Robert E. Bowman - US grants

These studies are investigating lead (Pb) toxicity at chronic doses generally be low those producing overt clinical symptoms of Pb poisoning. Pb has been administered at various developmental states (in utero, during year 1 postpartumor to adult animals). Measures of Pb dosages include daily Pb intake, blood Pb level, and zinc protoporphyrin concentration. Measures of clinical effects include assessments of general health, appetite, and hematocrit. The primary focus of the project is on measures of behavioral toxicity, particularly long-term behavioral deficits. We have observed Pb-induced alterations in scoptic visual ability, discrimination reversal learning, a spatial memory task, activity functions, and social behaviors. Most deficits have been replicated at more than one Pb dosage condition and some have been seen several years after termination of early Pb exposure. These behavioral functions will be further investigated in monkeys of different Pb exposure conditions to attempt to establish (i) the determining variables producing the impairment (e.g., developmental stage of Pb exposure, dosing duration, Pb intake, PbB) and (ii) the extent to which the impairments endure beyond the period of Pb exposure. In addition, tests of these behavioral functions will be further developed to facilitate characterization of the nature of the Pb-induced deficits. Finally, selected animals will be sacrificed to study Pb distribution in body tissue (including regional analyses of Pb in brain) as well as to study Pb-induced neuroanatomic lesions.

A model of early life, brief episodic lead (Pb) exposure at <70mug/DI blood lead (PbB), superimposed on chronic Pb exposure at -35mug/dl for the first year and 14 mug/dl from then on, is being studied in the rhesus monkey (cohorts Pb IX and Pb X). Cohort controls are carried in parallel (<-5 mug/dl PbB. These PbB levels are relevant to human episodic plus chronic childhood lead exposure followed by PbB well below the action level. Monkeys exposed to high Pb pulse without Pb after the first year (PbIII) and thus at <5 mug/dl PbB from 3 years of age on, showed a permanent deficit on Delayed Spatial Alternation (DSA) tested as adults at 5-8 years of age (Levin & Bowman, 1986). Monkeys exposed only to chronic Pb levels for the first year (no pulse and no Pb after the first year; Pb II and Pb V), had a marginal DSA facilitation as adults (Levin et al, 1988). Monkeys exposed at 25 mug/dl PbB for 6 months, and chronic PbB of 13 mug/dl since, had a DSA deficit at 8 years of age (Rice, 1985). Chronic L-dopa treatment alleviated the DSA deficit in pulse-chronic animals (P[unreadable] III) but cholinergic drugs had no effect (Levin & Bowman, 1987, 1988). Evidence suggests that these DSA effects (facilitation at lower dose-duration Pb exposure and deficits at higher dose-duration exposures) may be explained by sensory inattention resulting from damage to dopaminergic systems of the caudate nucleus, induced by Pb exposure during postnatal development in the monkey. Our latest data (on Pb IX and PB X) confirm that even without a high early Pb pulse, Pb exposure at 14 mug/dl following first year chronic Pb exposure as low as 40 mug/dl will induce a DSA deficit in the adolescent monkey. These animals will be tested longitudinally to confirm if the DSA deficit persists, and if so, whether it disappears with discontinuation of low level Pb dosing and decline of their PbB to <- mug/dl. If in the latter case the DSA deficit disappears, it will be restored by redosing with Pb. Then, studies of neurochemical mechanism will be resumed on this DSA deficit, to follow up mechanistic data on the Pb III (Levin & Bowman, 1987). In addition, attentional deficit, and if this correlates with the stages of DSA effects. Additionally, data indicating reduced turnover of brain norepinephrine associated with PbB levels, and to determine if other neurotransmitter effects are seen. To add replication and statistical power to the examination of all these relationships, an additional cohort of monkeys is proposed for Pb exposure.