Lifetime Exposure to Lead and Stress: Consequences for the HPA Axis and Brain Neurochemistry

D. A. CORY-SLECHTA1; A. ROSSI-GEORGE2; M. B. VIRGOLINI2; M. THIRUCHELVAM2; D. WESTON1; R. LISEK2

Seattle, Washington, USA

Congreso; ociety of Toxicology. 47th Annual Meeting.; 2008

Society of Toxicology

Lifetime Pb exposure alone (0, 50 or 150 ppm in drinking water 2 mos before dam mating and continuing after weaning; no stress (NS)) or Pb+maternal stress (MS) or Pb+maternal stress+offspring stress at 4 mos (MS+OS) markedly increased Fixed Interval (FI) response rates in female but not male offspring in a Pb/stress-dependent fashion, i.e, in 50MS+OS, 150NS and 150MS+OS groups. To determine mechanisms of gender differences in behavior, levels of serum corticosterone, and of dopamine (DA), its metabolites DOPAC and HVA, and 5-HT and 5-HIAA in frontal cortex, nucleus accumbens and striatum were measured. At 2 mos of age, prior to behavioral testing or offspring stress, females showed Pb concentration-dependent increases in corticosterone levels to 74%; these increases were reversed by concurrent MS (Pb+MS groups). Similar trends in males were non-significant. Corticosterone changes were dynamic, however, with levels of all Pb alone and Pb+stress female groups significantly lower than controls after behavioral testing (10 mos), with the greatest reductions seen with 150 ppm Pb alone (72%) and with Pb+MS+OS (60-73%); males showed no reductions. Females exhibited altered levels of DA and 5HIAA in frontal cortex, HVA in nucleus accumbens and DOPAC in striatum, and changes in DA turnover in frontal cortex and nucleus accumbens, but neither these nor corticosterone changes could be straightforwardly related to the profile of FI rate changes. Pb+stress treated females differed from controls in the absence of an involvement of frontal cortex DA coupled with the inclusion of striatal and frontal cortex DA turnover as significant components explaining data in principal component analyses exploring relationships among outcome measures. Future experiments will determine mechanisms of Pb+stress-induced corticosterone changes and HPA axis dysfunction as well as profiles of neurochemical changes that underlie the associated increases in FI response rates. ES02ES012712.