Superfund Research Program

Neurochemical, Neurobehavioral, And Endocrine Effects of Developmental Exposure of Rats to Individual PCB Congeners

Project Leader: Richard Seegal
Grant Number: P42ES004913
Funding Period: 1995 - 2000

Project-Specific Links

Final Progress Reports

Year:   1999 

Project investigators have shown that PCBs act synergistically with other environmentally relevant contaminants such as methylmercury (MeHg) to alter dopamine (DA) function. Initial experiments demonstrated that striatal punch DA and DOPAC, a major metabolite of DA, are significantly reduced following combined exposure to PCBs and MeHg compared to exposure to either PCBs or MeHg alone in the absence of biochemical signs of cytotoxicity. Researchers hypothesized that these interactive effects of PCBs and MeHg may be due to the similar actions of these toxicants on intracellular calcium. Additionnally, these studies are investigating the effects of these contaminants on intracellular calcium concentrations in cerebellar granule cells. The cells were pre-loaded with the calcium indicator dye fluo-4, and subsequently exposed to the ortho-substituted congener 2,2'-dichlorobiphenyl, MeHg, or the two contaminants in combination. The effects of co-exposure were dependent on the absolute concentration of the mixture: at low concentrations co-exposure resulted in a synergistic elevation in intracellular calcium, co-exposure to intermediate concentrations resulted in additivity, while exposure to the highest concentrations resulted in a reduction in intracellular calcium. Researchers hypothesized that the interactions between these two contaminants occur at the ryanodine receptor and involve PCB-enhanced entry of MeHg into the lumen of the receptor resulting in oxidative stress-induced activation of reactive cysteines, subsequent inactivation of the channel, and re-sequestration of calcium.

Project investigators have demonstrated that in vivo microdialysis is more sensitive in revealing early changes in basal release of DA following PCB exposure than micropunch brain dissection. Naive adult male rats were exposed to 25 mg/kg/day of Aroclor 1254 for 1, 2 or 8 weeks. Half of the animals were sacrificed to measure striatal DA content using the micropunch brain dissection technique while the other half of the animals were implanted with a microdialysis probe in the striatum to determine extracellular DA concentrations in vivo in awake animals. DA content in brain punches, was significantly reduced only after eight weeks of exposure, while basal release of extracellular DA, measured by microdialysis, was significantly reduced in animals from all exposure periods--as early as following one week of exposure. Using this increased sensitivity, researchers have expanded these studies to include exposure to Aroclor 1254 for 3 days--testing the hypothesis, based on increases in dopamine release seen in ex vivo striatal punch preparations, that short-term exposure will result in increased extracellular dopamine measured by microdialysis. 3-day exposure to 25 mg/kg/day of Aroclor 1254 resulted in a significant increase in the basal release of extracellular dopamine, which may reflect PCB-induced inhibition of the vesicular monoamine transporter.

Project investigators have previously shown that metabolizable coplanar PCB congeners are uterotropic, demonstrating that acute i.p. exposure to either 3,4,3',4' or 3,4,5,3',4', but not 3,4,5,3',4',5', significantly increases uterine wet weight (UWW) in prepubertal rats. Researchers hypothesized that these increases were due to the action of either the parent congener or their hydroxylated metabolites, acting at the estrogen receptor. They have now shown that co-exposure to ICI 182,780, an estrogen-receptor antagonist, blocks the increase in UWW seen following exposure to either 3,4,3',4' or 3,4,5,3',4' supporting the hypothesis. These results suggest that the long-lasting elevation in brain DA following developmental exposure to 3,4,3',4' may be due to developmental exposure to estrogen-like metabolites of coplanar PCB congeners.