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Lineage- and Sex-Dependent Behavioral and Biochemical Transgenerational Consequences of Developmental Exposure to Lead, Prenatal Stress, and Combined Lead and Prenatal Stress in Mice.

ABSTRACT: BACKGROUND:Lead (Pb) exposure and prenatal stress (PS) during development are co-occurring risk factors with shared biological substrates. PS has been associated with transgenerational passage of altered behavioral phenotypes, whereas the transgenerational behavioral or biochemical consequences of Pb exposure, and modification of any such effects by PS, is unknown. OBJECTIVES:The present study sought to determine whether Pb, PS, or combined Pb and PS exposures produced adverse transgenerational consequences on brain and behavior. METHODS:Maternal Pb and PS exposures were carried out in F0 mice. Outside breeders were used at each subsequent breeding, producing four F1-F2 lineages: [F1 female-F2 female (FF), FM (male), MF, and MM]. F3 offspring were generated from each of these lineages and examined for outcomes previously found to be altered by Pb, PS, or combined Pb and PS in F1 offspring: behavioral performance [fixed-interval (FI) schedule of food reward, locomotor activity, and anxiety-like behavior], dopamine function [striatal expression of tyrosine hydroxylase (Th)], glucocorticoid receptor (GR) and plasma corticosterone, as well as brain-derived neurotrophic factor (BDNF) and total percent DNA methylation of Th and Bdnf genes in the frontal cortex and hippocampus. RESULTS:Maternal F0 Pb exposure produced runting in F3 offspring. Considered across lineages, F3 females exhibited Pb-related alterations in behavior, striatal BDNF levels, frontal cortical Th total percentage DNA methylation levels and serum corticosterone levels, whereas F3 males showed Pb- and PS-related alterations in behavior and total percent DNA methylation of hippocampal Bdnf. However, numerous lineage-specific effects were observed, most of greater magnitude than those observed across lineages, with outcomes differing by F3 sex. DISCUSSION:These findings support the possibility that exposures of previous generations to Pb or PS may influence the brain and behavior of future generations. Observed changes were sex-dependent, with F3 females showing multiple changes through Pb-exposed lineages. Lineage effects may occur through maternal responses to pregnancy, altered maternal behavior, epigenetic modifications, or a combination of mechanisms, but they have significant public health ramifications regardless of mechanism. https://doi.org/10.1289/EHP4977.

SUBMITTER: Sobolewski M

PROVIDER: S-EPMC7064322 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Lineage- and Sex-Dependent Behavioral and Biochemical Transgenerational Consequences of Developmental Exposure to Lead, Prenatal Stress, and Combined Lead and Prenatal Stress in Mice.

Sobolewski Marissa M Abston Kadijah K Conrad Katherine K Marvin Elena E Harvey Katherine K Susiarjo Martha M Cory-Slechta Deborah A DA

Environmental health perspectives 20200205 2

<h4>Background</h4>Lead (Pb) exposure and prenatal stress (PS) during development are co-occurring risk factors with shared biological substrates. PS has been associated with transgenerational passage of altered behavioral phenotypes, whereas the transgenerational behavioral or biochemical consequences of Pb exposure, and modification of any such effects by PS, is unknown.<h4>Objectives</h4>The present study sought to determine whether Pb, PS, or combined Pb and PS exposures produced adverse tra ...[more]

PMID: 32073883

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Project description: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 50ppm Pb acetate from 2 to 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 45mg food pellets) after a long delay or a small reward (one 45mg food pellet) after a short delay, with the long delay value increased from 0s to 30s 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 remain consistent with sex-dependent differences in the impacts of both Pb and PS and with the need to understand both the role of contingencies of reinforcement and underlying neurobiological effects in these sex differences.

Project description:BACKGROUND:Lead is an established neurotoxicant and early life exposure to lead is associated with detrimental impacts on IQ and several neurobehavioral domains. Less is known, however, about effects of prenatal lead exposure below 5??g/dL on executive function and on social, emotional and self-regulatory behaviors in childhood. OBJECTIVES:To examine the association between prenatal lead exposure and childhood executive function and social, emotional and self-regulatory behaviors. METHODS:We included 1006 mother-child pairs from the Project Viva prospective pre-birth cohort. We measured prenatal maternal lead in second-trimester erythrocytes. In mid-childhood (median 7.7?years), parents and teachers rated executive function related behaviors using the Behavior Rating Inventory of Executive Function (BRIEF) and behavioral difficulties using the Strengths and Difficulties Questionnaire (SDQ). We used multivariable linear regression models adjusted for maternal, paternal, and child characteristics and metal co-exposures. RESULTS:Mean maternal erythrocyte lead concentration was 1.2??g/dL (interquartile range [IQR] 0.8-1.5??g /dL), equivalent to approximately 0.4??g/dL in whole blood. In adjusted models, associations with parent and teacher-rated scales were largely null, although effect estimates were consistently positive, suggesting worse scores with increasing lead levels. For an IQR increase in lead, BRIEF Global Executive Composite (GEC) was 0.73 (95% CI: -0.06, 1.52) points higher for parent-rated scores and 0.42 (95% CI: -0.39, 1.23) points higher for teacher-rated scores. Associations were strongest for parent-rated BRIEF plan/organize (??=?0.85; 95% CI: 0.12, 1.59) and shift (??=?0.88; 95% CI: 0.01, 1.75) subscales, as well as the SDQ emotional problems subscale (??=?0.18; 95% CI: 0.03, 0.33). DISCUSSION:In this cohort with lead levels commonly experienced by U.S. women, there were few statistically significant associations with childhood executive function and behavior. However, there was a trend of worse neurobehavioral scores with increasing prenatal lead concentrations, in particular for childhood emotional problems and capacity to plan/organize and shift. Our results highlight the importance of continuing efforts to eliminate lead exposure in the general population.

Project description:In children, behavioral inhibition is characterized by a disposition to withdraw in the presence of strangers and novel situations. Later in life, behavioral inhibition can result in an increased risk for anxiety and depression and a decrease in social behavior. We selected rhesus monkeys that, during infancy, showed evidence of behavioral inhibition in response to separation, and contrasted them with non-inhibited peers. To understand the development of behavioral inhibition at juvenile age, we collected behavioral data in response to relocation; in response to a human intruder challenge; and in naturalistic outdoor field corrals. At 4 years of age (young adulthood), we again collected behavioral data in the outdoor field corrals to understand the adult social consequences of behavioral inhibition. We also included sex, dominance rank, and number of available kin in our analyses. Finally, to understand the consistency in behavior in behaviorally inhibited animals, we conducted exploratory analyses contrasting behaviorally inhibited animals that showed high vs. low durations of non-social behaviors as adults. At juvenile age, behaviorally inhibited animals continued to show behavioral differences in the novel testing room and during the human intruder challenge, generally showing evidence of greater anxiety and emotionality compared to non-inhibited controls. In their outdoor corrals, behaviorally inhibited juveniles spent more time alone and less time in proximity and grooming with mother and other adult females. In young adulthood, we found that behavioral inhibition was not related to time spent alone. We did find that duration of time alone in adulthood was related to time alone exhibited as juveniles; sex, dominance rank, or the number of kin were not influential in adult non-social duration, either as main effects or as moderators. Finally, exploratory analyses revealed that behaviorally inhibited females that were more sociable (less time spent alone) as adults had spent more time grooming as juveniles, suggesting that high-quality social interaction at a young age might mitigate the social consequences of behavioral inhibition. Overall, we believe that the many similarities with the human data that we found suggest that this monkey model of naturally occurring behavioral inhibition can be valuable for understanding social development.

Dataset Information

Lineage- and Sex-Dependent Behavioral and Biochemical Transgenerational Consequences of Developmental Exposure to Lead, Prenatal Stress, and Combined Lead and Prenatal Stress in Mice.

Publications

Lineage- and Sex-Dependent Behavioral and Biochemical Transgenerational Consequences of Developmental Exposure to Lead, Prenatal Stress, and Combined Lead and Prenatal Stress in Mice.

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