, possibly during a critical period, helps to protect distant motor circuits from further damage and, as a result, may improve motor functional recovery and rehabilitation.SIGNIFICANCE STATEMENT Supraspinal injury to the motor system disrupts descending motor pathways, leading to movement impairments. Whether and how intrinsic spinal circuits are remodeled after a brain injury is unclear. Using a rat model of unilateral corticospinal tract lesion in the medulla, we show activity-dependent, transneuronal downregulation of the spinal premotor cholinergic system, which is mediated by microglial phagocytosis, possibly involving a rapid and transient increase in neuronal C1q before neuronal loss. Spinal cord neuromodulation after injury to augment spinal activity rescued the premotor cholinergic system. Our findings provide the mechanistic insight that maintaining activity, possibly during an early critical period, could protect distant motor circuits from further damage mediated by microglia and interneuronal complement protein and improve motor functional outcomes.

Abstract 907: Chemopreventive effects of a non-camellia tea against azoxymethane -induced precancerous colorectal lesions in male rats

Abstract Tea (the leaves from Camellia plants) is one of the most popular beverages in the world; substantial evidence supports its success in the prevention of carcinogenesis and other chronic diseases in animal models. Plants other than Camellia have been widely used as tea as well in various cultures. We have systematically collected and identified over 30 species of frequently used Non-Camellia teas, which have been consumed at least 300 years in China or other nations. Recently, non-Camellia teas have attracted much attentions due to high potentials of preventing and treating metabolic and inflammatory diseases, as well as cancers. Epidemiologic studies report that tea consumption significantly reduces risk of colorectal cancer (CRC). We here reported in vivo preventive effects of the Ku-jin-cha (KJC) tea for CRC. KJC tea is a kind of “Non-Camellia tea” prepared from leaves of the plant Acer ginnala and popularly used in some Chinese regions for thousands of years. KJC contains high levels of anti-inflammatory and anti-oxidative compounds such as ginnalins. However, the potential chemopreventive effect of KJC remains unknown. Here, we investigated modulatory effects of KJC on colon carcinogenesis using the rat azoxymethane (AOM) induced precancerous colorectal lesion model. Wistar rats (male, 4∼5 weeks old) were randomly divided into 4 groups (Control, KJC, AOM and AOM+KJC, 10 rats/group) and were fed either normal water or experimental water containing KJC for 12 weeks. After one week of water or KJC drinking, all rats except the Control Group were injected with 15 mg/kg AOM (s.c., once weekly for 3 weeks). At 16∼17 weeks of age, urine and sera were collected for metabolomic analysis using UPLC-QTOF/MS (ultra-HPLC coupled with time-of-flight mass spectrometry). Rats were sacrificed at the end of KJC administration, and colorectums collected for evaluation of aberrant crypt (AC), aberrant crypt foci (ACF) and Crypts/focus. Spleens, thymuses and bloods were also taken for immunological analysis. Our results show that the numbers of AC, ACF and Crypts/focus in rats of the KJC+AOM Group were significantly decreased, versus rats of the AOM Group (p < 0.01). No ACF was found in rats without AOM injection. In addition, significant metabolic alterations were observed in the groups with KJC. Although KJC administration did not cause marked weight changes of spleens and thymuses, the effect of KJC on levels of inflammatory cytokines and mediators were also examined. Our results indicated that KJC significantly inhibited AOM-induced colonic ACF formation, suggesting that KJC might have a chemopreventive effect against colon carcinogenesis at least in the initiation stage of CRC. Furthermore, KJC may exert the chemopreventive effects on ACF formation by changing metabolic pathways and modulating immunity and inflammatory responses. This warrants further studies on the cellular and molecular mechanisms of KJC tea. Citation Format: Chunnian He, Wu Bi, L. Harris Zhang, Li Cao, Pei-Gen Xiao. Chemopreventive effects of a non-camellia tea against azoxymethane -induced precancerous colorectal lesions in male rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 907. doi:10.1158/1538-7445.AM2015-907

Concordance of Noncarcinogenic Endpoints in Rodent Chemical Bioassays.

Prediction of noncancer toxicologic outcomes in rodent bioassays of 37 chemicals from the National Toxicology Program was evaluated. Using the nonneoplastic lesions noted by NTP pathologists, we evaluate both agreement in toxic lesions across experiments and the predictive value of the presence (or absence) of a lesion in one group for other groups. We compare lesions between mice and rats, male mice and male rats, and female mice and female rats in both short-term and long-term bioassays. We also examine whether lesions found in a specific organ in a short-term test are also found in the long-term test of the same chemical. We find agreement (concordance) across species for specific lesions, as evaluated by the Kappa statistic, ranging from 0.58 (for concordance of nasal lesions between female mice and rats in long-term studies) to -0.14 (lung lesions between mice and rats in long-term studies). Predictive values are limited by the relatively small numbers of observations of each type of lesion. Positive predictive values range from 100% to 0%. Comparing the lesions found in short-term tests to those found in long-term tests resulted in Kappa statistic values from 0.76 (spleen lesions in male rats) to -0.61 (lung lesions in female mice). Positive predictive values of short-term tests for long-term tests range from 70% to 0%. Overall, there is considerable uncertainty in predicting the site of toxic lesions in different species exposed to the same chemical and from short-term to long-term tests of the same chemical.

Hindbrain Catecholamine Neurons Control Rapid Switching of Metabolic Substrate Use during Glucoprivation in Male Rats

Using the retrogradely transported immunotoxin, antidopamine β-hydroxylase-saporin (DSAP), we showed previously that hindbrain catecholamine neurons innervating corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus are required for glucoprivation-induced corticosterone secretion. Here, we examine the metabolic consequences of the DSAP lesion in male rats using indirect calorimetry. Rats injected into the paraventricular nucleus of the hypothalamus with DSAP or saporin (SAP) control did not differ in energy expenditure or locomotor activity under any test condition. However, DSAP rats had a persistently higher respiratory exchange ratio (RER) than SAPs under basal conditions. Systemic 2-deoxy-D-glucose did not alter RER in DSAP rats but rapidly decreased RER in SAP controls, indicating that this DSAP lesion impairs the ability to switch rapidly from carbohydrate to fat metabolism in response to glucoprivic challenge. In SAP controls, 2-deoxy-D-glucose-induced decrease in RER was abolished by adrenalectomy but not adrenal denervation. Furthermore, dexamethasone, a synthetic glucocorticoid, decreased RER in both SAP and DSAP rats. Thus, rapid switching of metabolic substrate use during glucoprivation appears to be due to impairment of the catecholamine-mediated increase in corticosterone secretion. Sustained elevation of basal RER in DSAP rats indicates that catecholamine neurons also influence metabolic functions that conserve glucose under basal conditions.

Microsomal Lipid Peroxidation, Antioxidant Enzyme Activities in Brain of Male Rats during Long-Term Exposure to Isoniazid

Isoniazid, a broad-spectrum antibiotic employed clinically in the treatment of bacterial infections, is known to cause a number of biochemical dysfunctions and suspected to induce memory decline with age to animals and humans. The present study therefore evaluates the oxidative damage in brain albino male rats. Isoniazid was administered orally at the dose regimen level of 5.0 mg/kg body weight per day in three equal divided doses of 10, 20, 30mg/kg (12 h interval) for 60 days. Control rats were given distilled water for the same period. Administration of Isoniazid significantly decreased the activity of superoxide dismutase. The activity of gamma-glutamyltranspeptidase, the activity of alanine-amino transferase (ALT) and alkaline phosphatase (ALP) as well as the formation of malondialdehyde (MDA) increased (p<0.05) compared to the corresponding control. The toxic effects of Isoniazid to the brain antioxidant defence systems were significantly increased. Collectively, the results suggest that therapeutic dose of Isoniazid elicits brain lesions in male rats through induction of oxidative damage and via the inhibitory effect on protein synthesis.

Maternal Separation and Lesion of Adtn Alters Anxiety And Adrenal Activity in Male Rats

The present study investigated the effect of early maternal separation on anxiety and hypophyso-adrenal system activity to anterodorsal thalamic nuclei (ADTN) lesion in male rats as adults in order to compare this with previous results with female rats. During the first 3 weeks of life, male rats were isolated 4.5 hr daily and tested as adults. Thirty days after ADTN lesion we found that adrenocorticotropic hormone (ACTH) plasma levels were affected neither by maternal separation nor by ADTN lesion. Plasma corticosterone (CORT) concentration was increased with lesion of the ADTN in maternally separated rats. A significant increase in plasma catecholamine concentration was induced by early maternal separation. In ADTN-lesioned rats, plasma norepinephrine (NE) concentration was significantly lower than in the respective sham-lesioned groups. In terms of anxiety, there were no significant effects of early experience. However, the ADTN lesion tended to decrease anxiety-related behavior.

Comparative therapeutic use of Risedronate and Calcarea phosphorica - allopathy versus homeopathy - in bone repair in castrated rats

Osteoporosis, a disease characterized by progressive bone loss, has been the target of several studies in the past few years. It results in a much higher risk for fractures and might cause slower bone lesion healing. The aim of this work was to study the effects of Risedronate (allopathic medicine) and Calcarea phosphorica 6CH (homeopathic medicine) on the repair of bone lesions in male rats with osteoporosis induced by castration. Eighty-four three-month-old rats were used divided into four groups of twenty-one animals each. Three groups where castrated and one group was submitted to Sham surgery. One month later, cortical lesions were made in all animals' tibiae and, after one day, the different experimental treatments began according to the following groups: CR--castrated/Risedronate (1 mg/kg/day); CCp--castrated/Calcarea phosphorica 6CH (3 drops/day); CP--castrated/placebo and SP--Sham/placebo. The animals were sacrificed at seven, fourteen and twenty-eight days after the beginning of the treatments and had their tibiae removed. Digital radiographs of the tibiae were taken and analyzed in order to evaluate the optical density of the defect area. Then, they were decalcified and processed for histological and histomorphometrical analysis. The data were submitted to ANOVA, and to the Tukey and Dunnett tests (5%). The allopathic and homeopathic treatments led to different bone formation as regards remodeling and maturation aspects. Further research is necessary to access the resistance and quality of the newly formed bone.

Synaptic mitochondrial changes in the motor cortex following unilateral cortical lesions and motor skills training in adult male rats

Unilateral lesions of the forelimb sensorimotor cortex and motor skills training interact to enhance synaptic plasticity in layer V of the motor cortex contralateral to the lesion in male rats. In this study, we assessed the metabolic correlates of these synaptic changes by quantifying the number and size of mitochondria in synaptic axonal terminals with perforated or non-perforated post-synaptic densities (PSDs) and single or multiple post-synaptic contacts. The number of synaptic mitochondria per neuron was significantly greater in rats with lesions. Neither manipulation affected mitochondrial size or number of mitochondria per synapse. Independent of experimental condition, terminals with perforated PSDs had more mitochondria than those with non-perforated PSDs and, among those with non-perforated PSDs, terminals with multiple synaptic contacts had more mitochondria than those forming single synapses.

Decrease of serotonin and metabolite in the forebrain and facilitation of lordosis by dorsal raphe nucleus lesions in male rats.

In castrated male rats, a radiofrequency lesion was made in the dorsal raphe nucleus (DRL) and lordosis behavior was observed following treatment with estrogen. After the behavioral test, brains were removed and the contents of 5-HT and 5-HIAA in the forebrain were measured by high pressure liquid chromatography (HPLC). In the results, only 2 of 16 control males without brain surgery showed lordosis, and the mean lordosis quotient (LQ) was extremely low when compared to that in control females. In contrast, all male rats with DRL displayed lordosis and the mean LQ was higher than that of control males without brain surgery but lower than that in control females (P < 0.001). In the DRL males, 5-HT and 5-HIAA contents in the septum (SPT), the preoptic area (POA), the ventromedial hypothalamus (VMH) and the striatum (STM) were lower than those in control male and female groups (P < 0.001). These results suggest that the dorsal raphe nucleus prevents male rats from showing lordosis by serotonergic influence in the forebrain. In addition, HPLC results showed that levels of the 5-HT in the SPT, the POA and the VMH in the female group were higher than those in the control male group (P < 0.05). In female rats, the POA (P < 0.01) and the VMH (P < 0.05) contained larger 5-HT than those in the SPT and the STM, but there were no difference of 5-HT contents in the male rat.

BUTYLBENZYLPHTHALATE: HAZARD CHARACTERIZATION AND EXPOSURE–RESPONSE ANALYSIS

Butylbenzylphthalate (BBP) has been assessed as a Priority Substance under the Canadian Environmental Protection Act. Effects that occur at lowest concentrations in rats are increases in organ to body weight ratios, primarily for the liver and kidney, and histological effects on the pancreas and kidney. In studies with protocols specific for investigating reproductive toxicity, adverse effects on testes have been reported, although at dose levels higher than those that had effects on other organs, such as liver and kidney. Although results of available studies do not support the conclusion that BBP is estrogenic, the potential for other endocrine-mediated effects cannot be precluded at this time. A tolerable daily intake of 1300 μg/kg body weight per day has been derived, based upon the lower 95% confidence limit for the benchmark dose associated with a 5% increase in the incidence of pancreatic lesions in male rats in an oral subchronic assay.

ETHYLENE GLYCOL: HAZARD CHARACTERIZATION AND EXPOSURE–RESPONSE ANALYSIS

Ethylene glycol has been assessed as a Priority Substance under the Canadian Environmental Protection Act. Based on short- and long-term oral studies in experimental animals, the kidney is the critical target organ for effects of ethylene glycol, with non-neoplastic renal lesions observed consistently in a range of species. Ethylene glycol also induces developmental effects (including teratogenicity) in rats and mice by all routes of exposure, although at doses greater than those associated with renal effects. As a result of limitations of histopathological reporting of non-neoplastic effects in the most recent chronic bioassay, a tolerable intake of 0.05 mg ethylene glycol/kg body weight per day has been derived based upon the benchmark dose associated with a 5% increase in the incidence of renal tubular lesions in male rats exposed in the diet, in a subchronic study.

Lack of modifying effects of environmental estrogenic compounds on the development of thyroid proliferative lesions in male rats pretreated with N-bis(2-hydroxypropyl)nitrosamine (DHPN).

The modifying effects of various environmental estrogenic compounds on thyroid carcinogenesis were investigated in a rodent two‐stage carcinogenesis model. The compounds examined were a soy isoflavone mixture (SI) and genistein (GEN) as phytoestrogens, nonylphenol (NP) as a xenoestrogen, 3‐chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5H)‐furanone (MX) as a thyroid carcinogen and sulfadimethoxine (SDM) as a known thyroid tumor promoter. Five‐week‐old male F344 rats were given a single subcutaneous injection of N‐bis(2‐hydroxypropyl)nitrosamine (DHPN; 2800 mg/kg, body weight) or the vehicle alone. Starting one week thereafter, GEN (250 or 25 ppm in diet), SI (400 ppm in diet), NP (250 or 25 ppm in diet), MX (30 ppm, in drinking water) or SDM (1000 ppm in drinking water) was administered for 12 weeks. Major organs including the thyroid, pituitary, liver, kidney, testis, brain and pancreas were weighed and histopathological observation was performed. Thyroid weights were significantly increased (P < 0.001) only in the SDM treatment groups, especially with DHPN pretreatment. Kidney weights were slightly increased in the NP or MX treatment groups, albeit without statistical significance. Histopathologically, thyroid proliferative lesions were only observed in the SDM alone or DHPN+SDM group with significant focal hyperplasias, adenomas and adenocarcinomas limited to the combined treatment case. There were no organ weight changes or histopathological lesions in the major organs including the thyroid in the GEN, SI, NP, and MX treatment groups regardless of DHPN pretreatment. Our results thus indicate that the weakly estrogenic compounds GEN, SI and NP and the environmental rat thyroid carcinogen MX do not exert any modifying effects on thyroid carcinogenesis in rats under the present experimental conditions.

Effects of sex and MK-801 on auditory-processing deficits associated with developmental microgyric lesions in rats.

Neonatally induced microgyric lesions produce defects in rapid auditory processing in adult male rats. Given that females across species are less susceptible to the deleterious effects of neural injury and that treatment with neuroprotective agents at the time of injury can reduce neural damage, the authors tested the effects of sex and neuroprotectant exposure on the behavioral consequences of microgyric lesions in rats. Results showed that sham but not microgyric males were able to perform the task at the fastest rate of stimulus presentation. Microgyric females, in contrast, discriminated at all stimulus conditions and did not differ from female shams. Microgyric males treated with MK-801 had reduced cortical damage and performed the discrimination at the fastest condition. Results suggest that females are less susceptible to the behavioral effects of neocortical microgyria and that MK-801 may ameliorate the behavioral consequences of these lesions in male rats.

Potentiation of ejaculatory activity by median raphe nucleus lesions in male rats: effect of p-chlorophenylalanine.

The effect of radiofrequency lesions in the median or dorsal raphe nucleus (MRL or DRL) on copulatory behavior was examined in sexually inexperienced male rats. Three weeks after castration and the brain surgery, all males were subcutaneously implanted with Silastic capsules containing testosterone. In the first behavioral test, the frequency of ejaculation in the MRL group was significantly higher than that in sham and DRL males, but mount and intromission were not. Seven days after the first test, the second test was carried out after treatments with 100 mg/kg p-chlorophenylalanine (PCPA), a serotonin synthesis inhibitor, or saline daily for 4 days in MRL and DRL males. The frequencies of male sexual behavior in PCPA treated DRL males were higher than those in saline treated DRL males. In contrast, even after treatments with PCPA, male sexual activity in MRL males was comparable to those in saline treated MRL males. These results suggest that serotonergic neurons in the median raphe nucleus play an inhibitory role in the regulation of male sexual activity, especially ejaculation. Furthermore, it can be thought that PCPA acts on the median raphe neurons and facilitates ejaculatory behavior.

Effects of D&C yellow no. 11 ingestion on F344/N rats and B6C3F1 mice.

D&C yellow no. 11 (CAS no. 8003-22-3) was administered in the feed at concentrations of 500-50,000 ppm to groups of F344/N rats and B6C3F1 mice of each sex for 13 wk to determine the toxicity. In addition, a perinatal study was conducted to determine the effects of feeding diets containing D&C yellow no. 11 to female rats during reproduction and to their offspring. Although the estimated intake (g/kg) of D&C yellow no. 11 of mice was more than twice that of rats, the results were generally similar for both rats and mice. In both species, D&C yellow no. 11 caused no mortality, but it did reduce body weight gain slightly in both sexes of rats exposed to 17,000 and 50,000 ppm. Absolute and relative liver weights were significantly increased in all groups of rats and mice administered D&C yellow no. 11 in the feed. There was minimal to mild degeneration of the periportal hepatocytes in rats at doses of 1700 ppm and higher and in mice at 5000 ppm and above. A dose-related yellow-brown pigment was observed in hepatocytes, Kupffer cells, and biliary epithelium of the liver of both sexes of both species and in the renal tubule epithelium in both sexes of rats. In male rats, all treated groups had increased number and size of hyaline droplets in the renal tubule epithelium of the cortex and outer medulla. To determine if these renal and hepatic lesions were reversible, male rats were administered 5000 ppm dietary D&C yellow no. 11 for 70 d and then examined at 3, 14, and 28 d after the chemical was removed from the diet. Pigment persisted in the kidney and liver for as long as 28 d following removal of D&C yellow no. 11 from the diet, but hepatocellular degeneration and cytoplasmic alteration in the kidney completely resolved by d 3 and 14, respectively. In the perinatal toxicity study, body weight gain in rat dams given diets containing as much as 50,000 ppm D&C yellow no. 11 for 4 wk before mating to untreated males was similar to that of controls at the time of mating but was lower at parturition and weaning. However, fertility, gestation length, litter size, and pup birth weights were unaffected by treatment. At weaning, there was a significant dose-related decrease in pup body weights from the 5000, 17,000, and 50,000 ppm groups. At 8 wk of age, pups fed the same dosed-feed concentrations as the dams had depressed body weights in the 17,000 and 50,000 ppm treated groups. Microscopic lesions in the liver and kidney of the pups in all dose groups were similar to those described in the 13-wk study. The results of these studies indicate that compound-related effects occurred at all dietary concentrations of D&C yellow no. 11. Liver weights were increased in dosed rats and mice, minimal to mild hepatocellular degeneration was seen in rats receiving dietary concentrations of 1700 ppm and above and in mice at 5000 ppm and above, and there was an increase in the number and size of hyaline droplets in all dosed groups of male rats. Similar compound-related effects were also seen in all dosed rats in the perinatal toxicity study. With the exception of pigment accumulation, the treatment-related kidney and liver lesions in male rats were reversible by 14 d after chemical was withdrawn from the diet.

Central neurotoxicity induced by subchronic exposure to 2,4-pentanedione vapour.

1. Male and female Fischer 344 rats were exposed to 2,4-pentanedione (2,4-PD) vapour acutely (4 h) at 1265 or 1811 ppm, or for 6 h day-1, 5 days a week for 14 weeks to 0, 101, 307 or 650 ppm. 2. Mortality occurred during or within a few hours of the acute exposures (10% at 1265 ppm; 70% at 1811 ppm). No animal had gross or microscopic brain lesions. 3. All female rats (20) and 10 of 30 male rats exposed to 650 ppm 2,4-PD vapour died by the 38th study day (29 exposures); there were no subsequent male deaths. Twenty-five of the 30 animals that died, and seven of the 15 males that survived, had light microscopical evidence of degenerative lesions, principally within the caudate/putamen nuclei, nuclei of the cerebellar medulla, and vestibular nuclei. Less frequently involved, in animals that died, were various regions of the cerebral cortex. The early histopathological lesions, seen from the 16th study day (12 exposures) to the 38th study day (28 exposures) were characterised by malacia. When present, lesions in male rats surviving the 14-weeks of 650 ppm 2, 4-PD exposure were characterised by malacia and gliosis. No peripheral nerve lesions were seen by light or transmission electron microscopy. 4. Neither mortality nor neuropathology were seen in rats subchronically exposed to 101 or 307 ppm, 2,4-PD vapour.

Incidence of nonneoplastic lesions in historical control male and female Fischer-344 rats from 90-day toxicity studies.

The incidence of all spontaneously occurring histologic lesions was determined for control Fischer-344 (F-344) rats from 90-day (13-wk) prechronic National Toxicology Program (NTP) toxicity studies. A total of 319 rats, represented by control groups of 10 males and 10 females each from dosed feed (n = 8), inhalation (n = 4), and gavage (n = 4) studies were included in the review. All protocol required tissues routinely collected for evaluation were reexamined for potential nonneoplastic and neoplastic lesions. Histopathologic findings in tissues included a spectrum of degenerative and inflammatory lesions. The most common lesions in male rats were nephropathy [145/160 (90.6%)] and cardiomyopathy [125/158 (79.1%)]. These changes were also present in the female rats, however, at much lower incidence rates [nephropathy = 30/157 (19.1%); cardiomyopathy = 36/158 (22.8%)]. Other less frequently occurring lesions included inflammation of the preputial [36/152 (23.7%)] and clitoral [34/155 (21.9%)] glands and inflammation of the liver consisting of either foci of mononuclear inflammatory cells [19/159 (11.9%) in males and 33/159 (20.8%) in females] or focal granulomatous inflammation [1/159 (0.6%) in males and 14/159 (8.8%) in females]. Pancreatic acinar cell atrophy occurred in both males [11/160 (6.9%)] and females [8/159 (5.0%)]. A variety of other less common nonneoplastic lesions were identified in both sexes of rats. Also recorded in this review are histologic changes generally considered to be components of the normal morphology of a particular tissue or organ for the F-344 rat (i.e., extramedullary hematopoiesis and hemosiderin deposition in the spleen, renal mineralization, uterine dilation, etc.). These findings were included and discussed due to potential treatment effects that may result in an increase or decrease in these changes compared to controls. Neoplasms were not observed in rats from the prechronic studies evaluated.

Sensory and sympathetic contributions to nerve injury-induced sensory abnormalities in the rat

Peripheral neuropathy can be associated with a variety of symptoms, including spontaneous unpleasant sensations and pain, as well as increased sensitivity to sensory stimuli. A peripheral neuropathy model involving an L5 spinal nerve lesion in male rats has been used to gain insight into the mechanisms that underlie symptoms that develop after nerve injury. This model was used to study the involvement of sensory fibres, the sympathetic postganglionic neuron and the role of nerve growth factor in the induction and maintenance of altered sensory function in the nerve territory of the intact L4 spinal nerve. Sensory testing was done with calibrated von Frey filaments and a radiant heat apparatus [Hargreaves K. et al. (1988) Pain 32, 77-88] and the occurrence of abnormal spontaneous behaviour was recorded. L5 spinal nerve resection produced increased mechanical and heat sensitivity as well as abnormal spontaneous behaviours. Surgical sympathectomy at the L5 but not at the L4 spinal nerve level alleviated all sensory abnormalities. However, a lesion of preganglionic fibres to the L5 level had no significant effect on sensory abnormalities. Thus, sympathetic postganglionic neurons at the level of spinal nerve injury can contribute to neuropathy symptoms independent of input from preganglionic neurons. Postganglionic sympathetic nerve crush alone led to increased mechanical sensitivity but not to increased heat sensitivity nor to abnormal spontaneous behaviour, further emphasizing the role of sympathetic postganglionic neuron changes for the development of increased mechanical sensitivity. An L5 spinal nerve resection in rats treated neonatally with capsaicin induced increased mechanical sensitivity which was slower in onset and lower in magnitude than that in untreated littermates and was abolished by postganglionic sympathectomy. Nerve growth factor perfused onto the cut L5 spinal nerve also markedly delayed the onset of increased mechanical sensitivity. Two pathophysiological mechanisms leading to central changes may be necessary to produce altered sensations in this model: (i) ongoing activity in C-fibres, independent of sympathetic postganglionic neuron activity and (ii) activity in sensory fibres modulated by a sensory-sympathetic interaction in the injured spinal nerve or dorsal root ganglion. The sympathetic postganglionic neuron contribution is independent of preganglionic sympathetic outflow from the central nervous system, suggesting a novel mechanism by which sympathetic efferent terminals can regulate sensory fibre activity. A contribution of a loss of neurotrophic factors to the sympathetic postganglionic neuron following nerve lesion is also suggested to contribute to the symptoms induced by the spinal nerve lesion.