Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-2020, USA.
Environ Health Perspect. 2011 Jan;119(1):71-7. doi: 10.1289/ehp.1002524. Epub 2010 Sep 14.
Gestational lead exposure (GLE) produces novel and persistent rod-mediated electroretinographic (ERG) supernormality in children and adult animals.
We used our murine GLE model to test the hypothesis that GLE increases the number of neurons in the rod signaling pathway and to determine the cellular mechanisms underlying the phenotype.
Blood lead concentrations ([BPb]) in controls and after low-, moderate-, and high-dose GLE were ≤ 1, ≤ 10, approximately 25, and approximately 40 µg/dL, respectively, at the end of exposure [postnatal day 10 (PND10)]; by PND30 all [BPb] measures were ≤ 1 µg/dL. Epifluorescent, light, and confocal microscopy studies and Western blots demonstrated that late-born rod photoreceptors and rod and cone bipolar cells (BCs), but not Müller glial cells, increased in a nonmonotonic manner by 16-30% in PND60 GLE offspring. Retinal lamination and the rod:cone BC ratio were not altered. In vivo BrdU (5-bromo-2-deoxyuridine) pulse-labeling and Ki67 labeling of isolated cells from developing mice showed that GLE increased and prolonged retinal progenitor cell proliferation. TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and confocal studies revealed that GLE did not alter developmental apoptosis or produce retinal injury. BrdU birth-dating and confocal studies confirmed the selective rod and BC increases and showed that the patterns of neurogenesis and gliogenesis were unaltered by GLE.
Our findings suggest two spatiotemporal components mediated by dysregulation of different extrinsic/intrinsic factors: increased and prolonged cell proliferation and increased neuronal (but not glial) cell fate. These findings have relevance for neurotoxicology, pediatrics, public health, risk assessment, and retinal cell biology because they occurred at clinically relevant [BPb] and correspond with the ERG phenotype.
妊娠铅暴露（GLE）会导致儿童和成年动物的新型且持久的 rod 介导的视网膜电图（ERG）超敏。
我们使用我们的鼠类 GLE 模型来检验 GLE 是否会增加 rod 信号通路中的神经元数量的假设，并确定表型背后的细胞机制。
对照组和低、中、高剂量 GLE 暴露结束时（生后 10 天（PND10））的血铅浓度（[BPb]）分别≤1、≤10、约 25 和约 40μg/dL；到 PND30 时，所有[BPb]测量值均≤1μg/dL。荧光、光镜和共聚焦显微镜研究以及 Western blot 表明，晚期出生的 rod 光感受器以及 rod 和 cone 双极细胞（BC），但不是 Müller 胶质细胞，在 PND60 GLE 后代中以非单调方式增加了 16-30%。视网膜分层和 rod:cone BC 比例没有改变。体内 BrdU（5-溴-2-脱氧尿苷）脉冲标记和从发育中的小鼠分离的细胞 Ki67 标记显示，GLE 增加并延长了视网膜祖细胞的增殖。TUNEL（末端脱氧核苷酸转移酶 dUTP 缺口末端标记）和共聚焦研究表明，GLE 没有改变发育中的细胞凋亡或产生视网膜损伤。BrdU 出生日期和共聚焦研究证实了 rod 和 BC 的选择性增加，并表明神经发生和神经胶质发生的模式没有受到 GLE 的影响。
我们的发现表明，两种时空成分由不同的外在/内在因素的失调介导：增加和延长的细胞增殖和增加的神经元（而不是神经胶质）细胞命运。这些发现与神经毒理学、儿科学、公共卫生、风险评估和视网膜细胞生物学有关，因为它们发生在临床相关的[BPb]，并且与 ERG 表型相对应。
