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.

中文翻译：

---

小鼠发育暴露于铅、产前应激以及铅和产前应激的组合的谱系和性别依赖性行为和生化跨代后果。


背景铅（Pb）暴露和发育过程中的产前应激（PS）是具有共同生物底物的同时发生的危险因素。 PS 与行为表型改变的跨代传递有关，而 Pb 暴露的跨代行为或生化后果以及 PS 对任何此类效应的修改尚不清楚。目的 本研究旨在确定 Pb、PS 或 Pb 和 PS 的组合暴露是否会对大脑和行为产生不利的跨代后果。方法 在 F0 小鼠中进行母体 Pb 和 PS 暴露。随后的每次育种均使用外部育种者，产生四个 F1-F2 谱系：[F1 雌性-F2 雌性 (FF)、FM（雄性）、MF 和 MM]。从这些谱系中的每一个中产生 F3 后代，并检查之前发现 F1 后代中 Pb、PS 或 Pb 和 PS 组合改变的结果：行为表现 [固定间隔 (FI) 食物奖励时间表、运动活动和焦虑样行为]、多巴胺功能[纹状体酪氨酸羟化酶 (Th) 表达]、糖皮质激素受体 (GR) 和血浆皮质酮，以及脑源性神经营养因子 (BDNF) 以及 Th 和 Bdnf 基因的总 DNA 甲基化百分比额叶皮层和海马体。结果 母体 F0 铅暴露导致 F3 后代矮小。跨谱系考虑，F3 雌性在行为、纹状体 BDNF 水平、额叶皮层 Th 总百分比 DNA 甲基化水平和血清皮质酮水平方面表现出与 Pb 相关的改变，而 F3 雄性在行为和总 DNA 甲基化百分比方面表现出与 Pb 和 PS 相关的改变。海马 Bdnf。 然而，观察到了许多谱系特异性效应，大多数比跨谱系观察到的效应更大，并且结果因 F3 性别而异。讨论 这些发现支持前几代人接触 Pb 或 PS 可能影响后代大脑和行为的可能性。观察到的变化是性别依赖性的，F3 雌性在暴露于铅的谱系中表现出多种变化。谱系效应可能通过母亲对怀孕的反应、母亲行为的改变、表观遗传修饰或多种机制的组合而发生，但无论机制如何，它们都会对公共健康产生重大影响。 https://doi.org/10.1289/EHP4977。