Robert E. Bowman

Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The incidence of the reproductive disease endometriosis was determined in a colony of rhesus monkeys chronically exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) for a period of 4 years. Ten years after termination of dioxin treatment, the presence of endometriosis was documented by surgical laparoscopy and the severity of disease was assessed. The incidence of endometriosis was directly correlated with dioxin exposure and the severity of disease was dependent upon the dose administered (p < 0.001). Three of 7 animals exposed to 5 ppt dioxin (43%) and 5 of 7 animals exposed to 25 ppt dioxin (71%) had moderate to severe endometriosis. In contrast, the frequency of disease in the control group was 33%, similar to an overall prevalence of 30% in 304 rhesus monkeys housed at The Harlow Primate Center with no dioxin exposure. This 15-year study indicates that latent female reproductive abnormalities may be associated with dioxin exposure in the rhesus. Therefore, the effects of this toxin may be more diverse than previously recognized.

Learning in monkeys exposed perinatally to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

TCDD is an extremely toxic chemical pollutant which bioaccumulates in maternal adipose tissue, and is transferred to the developing organism during gestation and lactation. Long-term cognitive deficits have been reported following perinatal exposure to polychlorinated biphenyls, which are structurally and toxicologically similar to TCDD. In the current study, monkeys exposed to TCDD perinatally were later tested in two cognitive paradigms, discrimination-reversal learning (RL) and delayed spatial alternation (DSA). RL detected effects; whereas DSA, as analyzed, did not. RL consisted of a series of simple spatial reversals, followed by spatial reversals with color and shape as irrelevant cues, then by color reversals and finally by shape reversals. TCDD-exposed monkeys exhibited retarded learning of the shape reversals. The deficit was most pronounced on the first reversal following overtraining. There were no group differences on the spatial or color reversals. However, the number of trials the TCDD-exposed monkeys individually took to learn the spatial reversals was positively correlated with TCDD concentration in body fat. Conversely, the number of trials they took to learn the color reversals was negatively correlated with TCDD in body fat.

Effects of perinatal PCB exposure on discrimination-reversal learning in monkeys

Monkeys exposed to PCB mixtures during gestation and lactation were tested on two-choice discrimination-reversal learning (DR). In Experiment 1, offspring of mothers fed 1.0 ppm Aroclor 1248, and offspring born 1.5 years after maternal exposure to 2.5 ppm Aroclor 1248 ended did not differ from controls on spatial, color or shape DR problems. In Experiment 2, offspring of mothers fed 0.25 or 1.0 ppm Aroclor 1016 and offspring born 3 years after maternal exposure to 2.5 ppm Aroclor 1248 ended were tested on the same spatial, color and shape problems, but a spatial problem with color and shape as irrelevant cues was inserted after the initial spatial problem. Performance of the high dose Aroclor 1016 offspring was impaired on the initial spatial problem, and facilitated on the shape problem. Performance of the Aroclor 1248 postexposure offspring was facilitated on the shape problem. This apparently facilitatory effect may represent a failure of PCB-exposed monkeys to learn the irrelevancy of the shape cue when it was initially presented.

Correlation of PCB body burden with behavioral toxicology in monkeys

Eight monkeys fed 2.5 ppm PCB in their daily diet conceived, delivered and nursed five infants, three of which survived past weaning at four months of age. PCB residues in fat in the surviving infants at 8, 10 1/2, and 23 months of age declined linearly when plotted as log concentration versus time (first order clearance), and these functions extrapolated to presumed peak PCB levels of 21, 114, and 123 microgram/g fat (ppm) at 4 months of age. Behavioral tests on these three infants and four normal controls revealed hyperlocomotor activity at 6 and 12 months of age correlated with peak PCB body burdens. Higher peak PCB body burdens also were correlated with increased errors in five of nine learning tasks conducted between 8 and 24 months of age. Point estimates of zero-effect levels of PCB body burdens ranged around 21 ppm, although it was clear that even the monkey carrying only 21 ppm PCBs at four months of age exhibited some behavioral deficits persisting through the final testing at 24 months of age.

Delayed spatial alternation deficits resulting from perinatal PCB exposure in monkeys.

Monkeys exposed to low, chronic levels of polychlorinated biphenyls (PCBs) in utero and during nursing until 4 months after birth were tested at 4–6 years of age on delayed spatial alternation (DSA), a spatial learning and memory task. Deficits in performance accuracy were detected in two cohorts of monkeys whose mothers had been fed 2.5 ppm of the PCB mixture, Aroclor 1248, in their diet for an 18-month period ending at least 12 months prior to pregnancy. The deficit was most apparent at the shorter delays, suggesting that it was not due to memory impairment, but may have been due to impairments in associational or attentional processes. There may also have been a deficit in a group of monkeys whose mothers were fed 1.0 ppm of the PCB mixture, Aroclor 1016. However, the deficit in this group was less pronounced than in the other groups. The appearance of a PCB-induced cognitive deficit more than 3 years after the end of exposure indicated the existence of very long-term adverse consequences of low-level perinatal PCB exposure.

Reversal learning deficits in young monkeys exposed to lead.

The reversal learning capacity of young rhesus monkeys in visual discrimination tasks was examined during daily exposure to dietary lead acetate throughout the first year of life. While not affected in physical development, all lead-treated monkeys showed performance deficits on reversal learning tasks. These deficits were independent of lead-induced changes in motivation. Over a series of problems, the overall learning rate of monkeys with blood lead concentrations in the range of 70-90 microgram/dl was retarded, which resulted partly from a pronounced difficulty in attaining criterion on the first of a series of reversals within a given problem. This latter deficit resulted from an increase in errors, balks, and total trials to criterion on the first reversal. Monkeys exposed to blood lead concentrations of 40-60 microgram/dl required significantly more trials to finish all problems, but did not show the first-reversal deficit. Theoretical implications of these data were discussed.

The effects of ACTH, adrenalectomy and dexamethasone on the acquisition of an avoidance response in rats

Abstract Exogenous elevation of circulating ACTH level facilitated the acquisition of a two-way avoidance response at a high but not at a moderate US intensity. Injections of ACTH had no general effect on spontaneous shuttling activity, escape behavior to light-onset, or intertrial responding during avoidance conditioning. Adrenalectomy, which resulted in minimal plasma levels of adrenocortical hormones and, presumably, elevated levels of ACTH, also facilitated avoidance responding. Injection of dexamethasone, a synthetic glucocorticoid and ACTH inhibitor, produced severe weight loss and hypophagia, but did not influence avoidance performance. However, the failure of dexamethasone to affect acquisition of avoidance responding was not related to its effect on body weight and food intake. The action of ACTH on avoidance conditioning is clearly extra-adrenal, but ACTH is not essential to normal performance, at least when high levels of glucocorticoids are present.

Enduring Learning Deficits and Cerebral Synaptic Malformation from Exposure to 10 Parts of Halothane per Million

Chronic exposure of rats to 10 parts of halothane per million during early life produced later deficits in learning a shock-motivated light-dark discrimination and a food-motivated maze pattern, correlated with enduring synaptic nembrane malformation in cerebral cortex. Adult exposure had no effect. Halothane may provide a useful analytical tool for study of brain. The behavioral-ultrastructural techniques also suggest a standard for assessing the safety of trace toxicants with central nervous system effects.

Persistence of impaired reversal learning in young monkeys exposed to low levels of dietary lead

Lead acetate in milk was fed daily to infant rhesus monkeys at doses averaging 0 (control), 0.287 (low-Pb), or 0.880 (high-Pb) mg/kgd for the first year of life. Pb concentrations in whole blood (PbB) averaged 4.15, 31.71, and 65.17 microgram/dl for the control, low-Pb, and high-Pb groups, respectively, during the year of treatment and declined toward control levels when Pb dosing was stopped. Behavioral observations during the year of treatment had shown that both experimental groups were retarded in their acquisition of object-cue discrimination reversal learning sets. At 4 yr of age, when PbB levels in all animals were normal, the ability of the same monkeys to acquire a series of 3 spatial-cue reversal learning sets was examined; these data form the basis for this report. In the first problem, the high-Pb group was significantly retarded in acquisition of the original discrimination and of most reversals, and the low-Pb group was retarded on reversal 1 only. These deficits declined in severity across the three problems administered, in a manner similar to that seen in the tests given during the first year of life. These data demonstrate that reversal learning retardation, observed early in life, can recur in postadolescent primates with a history of chronic, low-level Pb intoxication during infancy.

Effects of halothane on synaptogenesis and learning behavior in rats

Synaptic density was quantitated in the entorhinal cortex and subiculum of rats at 5, 21, 34, and 95 postnatal days. These rats were offspring of mothers that had been subjected to four different concentrations of halothane during gestation and for 60 days after birth. The exposure conditions were control, intermittent halothane (25 +/- 5 ppm or 100 +/- 5 ppm, 8 h/day, 5 days/week) and continuous halothane (25 +/- 5 ppm, 24 h/day, 7 days/week). Synaptic density in rats exposed to halothane was significantly less than in control rats. Animals exposed intermittently to 25 +/- 5 ppm halothane had higher synaptic density than animals exposed continuously to 25 +/- 5 ppm halothane or intermittently to 100 +/- 5 ppm halothane. The latter two exposure conditions exerted similar effects. The lag in synaptic development was established at 5 days postnatal and remained the same throughout the first 95 postnatal days in both the entorhinal cortex and subiculum. Delayed synaptogenesis caused by halothane was indicated by the presence of growth cones in halothane-exposed rats to 34 days compared with 21 days in the control rats. The spontaneous alternation test indicated that the delayed synaptogenesis by halothane was sufficient to suppress behavioral development. Thus, the delay in the initial synaptic maturation caused by halothane exposure in utero may result in permanent morphologic and functional deficits of the brain.