Alterations in Glucocorticoid Negative Feedback Following Maternal Pb, Prenatal Stress and the Combination: a Potential Biological Unifying Mechanism for their Corresponding Disease Profiles

ROSSI-GEORGE A., M. B. VIRGOLINI, D. WESTON AND D.A. CORY-SLECHTA

TOXICOLOGY AND APPLIED PHARMACOLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2009 vol. 234 p. 117 - 127

0041-008X

Combined exposures to maternal lead (Pb) and prenatal stress (PS) can act synergistically to enhancebehavioral and neurochemical toxicity in offspring. Maternal Pb itself causes permanent dysfunction of thebody´s major stress system, the hypothalamic pituitary adrenal (HPA) axis. The current study sought todetermine the potential involvement of altered negative glucocorticoid feedback as a mechanistic basis of theeffects in rats of maternal Pb (0, 50 or 150 ppm in drinking water beginning 2 mo prior to breeding), prenatalstress (PS; restraint on gestational days 16–17) and combined maternal Pb+PS in 8 mo old male and femaleoffspring. Corticosterone changes were measured over 24 h following an i.p. injection stress containingvehicle or 100 or 300 μg/kg (females) or 100 or 150 μg/kg (males) dexamethasone (DEX). Both Pb and PSprolonged the time course of corticosterone reduction following vehicle injection stress. Pb effects were nonmonotonic,with a greater impact at 50 vs. 150 ppm, particularly in males, where further enhancementoccurred with PS. In accord with these findings, the efficacy of DEX in suppressing corticosterone wasreduced by Pb and Pb+PS in both genders, with Pb efficacy enhanced by PS in females, over the first 6 h postadministration.A marked prolongation of DEX effects was found in males. Thus, Pb, PS and Pb+PS,sometimes additively, produced hypercortisolism in both genders, followed by hypocortisolism in males,consistent with HPA axis dysfunction. These findings may provide a plausible unifying biological mechanismfor the reported links between Pb exposure and stress-associated diseases and disorders mediated via theHPA axis, including obesity, hypertension, diabetes, anxiety, schizophrenia and depression. They also suggestbroadening of Pb screening programs to pregnant women in high stress environments.