Deborah C. Rice

Effect of postnatal exposure to a PCB mixture in monkeys on multiple fixed interval-fixed ratio performance.

Behavioral impairment as a consequence of PCB exposure beginning in utero has been reported in both humans and animals. The present study assessed the behavioral consequences of postnatal exposure to PCBs. Male monkeys (Macaca fascicularis) were dosed from birth to 20 weeks of age with 7.5 microgram(s)/kg/day of a PCB mixture representative of the PCBs typically found in human breast milk (eight monkeys) or vehicle (four monkeys). At 4 years of age, performance under a multiple fixed interval (FI)-fixed ratio (FR) schedule of reinforcement was assessed. The FI component was more sensitive to disruption as a result of PCB exposure than was the FR component. PCB-exposed monkeys displayed shorter mean interresponse times (IRTs) than controls, particularly during the earlier sessions of the experiment. Similarly, the increase in pause time characteristic of the acquisition of typical FI performance emerged more slowly across sessions in the PCB-treated group. However, the number of short IRTs (less than 5 s) remained greater in the treated group compared to controls over the 48-session duration of the experiment. On the FR component, control monkeys decreases the mean pause time across sessions whereas the PCB-treated group did not; there were no differences between groups for absolute value of average IRT or pause time. The results of this study extend previous research in this cohort of monkeys, and provide further evidence that PCB exposure limited to the early postnatal period and resulting in environmentally relevant body burdens produces long-term behavioral effects.

Effects of Postnatal Exposure of Monkeys to a PCB Mixture on Spatial Discrimination Reversal and DRL Performance

Behavioral impairment as a consequence of PCB exposure beginning in utero has been reported in both humans and animals. The present study assessed the behavioral consequences of postnatal exposure to PCBs. Male monkeys (Macaca fascicularis) were dosed from birth to 20 weeks of age with 7.5 microg/kg/ day of a PCB mixture representative of the PCBs typically found in human breast milk (eight monkeys) or vehicle (four monkeys). Blood PCB levels at 20 weeks of age were 0.30-0.37 ppb for control and 1.84-2.84 ppb for treated monkeys, and fat levels were 50-198 and 1694-3560 ppb for the two groups, respectively. At about 4.5-5.0 years of age, monkeys performed on a series of three spatial discrimination reversal tasks, followed by a differential reinforcement of low rate (DRL) 30-s schedule of reinforcement. There were no differences between groups for the number of errors across reversals for any of the discrimination reversal tasks, whereas the PCB-treated group tended to have shorter median response latencies than the control group. On the DRL schedule, there were robust differences in performance between the treated and control groups. Treated monkeys displayed shorter mean and median interresponse times (IRTs), obtained fewer reinforcements, and emitted more nonreinforced responses. The treated groups also had more short IRTs (< or =10 s) than control monkeys. Performance of the treated group did not improve to control levels over the 51 sessions of the DRL 30-s schedule; their performance remained much less efficient than that of controls. The results of this study extend previous research in this cohort of monkeys, and provide further evidence that PCB exposure limited to the early postnatal period and resulting in environmentally relevant body burdens produces long-term behavioral effects.

Effects of postnatal exposure of monkeys to a PCB mixture on concurrent random interval-random interval and progressive ratio performance.

Behavioral impairment as a consequence of PCB exposure beginning in utero has been reported in both humans and animals. The present study assessed the behavioral consequences of postnatal exposure to PCBs. Male monkeys (Macaca fascicularis) were dosed from birth to 20 weeks of age with 7.5 microg/kg/day of a PCB mixture representative of the PCBs typically found in human breast milk (eight monkeys) or vehicle (four monkeys). Blood PCB levels at 20 weeks of age were 0.30-0.37 ppb for control and 1.84-2.84 ppb for treated monkeys, and fat levels were 50-198 and 1694-3560 ppb for the two groups, respectively. Beginning at about 5.0 years of age, monkeys performed under concurrent schedules of reinforcement in which separate random intervals were in effect on two buttons independently. After steady-state performance was reached, the relative reinforcement ratio on the buttons was changed a total of four times, and performance both during transition and steady state was examined. There was no evidence for treatment-related differences in performance across the series of changes in schedule contingencies. The negative results failed to support the hypothesis that performance on an intermittent schedule, combined with the requirement for shifting response strategy, would prove particularly sensitive to postnatal PCB exposure. Following the concurrent schedules, monkeys were tested under a progressive ratio (PR) schedule preceded by a training procedure consisting of a within-session series of increasing fixed ratios. PCB-treated monkeys emitted more responses than controls over the first few sessions of the PR, which may be indicative of retarded acquisition of their steady-state PR performance. These results extend previous studies in these monkeys on the characterization of PCB-induced behavioral deficits.

Fixed interval/fixed ratio performance in adult monkeys exposed in utero to methylmercury

Previous studies in monkeys and rodents have shown the fixed interval/fixed ratio (FI/FR) schedule to be a sensitive indicator of neurotoxicity. In the present study, monkeys (Macaca fascicularis) were exposed in utero to methylmercury (MeHg). Maternal doses of MeHg of 50, 70, or 90 micrograms/kg b.wt./day resulted in infant blood mercury levels at birth ranging from 1.04 to 2.45 ppm. Monkeys were tested on a multiple FI/FR schedule of reinforcement at 8-10 years of age. Four FI/FR cycles were run per session. Pause time and run rate were calculated for FI and FR components, as well as FI quarter-life and local FI response rates. MeHg treatment and sex effects were investigated by fitting a linear orthogonal polynomial regression to each monkeys profile across sessions and performing two-way ANOVAs on the resulting linear and intercept terms. There were no treatment-related effects on either the FI or FR component for pause time or run rate. Analysis of the quarter-life revealed a significant treatment by sex effect as well as a main effect for sex. Post hoc t-tests revealed a significant difference in quarter-life of treated male and female monkeys and a marginal difference between treated and control males. The FI run rate of the male monkeys was significantly greater than that of the female monkeys whereas the FR run rate of the males was marginally greater. These results indicate that there may be a differential effect of MeHg on male and female monkeys, which could be interpreted as an effect on temporal discrimination. Overall, adult monkeys exposed to in utero MeHg exhibited a very limited sex-related effects on the FI/FR intermittent schedule of reinforcement.

Lack of Effect of Methylmercury Exposure From Birth to Adulthood on Information Processing Speed in the Monkey

Although it is established that developmental methylmercury exposure produces severe motor and sensory impairment, the effect on cognitive function is less clear. To explore this issue, monkeys with robust methylmercury-induced deficits in visual, auditory, and somatosensory function were tested on a series of tasks assessing central processing speed, which is highly correlated with intelligence in humans. Five monkeys (Macaca fascicularis) were dosed from birth to 7 years of age with 50 micrograms/kg/day of mercury as methylmercuric chloride. Blood mercury levels were stable at 0.8-1.1 micrograms/g until cessation of dosing. When they were 20 years old, these monkeys and four age- and rearing-matched controls were tested on a series of simple and complex reaction time tasks. The monkey sat in a primate chair with a stainless steel bar centered at waist height. Four push buttons equidistant from the steel bar were mounted on a vertical Plexiglas panel in front of the monkey. The monkey was required to make contact with the bar, then release the bar and push the appropriate button in response to a change in stimulus conditions. For the first task (simple reaction time), the monkey was required to respond on a button when it changed from unlit to red. The monkey then performed a sequence of complex reaction time tasks: two-button, four-button, and several tasks of increasing complexity using four buttons and multiple colors. For each task, the latency to release the bar after the stimulus change (central processing speed) and to move the hand from the bar to the button (motor speed) were determined. Lastly, the monkey was required to make the quickest possible motor response on the simple reaction time task. There were no differences between groups on any aspect of the experiment. These data provide further evidence for absence of cognitive impairment in monkeys exposed developmentally to methylmercury.

Chronic lead exposure effects in the cynomolgus monkey (Macaca fascicularis) testis.

Although reproductive consequences of high circulating blood lead levels (> or = 60 micrograms/dL) have been reported, potential adverse effects of chronic lead exposure in males that result in low to moderate blood lead levels (10-25 and 26-60 micrograms/dL, respectively) are unknown. Effects of chronic lead exposure to testis ultrastructure were determined in the cynomolgus monkey after oral administration of lead acetate (1500 micrograms/kg BW/day) in a vehicle in the following groups: from birth to 10 years (lifetime), postnatal day 300 to 10 years (postinfancy), and postnatal day 0-400 (infancy); monkeys in the control group received only the vehicle (95% glycerol and 5% distilled water). At age 10 years, circulating lead concentrations in lifetime and postinfancy-dosed monkeys were approximately 35 micrograms/dL, and in control and infancy animals the concentrations were < 1.0 microgram/dL. Sertoli and spermatogenic cells of dosed monkeys from the infancy and lifetime groups revealed injuries. Chronic exposure to lead that results in moderate blood lead concentrations induced persistent ultrastructural alterations in the cynomolgus monkey testis. Results of this study on the primate, following extrapolation to humans, could influence further refining of the impact of environmental lead contamination concentrations vis-à-vis the health of children, adults, and aged human beings.

Subclinical Changes in Luteal Function in Cynomolgus Monkeys with Moderate Blood Lead Levels

The objective of the present study was to investigate luteal function in cynomolgus monkeys (n = 32), aged 15–20 years with blood lead levels (BLLs) in the range of <3.0 μg dl−1 (control, n = 20), 10–15 μg dl−1 (low, n = 7) and 25–30 μg dl−1 (moderate, n = 5). Sampling was performed daily beginning with day 10 of the menstrual cycle and concluding on the first day of the subsequent menstrual cycle. Circulating levels of oestradiol (E2), progesterone (P4) and 20α‐hydroxyprogesterone (20‐OHP) were normalized to the day of the ovulatory E2 surge. The area under the concentration curve (AUC) for P4 was significantly lower in monkeys with moderate BLLs compared to the control group (P = 0.04). The number of days for which circulating levels of P4 were greater than 1.0 ng ml−1 were also significantly fewer (P = 0.03) in monkeys with moderate BLLs compared to controls. There was no statistical evidence of a lead effect on circulating levels of E2, 20‐OHP or menstrual cycle characteristics. These data suggest that chronic lead exposure suppresses corpora luteal production of P4 in the monkey at circulating BLLs lower than previously reported and relevant to humans with occupational exposure to lead.