Lloyd Hastings

Behavioral effects of low level neonatal lead exposure.

Rats exposed to lead via maternal milk were tested at various stages of development on a number of behavioral tasks. Beginning at paturition, the dams were given either tap water, 0.02%, or 0.10% lead acetate in the drinking water. Pups from all three groups were weaned to normal chow and tap water at 21 days of age. The mean lead concentration of the dams blood and of neonatal (20 days of age) brain and blood were all below 50 microgram/100 ml. No significant differences were found between the high lead-exposed group and controls in general as measured by wheel running over a 21 day period beginning at 30 days of age. However, there was a significant difference in wheel running behavior during the first three hr of testing. Both lead-exposed groups were found to display significantly less aggressive behavior as measured by the shock-elicited aggression test. Low level lead exposure had no discernable effect on the acquisition and subsequent reversal of a successive brightness discrimination task. Lead exposure under these conditions appears to affect some aspects of emotional behavior, while having little effect on general activity or cognitive function.

Microvillar cells of the olfactory epithelium: morphology and regeneration following exposure to toxic compounds

In recent years microvillar cells (MVC) have been identified in the olfactory epithelium of numerous species, including rodents, canines, and primates. However, there is no consensus on the morphologic or histochemical features of this cell, nor is the function of these cells currently known. Previous studies have examined MVC during development and in the mature olfactory epithelium, but not after toxic insult. A microvillar cell, defined by specific morphologic criteria, was studied in adult male Long-Evans rats exposed via inhalation to either 200 ppm methyl bromide for 4 h/day, 4 days/week for 2 weeks, or to 635 micrograms/m3 nickel for 6 h/day for 16 consecutive days, and sacrificed serially over several months. The pattern of recovery for MVC differed according to the severity and specificity of the insult to the olfactory epithelium. With methyl bromide, all cell types were completely depleted from olfactory epithelium immediately after injury, including MVC. MVC were slow to repopulate the epithelium, and appeared only when olfactory epithelium was complete in other respects. With nickel exposure, where the major effect was a gradual decrease in sustentacular cells with a thinning of the apical cytoplasm thickness, MVC showed a decline during exposure, but reappeared during recovery. In both cases, there was no difference in olfactory function, even when MVC were absent from the olfactory epithelium. A mature olfactory epithelium appears to be necessary to support the presence of this MVC, suggesting that it is not crucial to the regeneration processes or recovery of olfactory function, but perhaps plays some role, as yet undefined, in the unperturbed olfactory epithelium.

Chronic cadmium exposure: relation to male reproductive toxicity and subsequent fetal outcome.

Acute injections of high doses of Cd induce marked testicular necrosis. However, the effects of low-dose, oral Cd exposure on a chronic basis are not well documented. The present investigation was designed to examine the effects of such exposure as reflected in parameters of spermatotoxicity and histology. Moreover, the impact on fetal outcome was measured by evaluating teratological and postnatal neurobehavior endpoints. Male Long-Evans hooded rats (100 d of age) were exposed to 0, 17.2, 34.4, or 68.8 ppm Cd for 70 d. During this period, the animals were maintained on a semipurified diet to control for the contributions of Zn and other trace elements. Near the end of exposure the males were mated to three female rats. One was sacrificed on d 21 of pregnancy for teratological assessment, including fetal weight, and determination of preimplantation and postimplantation loss. The other two dams were allowed to deliver, and their offspring were tested on tasks of exploratory behavior (d 21) and learning (d 90). Subsequently, the male parent was sacrificed and a variety of measures recorded including weights of testes and caudae epididymides, sperm count and sperm morphology, and Cd content of liver and kidney. One of the testes was also evaluated histologically. No significant effects were observed on any of the parameters of reproductive toxicity or fetal outcome. These findings suggest that, at the doses employed in this study, Cd did not have significant deleterious effects on the male reproductive system. Morever, the traditional view of Cd-related testicular insult, based on acute exposure, injection protocols, needs to be reevaluated in terms of environmental relevance.

Behavioral toxicity in the offspring of rats following maternal exposure to dichloromethane

Abstract Rats divided in four treatment groups were exposed to dichloromethane (DCM) (4500 ppm) or filtered air before and/or during gestation in order to assess the occurrence and extent of toxic effects on developing offspring. The progeny of dams exposed to DCM either prior to and/or during gestation exhibited altered rates of behavioral habituation to novel environments. No simple relationship between exposure period and behavioral outcome was observed. Each of the treatment groups showed effects as a function of age at testing and the behavioral task used. Treatment effects were detectable in offspring as early as 10 days of age and were still demonstrable in 150-day-old male rats. Treatment effects were observed in rats of both sexes in preweaning tests but were not seen in adult female rats. No effects of subacute DCM exposure were evident in growth rate, long-term food and water consumption, wheel running activity, or avoidance learning. This study, which should be viewed as preliminary, is cf interest since altered rates of habituation to novel environments were observed in the absence of overt maternal toxicity, or teratogenicity. The effects cannot be definitely attributed to a direct effect of DCM since elevated maternal carboxyhemoglobin (COHb)- or DCM-induced changes in maternal-litter interactions could have been contributing factors. The findings do suggest that the functional development of progency of DCM-exposed dams should be further investigated.

Discriminability of intracranial stimuli: The role of anatomical connectedness.

Abstract We have previously demonstrated a high degree of perceptual similarity between rewarding hypothalamic and septal brain shock. The present experiment attempted to evaluate the contribution of anatomical factors in determining the degree of stimulus equivalence. Eight rats were each implanted with positively reinforcing electrodes in the septum and the hypothalamus. They were then tested for their ability to solve a thirst-motivated water-reinforced successive discrimination task with stimulation of the two structures serving as the discriminative stimuli. Four animals had both electrodes placed on the same side of the brain (Ipsilateral Group), while in another four rats the electrodes were aimed at structures on opposite sides of the brain (Contralateral Group). The contralateral group reached the discrimination criterion significantly faster than the ipsilateral group. (i.e., the distributions were nonoverlapping.) The difficulty of making a discrimination between the stimulus properties of two types of rewarding brain shock seems to be directly related to the intimacy of the connections between the anatomical structures being stimulated.

Evaluation of teratogenicity and neurotoxicity with maternal inhalation exposure to methyl chloroform

Female Long‐Evans rats were exposed by inhalation of 2100 ±. 200 ppm methyl chlorofrom (MC) to determine whether exposure before mating and during pregnancy was more detrimental to the offspring than exposure either before mating or during pregnancy alone. Four groups were exposed for 2 wk before mating and through d 20 of gestation in a 2 X 2 factorial design: (1) MC exposure before and during pregnancy, (2) MC before mating alone, (3) MC during pregnancy alone, and (4) filtered air before and during pregnancy. A t term, half of each group were sacrificed and assessed for maternal toxicity, embryotoxicity, and teratogenicity; the other half delivered their young for later behavioral evaluation and examination for gross lesions. No significant differences were found in measurements of maternal toxicity or embryotoxicity except for a decrease in fetal body weight when dams were exposed during pregnancy alone. Significantly increased incidences of skeletal and soft tissue variations were seen in fetuses fro...

Chronic dexamethasone treatment potentiates insult to olfactory receptor cells produced by 3-methylindole

The effect of chronic dexamethasone treatment on damage to olfactory receptor cells produced by 3-methylindole (3-MI) was examined. Twelve rats were injected, every other day, with dexamethasone (1.5 mg/kg, i.p.), and 12 rats with saline alone. Injections began 1 week before and continued, in different rats, from 1 to 4 weeks after a single intraperitoneal administration of 150 mg/kg 3-MI. One, two, three, and four weeks after exposure to 3-MI, different groups of rats, three specimens per each treatment condition, received bilateral application of horseradish peroxidase to the olfactory mucosa and were subsequently sacrificed. Anterograde labeling of primary afferents, i.e., an inverse correlate of the degree of cellular damage, was quantitatively determined by measuring the mean optical density (MOD) of staining in sections of the olfactory bulb. In saline-injected rats, the MOD values were 27.0, 46.6, 87.1, and 104.7 for one, two, three, and four post-3-MI weeks, respectively. The corresponding values in the dexamethasone-treated rats were 15.7, 29.7, 87.5, and 110.5. The MOD values of the dexamethasone-injected rats were significantly lower than those of the saline-injected rats for post-3-MI weeks 1 and 2, indicative of stronger damage to olfactory receptor cells in the rats treated with the glucocorticoid. The data suggest that dexamethasone potentiates the 3-MI olfactotoxicity during the first 2 weeks after insult. This effect, at least partly, may be due to the inducing action of dexamethasone on the cytochrome P450 responsible for metabolic bioactivation of 3-MI.

3-Methylindole alters both olfactory and trigeminal nasal mucosal potentials in rats.

Data from human studies imply that vanillin is an olfactory stimulant, whereas CO2 activates intranasal trigentinal nociceptors. We examined the effects of the olfactotoxin 3-methylindole (3-MI) on nasal mucosal potentials evoked by vanillin and CO2 in rats. A single i.p. administration of 300 mg/kg 3-MI altered both olfactory and trigeminal mucosal responses. Relative to amplitude values determined in non-3-MI-injected rats, the response to vanillin was reduced to 6%, 7%, and 43%, and the response to CO2, recorded in the same rats, decreased to 25%, 38%, and 51% at 4, 8 and 16 days post-3-MI, respectively. The results suggest that 3-MI affects both olfactory and trigeminal elements within the nasal mucosa.

Olfactory neurons in vitro show phenotypic orientation in epithelial spheres

Production and differentiation of olfactory neurons occur in spherical, multi-neuronal aggregates that form in cultures where dissociated newborn rat nasal cells are plated on to CNS glial cells. We show here that neuronal cell bodies were primarily located in the peripheral layers of the spheres, and almost every neuronal sphere contained one or several non-cellular central cavities. The dendrite-like processes of the olfactory neurons, immunostained for neuron-specific tubulin or the olfactory marker protein, were aligned and directed towards the central cavities. Olfactory neurons in the intact animal show a similar relationship with the nasal lumen. Non-neuronal cells formed multiple layers centrally, bordering the cavities. This degree of phenotypic re-creation is unusual in a dissociated monolayer culture system.

Relationship between hematopoietic parameters and behavioral measures in lead-exposed rats

The effects of low level lead (Pb) exposure on learning tasks in developing rats were investigated and the results correlated with individual hematopoietic indices. Pups received exposure via the dams milk; dams were exposed to either 0-, 545-, or 1090-ppm Pb during the lactation period. At Day 30 of age, half of the high Pb group was placed on distilled water; the remaining groups continued on the same exposure regimens as their dams. On Days 20, 30, and 90, blood samples for all rats were obtained via cardiac puncture. Each sample was analyzed for Pb concentration, free erythrocyte protoporphyrin (FEPs), hematocrit, and hemoglobin. Beginning at Day 90, all rats were tested on a battery of tasks designed to investigate the following questions: (1) to what degree lead exposure interferes with reversal learning; (2) whether changing of task requirements adversely affects acquisition of a new task; (3) to what extent task difficulty contributes to lead-induced deficits; and (4) whether lead exposure affects the capacity to retain information over short or long periods of time. The actual testing paradigms included spatial discrimination with reversal, visual discrimination with reversal, and visual discrimination task with delay. No significant differences were observed among any of the groups on any of the tasks. Correlation of individual learning scores with individual measures of hematopoietic function also failed to reach significance. These findings indicate that at low exposure levels, lead has little appreciable effect on learning and memory function as measured by these tasks.