Chronic Developmental Lead Exposure Reduces Neurogenesis in Adult Rat Hippocampus but Does Not Impair Spatial Learning

Abstract

The dentate granule cell (DG) layer of the hippocampal formation has the distinctive property of ongoing neurogenesis that continues throughout adult life. Although the function of these newly generated neurons and the mechanisms that control their birth are unknown, age, activity, diet and psychosocial stress have all been demonstrated to regulate this type of neurogenesis. Little information on the impact of environmental insults on this process has appeared to date. Developmental lead (Pb) exposure has been well documented to impair cognitive function in children and animals and reduce activity-dependent synaptic plasticity in the hippocampus of rodents. Therefore, we examined the effects of this classic environmental neurotoxicant on hippocampal-dependent learning and adult neurogenesis in the hippocampus. Pregnant rats were exposed to a low level of Pb-acetate (0.2%) via the drinking water from late gestation (GD 16) until weaning on postnatal day 21 (PN 21). At weaning, half of the Pb-exposed animals were weaned to control drinking water and the remainder were maintained on Pb water until termination of the study. Animals were paired- housed and on PN 75 were administered a series of injections of a thymidine analog bromodeoxyuridine (BrdU), a marker of DNA synthesis that labels proliferating cells and their progeny. At 12-h intervals for 12 days, rats received an ip injection of BrdU (50 mg/kg). Subjects were sacrificed and perfused 24 h and 28 days after the last injection. Spatial learning was assessed in an independent group of animals beginning on PN 110 using a Morris water maze. No Pb-induced impairments were evident in water maze learning. Immunohistochemistry for the detection of BrdU-labeled cells was performed on 40-microm coronal sections throughout the hippocampus. Continuous exposure to Pb (Life) reduced the total number of BrdU-positive cells at 28 days without affecting the total number of labeled cells evident 24 h after the last injection. No differences in the number of progenitor cells labeled or surviving were seen between control and treated animals whose Pb exposure was terminated at weaning. Double labeling with BrdU and the glial specific marker, glial acidic fibrillary protein (GFAP) indicated that the bulk of the surviving cells were of a neuronal rather than a glial phenotype. These data reveal that chronic low-level Pb exposure reduces the capacity for neurogenesis in the adult hippocampus. Despite deficits in synaptic plasticity previously reported from our laboratory, and now structural plasticity, no significant impact on spatial learning was detected.

Can endocrine disruptors influence neuroplasticity in the aging brain?

“…We can be certain as well that other neurotoxic exposures during adulthood and beyond may exert effects on brain structure and function whose roots are planted in the inability of the brain to regrow and repair itself. One example is the work of Gilbert et al (2005). These investigators found that chronic lead exposure reduced neurogenesis in the dentate granule cell layer of the hippocampus.…”

Low-Dose Exposure to Lead during Pregnancy Affects Spatial Learning, Memory and Neurogenesis in Hippocampus of Young Rats

“…In a study where the dams were exposed to Pb prior to mating, during pregnancy and lactation, results showed age-dependent impairment of performance in the water maze [30]. In a later study, when low-level Pb-exposure lasted from gestational day 16 to PND 21, there was a negative effect on neurogenesis in the hippocampus, but there was no significant impact on spatial learning [31]. In a comparable study on human subjects, it was noted that the Pb-exposure during the first trimester was predictive of adverse neurodevelopment later in life as indicated by the Medical Development Index scores [32].…”

“…Since hippocampus is associated with learning and memory, studies have reported the effect of Pb on hippocampal neurogenesis [31,34]. However, both these studies used bromodeoxyuridine (BrdU), a marker for DNA sysnthesis that labels proliferating cells and their progeny.…”

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…The majority of the studies addressing the effects of Pb2+ on hippocampal-associated spatial learning and memory processes have been carried out mainly in male rats (Cao et al, 2008, Gilbert et al, 2005; only a few studies have examined both sexes simultaneously (Jett et al, 1997. Female rats exposed to Pb2+ through gestation and lactation have shown more severe impairment of memory than male rats with similar Pb2+ exposures (Jett et al, 1997).…”