Electrophysiologic and behavioral effects of perinatal and acute exposure of rats to lead and polychlorinated biphenyls.

Abstract

Lead and polychlorinated biphenyls (PCBs) both cause a reduction of intelligence quotient and behavioral abnormalities in exposed children that have features in common with attention deficit hyperactivity disorder. We have used rats as a model to study the effects of both perinatal and acute exposure to lead or PCBs in an effort to compare and understand the mechanisms of these nervous system decrements. Long-term potentiation (LTP) is an electrophysiologic measurement that correlates well with cognitive ability. We have determined the effects of chronic perinatal exposure to lead or PCB 153 as well as acute application of these substances to isolated brain slices, with recordings in two areas of the hippocampus, CA1 and CA3. Both substances, whether chronically or acutely applied, significantly reduced LTP in CA1 in animals at age 30 and 60 days. In CA3, they reduced LTP in 30-day animals but potentiated it in 60-day animals. Although neither lead nor PCB 153 alters baseline synaptic transmission at low stimulus strengths, at higher levels they induce changes in the same direction as those of LTP. These results show surprisingly similar actions of these quite different chemicals, and the similarity of effects on chronic and acute application indicates that effects are both pharmacologic and developmental. Behavioral studies of rats exposed to PCBs from contaminated fish show hyperactivity, impulsiveness, and increased frustration relative to unexposed controls. These results demonstrate that lead and PCBs have similar effects on synaptic plasticity and behavior and suggest that the compounds may act through a common mechanism. Key words: brain slice, extinction, frustration, hippocampus, hyperactivity, input-output curves, long-term potentiation, perinatal exposure.

A Comparison of the Roles of Protein Kinase C in Long-Term Potentiation in Rat Hippocampal Areas CA1 and CA3

“…When phorbol ester is perfused on brain slices from rats chronically exposed to lead, the potentiation of the fEPSP in CA3 is reduced as compared to that from unexposed controls in 30-day animals, but increased as compared to controls in 60-day animals (Hussain et al, 2000a). When the PCB congener 2,2 ,4,4 ,5,5 -hexachlorobiphenyl (PCB 153) was administered either chronically in 30-day-old animals or acutely perfused over a control slice, it blocked LTP at both the SC-CA1 and MF-CA3 synapse (Hussain et al, 2000b), but acute perfusion of PCB 153 in a slice from a 60-day-old animals potentiated LTP at the MF-CA3 synapse (Carpenter et al, 2002). While we do not have definitive proof that these alterations in sensitivity as a function of age are due to effects on PKC, the observations are most consistent with the hypothesis that both lead and PCBs have different effects on different PKC isozymes, and that this is reflected in the changes in sensitivity in the two regions with age.…”

“…PKC inhibitors also prevent development of LTP in the MF-CA3 pathway in 30-day-old rats (Son and Carpenter, 1996a), but in this case they do not alter the baseline synaptic response (Hussain and Carpenter, 2003). However PKC activators, such as phorbol esters, produce a very marked potentiation of the baseline response at this synapse (Son and Carpenter, 1996a;Carpenter et al, 2002). These results indicate that while PKC plays a critical role in both synaptic transmission and LTP at both synapses, there are differences is content, distribution and/or isozyme composition between these two pathways.…”

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

“…In CA3, there have been no differences with time of exposure, but there was a dramatic difference in response as the age of animals increased. At 30 days LTP was significantly reduced, but at 60 days LTP was increased by about 30% (Carpenter et al, 2002). In the same brain structure and area (CA3) the effects of Pb2+ on LTP have been different in 30 PND and 60 PND rats after either acute perfusion of Pb2+ or from slices derived from rats after chronic developmental exposure to Pb2+, as inhibition of LTP has been recorded in 30 PND CA3, whereas potentiation has been measured in 60 PND CA3 with either exposure paradigm that have been attributed to possible involvement of protein kinase C (Hussain et al, 2000).…”

“…Pb2+ chronically or acutely applied, significantly reduces LTP in CA1 region of hippocampus from Wistar or Sprague-Dawley rats (30 and 60 PND) (Carpenter et al, 2002). These animals were exposed to Pb2+ via the mother's drinking water either through gestation and lactation (upto day 21) (perinatal), only by lactation through the mother's drinking water and then in the pup's drinking water (post) or from gestation (pre and post).…”

Environmental Factors and Limbic Vulnerability in Childhood Autism

“…Generally, a combination of agents can cause significant damage even when each is at sub-threshold or "safe" levels, exemplified by multiple xenoestrogen exposure [188] . Environmental chemicals appear to synergize with heavy metals to increase the extent of damage produced [189] : synergy between mercury and polychlorinated biphenyl toxicity has been reported in dual-exposed children [190] . Specific evidence for chemical toxicity in ASD is provided by increased levels of trichloroethylene and toluene [191] , polychlorinated biphenyls and dioxins [192] , further underscored by evidence of genetic linkage to chemical detoxification gene alleles.…”