Sex-dependent impacts of low-level lead exposure and prenatal stress on impulsive choice behavior and associated biochemical and neurochemical manifestations

Abstract

A prior study demonstrated increased overall response rates on a Fixed Interval (FI) schedule of reward in female offspring that had been subjected to maternal lead (Pb) exposure, prenatal stress (PS) and offspring stress challenge relative to control, prenatal stress alone, lead alone and lead + prenatal stress alone (Virgolini et al., 2008). Response rates on FI schedules have been shown to directly relate to measures of self-control (impulsivity) in children and in infants (Darcheville et al., 1992; 1993). The current study sought to determine whether enhanced effects of Pb ± PS would therefore be seen in a more direct measure of impulsive choice behavior, i.e., a delay discounting paradigm. Offspring of dams exposed to 0 or 50 ppm Pb acetate from 2–3 months prior to breeding through lactation, with or without immobilization restraint stress (PS) on gestational days 16 and 17, were trained on a delay discounting paradigm that offered a choice between a large reward (three 45 mg food pellets) after a long delay or a small reward (one 45 mg food pellet) after a short delay, with the long delay value increased from 0 sec to 30 sec across sessions. Alterations in extinction of this performance, and its subsequent re-acquisition after reinforcement delivery was reinstated were also examined. Brains of littermates of behaviorally-trained offspring were utilized to examine corresponding changes in monoamines and in levels of brain derived neurotrophic factor (BDNF), the serotonin transporter (SERT) and the N-methyl-D-aspartate receptor (NMDAR) 2A in brain regions associated with impulsive choice behavior. Results showed that Pb ± PS-induced changes in delay discounting occurred almost exclusively in males. In addition to increasing percent long delay responding at the indifference point (i.e., reduced impulsive choice behavior), Pb ± PS slowed acquisition of delayed discounting performance, and increased numbers of both failures to and latencies to initiate trials. Overall, the profile of these alterations were more consistent with impaired learning/behavioral flexibility and/or with enhanced sensitivity to the downshift in reward opportunities imposed by the transition from delay discounting training conditions to delay discounting choice response contingencies. Consistent with these behavioral changes, Pb ± PS treated males also showed reductions in brain serotonin function in all mesocorticolimbic regions, broad monoamine changes in nucleus accumbens, and reductions in both BDNF and NMDAR 2A levels and increases in SERT in frontal cortex, i.e., in regions and neurotransmitter systems known to mediate learning/behavioral flexibility, and which were of greater impact in males. The current findings do not fully support a generality of the enhancement of Pb effects by PS, as previously seen with FI performance in females (Virgolini et al., 2008), and suggest a dissociation of the behaviors controlled by FI and delay discounting paradigms, at least in response to Pb ± PS in rats. Collectively, however, the findings re...

Lead exposure induces changes in 5-hydroxymethylcytosine clusters in CpG islands in human embryonic stem cells and umbilical cord blood

“…41 In animal models, sex-specific differences in the effects of Pb exposure have also been observed in spatial learning and memory, motor behavior, dopamine metabolism, and brain gene expression. 8,42,43 Some of the sex-biased response to Pb toxicity can be attributed to sex hormones, or to the differential expression of sex and/or autosomal genes. 44 A mechanism through which exposure to heavy metals such as Pb might contribute to altering gene expression is by changing the 5hmC and 5mC profiles in the genome.…”

Sexually Dimorphic Effects of Early-Life Exposures to Endocrine Disruptors: Sex-Specific Epigenetic Reprogramming as a Potential Mechanism

“…Weston et al showed that when exposed to a more modest dose of Pb during development, male rats are more susceptible to Pb plus stress resulting in changes in neurochemicals and protein production (e.g. BDNF) [46]. Together these studies reviewed here indicate that exposure responses can vary by Pb dose, stress, and sex.…”

CURCUMIN ATTENUATES LEAD (Pb)–INDUCED NEUROBEHAVIORL AND NEUROBIOCHEMICAL DYSFUNCTION: A REVIEW

“…Prevention of lead toxicity mainly involved in the screening of blood lead level in children. Medical intervention is also recommended if lead content is very high in the blood mainly to control blood poisoning [35][36][37][38]. Many preventive measures have been suggested to control lead exposure.…”