ABSTRACT
Previous studies have reported that environmental lead (Pb) exposure can result in neurological alterations in children leading to reduced IQ, attention deficit hyperactivity disorder, and diminished reading and learning abilities. However, the specific alterations in neurodevelopmental morphology and the underlying genetic mechanisms of these alterations have not yet been thoroughly defined. To investigate alterations in neurologic morphology and test the hypothesis that developmental Pb neurotoxicity is partially mediated through alterations in neuronal growth and transport function of axons, the changes of specific axon tracts in the embryonic zebrafish brain were observed with anti-acetylated α-tubulin staining at several developmental time points through 36hours post fertilization (hpf). In addition, the role of a subset of axonogenesis-related genes including shha, epha4b, netrin1b, netrin2, and noiwas investigated with real-time quantitative PCR (qPCR). Pb treatment resulted in decreased axonal density at 18, 20, and 24hpf for specific axon tracts in the midbrain and forebrain. These observations corresponded to an observed down-regulation of shha and epha4b at 14 and 16hpf, respectively. The axonal density in Pb exposed individuals at later stages (30 and 36hpf) was not significantly different from controls. An overexpression of netrin2 at these two developmental stages suggests a novel role for this gene in regulating axonal density specific to Pb neurotoxicity. Although no significant differences in axonal density was observed in the two later developmental stages, further studies are needed to determine if the morphologic alterations observed at the earlier stages will have lasting functional impacts.
Subject(s)
Axonal Transport/drug effects , Axons/drug effects , Embryo, Nonmammalian/drug effects , Gene Expression Regulation, Developmental/drug effects , Lead Poisoning, Nervous System/embryology , Zebrafish/embryology , Animals , Axonal Transport/genetics , Axons/pathology , Brain/drug effects , Brain/embryology , Disease Models, Animal , Embryo, Nonmammalian/metabolism , Embryo, Nonmammalian/pathology , Gene Expression Profiling , Lead Poisoning, Nervous System/genetics , Real-Time Polymerase Chain Reaction , Zebrafish/genetics , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolismABSTRACT
The purpose of this investigation was to determine if lead exposure during pregnancy and nursing alters cocaine sensitivity later in the adult cycle, although lead exposure had been discontinued following early development. Female rats were exposed via gavage to 0 or 16 mg/kg lead daily for 30 days prior to breeding with nonexposed males. The respective daily exposure regimens continued throughout gestation and lactation (perinatal lead exposure). Lead exposure was discontinued on the day of weaning (postnatal day [PND] 21). Beginning on PND 70, male offspring were trained to self-administer cocaine HCl intravenously. Examination of a range of cocaine doses (0.030, 0.060, 0.125, 0.250, and 0.500 mg/kg/infusion) revealed that, as adults, animals exposed to lead during early development self-administered cocaine at significantly greater rates at a low dose of the drug. In addition, self-administration rates were lower among lead-exposed animals at higher doses of cocaine. These findings were observed in metal-exposed animals where blood and brain tissue levels had returned to the levels of controls. Collectively, these data suggest that early developmental lead exposure may increase sensitivity to cocaine later in the life cycle.
