Lead-induced behavioral impairment on a spatial discrimination reversal task in monkeys exposed during different periods of development

doi:10.1016/0041-008X(90)90251-O

Toxicology and Applied Pharmacology

Volume 106, Issue 2, November 1990, Pages 327-333

https://doi.org/10.1016/0041-008X(90)90251-O Get rights and content

Abstract

A total of 52 monkeys (Macaca fascicularis) were dosed orally with vehicle or 1.5 mg/kg/day of lead on one of four dosing regimens (13 monkeys/group): Group 1, vehicle only; Group 2, dosed with lead from birth onward; Group 3, dosed with lead from birth to 400 days of age and vehicle thereafter; Group 4, dosed with vehicle from birth to 300 days of age and lead thereafter. Blood lead concentrations averaged 3–6 μg/dl when monkeys were not being dosed with lead, 32–36 μg/dl when being dosed with lead having access to infant formula, and 19–26 μg/dl when being dosed with lead after weaning from infant formula. When monkeys were 7–8 years old, they were tested on three spatial discrimination reversal tasks: no irrelevant cues, irrelevant form cues, and irrelevant form and color cues. Fifteen reversals were run for each task. Only Group 2 was impaired in the absence of irrelevant cues, while all three treated groups were impaired in the presence of irrelevant cues. These results are in contrast to results from a series of nonspatial discrimination reversal tasks in these monkeys in which Groups 2 and 4 were impaired and Group 3 was unimpaired. The present results are in agreement with results from another spatial task, delayed alternation, in which all three treated groups were impaired.

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Future efforts to tease out the interaction between sensory and cognitive deficits will inform the design and implementation of early-life intervention approaches. We and others have uncovered a wide array of cognitive and behavioral deficits due to early-life lead exposure, including impaired visual discrimination and spatial memory, attention deficits, and decreased IQ in children (Needleman et al., 1979; Evans et al., 1994; Canfield et al., 2004), along with impaired spatial learning, memory, fear/avoidance conditioning, and altered social behaviors across primates, rodents, and zebrafish (Rice, 1990; Bazrgar et al., 2015; Anderson et al., 2016; Xu et al., 2016; Chen et al., 2012; Weber and Ghorai, 2013). As found in our pathway analysis results, nervous system development and function is one of the primary targets of early-life lead exposure.
Lead (Pb²⁺) is a major public health hazard for urban children, with profound and well-characterized developmental and behavioral implications across the lifespan. The ability of early Pb²⁺ exposure to induce epigenetic changes is well-established, suggesting that Pb²⁺-induced neurobehavioral deficits may be heritable across generations. Understanding the long-term and multigenerational repercussions of lead exposure is crucial for clarifying both the genotypic alterations behind these behavioral outcomes and the potential mechanism of heritability. To study this, zebrafish (Danio rerio) embryos (<2 h post fertilization; EK strain) were exposed for 24 h to waterborne Pb²⁺ at a concentration of 10 μM. This exposed F₀ generation was raised to adulthood and spawned to produce the F₁ generation, which was subsequently spawned to produce the F₂ generation. Previous avoidance conditioning studies determined that a 10 μM Pb²⁺ dose resulted in learning impairments persisting through the F₂ generation. RNA was extracted from control- and 10 μM Pb²⁺-lineage F₂ brains, (n = 10 for each group), sequenced, and transcript expression was quantified utilizing Quant-Seq. 648 genes were differentially expressed in the brains of F₂ lead-lineage fish versus F₂ control-lineage fish. Pathway analysis revealed altered genes in processes including synaptic function and plasticity, neurogenesis, endocrine homeostasis, and epigenetic modification, all of which are implicated in lead-induced neurobehavioral deficits and/or their inheritance. These data will inform future investigations to elucidate the mechanism of adult-onset and transgenerational health effects of developmental lead exposure.
Using the delayed spatial alternation task to assess environmentally associated changes in working memory in very young children
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Tests purporting to assess WM in very young children need to be assessed for their expected correlations with validated tests of infant general development and well-established predictors such as age, sex and parental education. The delayed spatial alternation tasks (DSAT), a classical A not B task, has been widely used in exposure studies in rodents and non-human primates to demonstrate the impact of lead exposure on working memory (Rice and Karpinski, 1988; Alber and Strupp, 1996; Rice, 1990; Levin and Bowman, 1988). While the DSAT has been used in psychological literature to understand the developmental trajectory of WM in typically developing children, the DSAT has not been used to assess lead-associated changes in WM in very young children.
Working memory (WM) is critical for problem solving and reasoning. Beginning in infancy, children show WM capacity increasing with age but there are few validated tests of WM in very young children. Because rapid brain development may increase susceptibility to adverse impacts of prenatal neurotoxicant exposure, such as lead, tests of WM in very young children would help to delineate onset of developmental problems and windows of susceptibility.
Our objective was to assess the feasibility of administering a Delayed Spatial Alternation Task (DSAT) to measure WM among 18- and 24-month old children enrolled in an ongoing longitudinal birth cohort study and compare DSAT performance with age and general cognitive development. We further explored whether prenatal lead exposure impacted DSAT performance.
We assessed 457 mother-child pairs participating in the Programming Research in Obesity, GRowth, Environment and Social Stressors (PROGRESS) Study in Mexico City. The DSAT and Bayley Scales of Infant Development (BSID-III) were administered at 18- and 24-months. Lead was measured in maternal blood collected during pregnancy (MBPb) and in a subsample of children at 24-months (CBPb). We regressed DSAT measures on MBPb and CBPb, child sex, and maternal age, education, socioeconomic status, and household smoking. We compared DSAT performance to BSID-III performance with adjusted residuals.
24-month children perform better on the DSAT than 18-month children; 24-month subjects reached a higher level on the DSAT (3.3 (0.86) vs. 2.4 (0.97), p < 0.01), and had a higher number of correct responses (20.3 vs. 17.2, p < 0.01). In all DSAT parameters, females performed better than males. Maternal education predicted better DSAT performance; household smoking predicted worse DSAT performance. A higher number of correct responses was associated with higher BSID-III Cognitive scales at 18 months (r = 0.20, p < 0.01) and 24 months (r = 0.27, p < 0.01). MBPb and CPBb did not significantly predict DSAT performance.
Improved performance on the DSAT with increasing age, the positive correlation with the BSID-III cognitive and language scales and the correlation with common sociodemographic predictors of neurodevelopment demonstrate the validity of the DSAT as a test of infant development.
Biometals in Autism Spectrum Disorders
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Psychometric tools to study cognition, sensory functioning, and social behavior in infant and adolescent nonhuman primates
2018, Handbook of Developmental Neurotoxicology
The behavioral repertoire of nonhuman primates is highly evolved and includes advanced problem-solving capabilities, complex social relationships, and sensory acuity equal or superior to humans. For some potential neurotoxicants, nonhuman primate models have provided valuable data that are helpful in identifying the likely effects of developmental exposures on human infants and children. The ability to identify subtle effects of neurotoxicant exposure is highly dependent on the selection of measurement tools that can identify meaningful individual differences in performance. This chapter provides brief descriptions of assessment measures that have been developed for young monkeys, both infants and adolescents, to investigate emerging cognitive skills, sensory functioning, and social behaviors. Examples of how these tests have been used in previous research investigating the developmental effects of neurotoxicants are provided to illustrate the contribution of this research to our knowledge regarding important environmental determinants of behavior.
Developmental stress and lead (Pb): Effects of maternal separation and/or Pb on corticosterone, monoamines, and blood Pb in rats
2016, NeuroToxicology
The level of lead (Pb) exposure in children has decreased dramatically since restrictions on its use were implemented. However, even with restrictions, children are exposed to Pb and still present with cognitive and behavioral deficits. One prominent aspect of the exposome of these children is that many come from low social economic status (SES) conditions, and low SES is associated with stress. In order to compare the combined effects of early stress and Pb, Sprague-Dawley rats were exposed to vehicle or Pb either alone or in combination with maternal separation stress during brain development (i.e., postnatal day (P)4–P11, P19, or P28). Maternally separated/isolated pups had lower body and thymus weights during exposure and had increased levels of blood Pb compared with vehicle controls. Isolation, but not Pb, affected the response to an acute stressor (standing in shallow water) when assessed on P19 and P29, but not earlier on P11. Interactions of Pb and isolation were found on monoamines in the neostriatum, hippocampus, and hypothalamus on turnover but not on levels, and most changes were on dopamine turnover. Isolation had greater short-term effects than Pb. Interactions were dependent on age, sex, and acute stress.
Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb)
2013, NeuroToxicology
Citation Excerpt :
In 1980, a cohort of female monkeys (Macaca fascicularis) were randomly assigned at birth to one of two exposure groups: one received 1.5 mg/kg/day of Pb-acetate (Sigma–Aldrich, MO) from birth until 400 days of age via infant formula and vehicle after weaning (n = 5), whereas the other group served as a control group and received formula or vehicle only (n = 4). No overt signs of toxicity or health-related problems were observed in the animals as a result of Pb exposure (Rice, 1990, 1992). The primates were then transferred to the National Institutes of Health (NIH) facility until termination in 2003 at ∼23 years of age.
Late Onset Alzheimer Disease (LOAD) constitutes the majority of AD cases (∼90%). Amyloidosis and tau pathology, which are present in AD brains, appear to be sporadic in nature. We have previously shown that infantile lead (Pb) exposure is associated with a change in the expression and regulation of the amyloid precursor protein (APP) and its beta amyloid (Aβ) products in old age. Here we report that infantile Pb exposure elevated the mRNA and protein levels of tau as well as its transcriptional regulators namely specificity protein 1 and 3 (Sp1 and Sp3) in aged primates. These changes were also accompanied by an enhancement in site-specific tau phosphorylation as well as an increase in the mRNA and protein levels of cyclin dependent kinase 5 (cdk5). There was also a change in the protein ratio of p35/p25 with more Serine/Threonine phosphatase activity present in aged primates exposed to Pb as infants. These molecular alterations favored abundant tau phosphorylation and immunoreactivity in the frontal cortex of aged primates with prior Pb exposure. These findings provide more evidence that neurodegenerative diseases may be products of environmental influences that occur during the development.

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Regular articleLead-induced behavioral impairment on a spatial discrimination reversal task in monkeys exposed during different periods of development

Abstract

Pharmacol. Biochem. Behav.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Regular article
Lead-induced behavioral impairment on a spatial discrimination reversal task in monkeys exposed during different periods of development