No abstract

Lead exposure is higher among children with low socioeconomic status (SES) compared with other children in the United States. Low SES itself is a known risk factor for various diseases and dysfunctions, effects that have been ascribed to chronic stress and associated elevation of glucocorticoids. Chronically elevated glucocorticoids and Pb provoke similar behavioral changes, and both can act on mesocorticolimbic systems of the brain. In this study we examined the hypothesis that these co-occurring risk factors, Pb and environmental stress, would interact and modulate each others' effects. Using a rodent model, we focused on the specific contributions of maternal stress (restraint) and maternal Pb exposure (150 ppm in drinking water) on corticosterone levels of offspring, as well as on neurotransmitter changes and a behavioral baseline (fixed-interval schedulecontrolled performance) with known sensitivities to Pb. We observed interactions of Pb and stress that differed in relation to outcome measure and sex. In addition, potentiated effects (effects of Pb plus stress but showing no changes produced by either alone) were observed more frequently in females. Importantly, Pb alone (in males) and Pb plus stress (in females) permanently elevated corticosterone levels in offspring; even short-term Pb exposure to dams could cause this effect. Such increases could suggest a potential new mechanism by which Pb exposure could directly or indirectly enhance susceptibility to diseases and dysfunctions and induce cognitive deficits. Moreover, the interactive effects of Pb and stress, and particularly the potentiated effects of Pb plus stress, raise questions about whether current risk assessment strategies sufficiently consider the potential for modulation of toxicity that can accrue from intercurrent risk factors.

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 ug/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 mos 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 ug/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 nonbehaviorally 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.