Low-level gestational lead exposure increases retinal progenitor cell proliferation and rod photoreceptor and bipolar cell neurogenesis in mice

Abstract

Background: Gestational lead exposure (GLE) produces novel and persistent rod-mediated electro retino graphic (ERG) supernormality in children and adult animals. oB je c t iv e s: 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 under lying the phenotype. results: 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. Epifuorescent, light, and confocal microscopy studies and Western blots demonstrated that late-born rod photo receptors and rod and cone bipolar cells (BCs), but not Müller glial cells, increased in a nonmonotonic manner by 16-30% in PND60 GLE ofspring. 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 con-focal studies revealed that GLE did not alter developmental apoptosis or produce retinal injury. BrdU birth-dating and confocal studies confrmed the selective rod and BC increases and showed that the patterns of neuro genesis and gliogenesis were unaltered by GLE. co n c l u sio n s: Our fndings suggest two spatiotemporal components mediated by dysregulation of diferent extrinsic/intrinsic factors: increased and prolonged cell proliferation and increased neu-ronal (but not glial) cell fate. Tese fndings 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.