Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York, USA.
Environ Health Perspect. 2020 Feb;128(2):27001. doi: 10.1289/EHP4977. Epub 2020 Feb 5.
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.
The present study sought to determine whether Pb, PS, or combined Pb and PS exposures produced adverse transgenerational consequences on brain and behavior.
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 and genes in the frontal cortex and hippocampus.
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 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 . However, numerous lineage-specific effects were observed, most of greater magnitude than those observed across lineages, with outcomes differing by F3 sex.
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.
铅（Pb）暴露和发育过程中的产前应激（PS）是具有共同生物学基础的共同发生的风险因素。PS 与改变行为表型的跨代传递有关，而 Pb 暴露的跨代行为或生化后果，以及 PS 对任何此类影响的修饰，尚不清楚。
本研究旨在确定 Pb、PS 或两者联合暴露是否对大脑和行为产生不利的跨代影响。
在 F0 小鼠中进行母体 Pb 和 PS 暴露。在随后的每一次繁殖中，都使用外部繁殖者，产生了四个 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了 F3 后代，并检查了以前在 F1 后代中发现的被 Pb、PS 或两者联合改变的结果：行为表现[固定间隔（FI）食物奖励时间表、运动活性和焦虑样行为]、多巴胺功能[纹状体酪氨酸羟化酶（Th）的表达]、糖皮质激素受体（GR）和血浆皮质酮，以及大脑源性神经营养因子（BDNF）和前额皮质和海马体中 和 基因的总 DNA 甲基化百分比。
母体 F0 Pb 暴露导致 F3 后代生长迟缓。考虑到谱系，F3 雌性表现出与行为、纹状体 BDNF 水平、前额皮质 总 DNA 甲基化水平和血清皮质酮水平相关的 Pb 相关改变，而 F3 雄性则表现出与行为和海马体 总 DNA 甲基化百分比相关的 Pb 和 PS 相关改变。然而，观察到了许多谱系特异性效应，其中大多数效应比谱系间效应更大，并且与 F3 性别有关。
这些发现支持了前几代人接触 Pb 或 PS 可能会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 雌性通过 Pb 暴露的谱系表现出多种变化。谱系效应可能通过怀孕时的母体反应、改变的母体行为、表观遗传修饰或多种机制的组合发生，但无论机制如何，它们都具有重大的公共卫生意义。https://doi.org/10.1289/EHP4977.
