CNS effects of developmental Pb exposure are enhanced by combined maternal and offspring stress.

Lead (Pb) exposure and elevated stress are co-occurring risk factors. Both impact brain mesolimbic dopamine/glutamate systems involved in cognitive functions. We previously found that maternal stress can potentiate Pb-related adverse effects in offspring at blood Pb levels averaging approximately 40 microg/dl. The current study of combined Pb exposure and stress sought to extend those results to lower levels of Pb exposure, and to examine relationships among consequences in offspring for fixed interval (FI) schedule-controlled behavior, neurochemistry and corticosterone levels. Dams were exposed to maternal Pb beginning 2 months prior to breeding (0, 50 or 150 ppm in drinking water), maternal restraint stress on gestational days 16 and 17 (MS), or the combination. In addition, a subset of offspring from each resultant treatment group was also exposed intermittently to variable stressors as adults (MS+OS). Marked "Pb-stress"-related increases in response rates on a fixed interval schedule, a behavioral performance with demonstrated sensitivity to Pb, occurred preferentially in female offspring even at mean blood Pb levels of 11 microg/dl when 50 ppm Pb was combined with maternal and offspring stress. Greater sensitivity of females to frontal cortex catecholamine changes may contribute to the elevated FI response rates as mesocorticolimbic systems are critical to the mediation of this behavior. Basal and final corticosterone levels of offspring used to evaluate FI performance differed significantly from those of non-behaviorally tested (NFI) littermates, demonstrating that purported mechanisms of Pb, stress or Pb/stress effects determined in non-behaviorally trained animals cannot necessarily be generalized to animals with behavioral histories. Finally, the persistent and permanent consequences of Pb, stress and Pb+stress in offspring of both genders suggest that Pb screening programs should include pregnant women at risk for elevated Pb exposure, and that stress should be considered as an additional risk factor. Pb+stress effects observed in the absence of either risk factor alone (i.e., potentiated effects) raise questions about the capacity of current hazard identification approaches to adequately identify human health risks posed by neurotoxicants.

Permanent alterations in stress responsivity in female offspring subjected to combined maternal lead exposure and/or stress.

Elevated lead (Pb) exposures preferentially impact low socioeconomic status (SES) populations, the same groups thought to sustain the highest levels of environmental stress. As co-occurring risk factors, therefore, Pb and stress could interact, a possibility further supported by the fact that both act on mesocorticolimbic dopamine systems of the brain. We recently demonstrated in rats that maternal Pb exposure could permanently increase basal corticosterone levels of offspring consistent with altered hypothalamic pituitary adrenal (HPA) axis function. The current study was thus designed to test the hypothesis that stress responsivity of offspring should likewise be altered, with the outcome differing in response to Pb, stress or Pb+stress. The impact of intermittent variable stress challenges (restraint, novelty, cold) on behavior sensitive to Pb exposure (fixed interval (FI) schedule-controlled responding) and on stress-induced corticosterone changes were evaluated in adult female offspring of dams that had been exposed to Pb (150 ppm) in drinking water from 2 months prior to breeding through lactation with or without maternal restraint stress on days 16 and 17 of gestation. This design yielded four treatment groups: (NS/0, no maternal Pb, no maternal stress; S/0, no maternal Pb, maternal stress; NS/150, maternal Pb, no maternal stress; and S/150, maternal Pb exposure and maternal stress). While maternal Pb alone and stress alone each altered components of stress responsivity, the greatest number of effects was seen in response to Pb + stress. This included alterations in FI performance following both restraint and cold stress and in the corticosterone response to cold stress. Collectively, these studies reveal that maternal Pb exposure alone can permanently alter stress responsivity and that the profile of effects produced by maternal Pb differ from those produced by maternal Pb in conjunction with stress, findings which have both mechanistic and risk assessment significance.