Low-level gestational lead exposure increases retinal progenitor cell proliferation and rod photoreceptor and bipolar cell neurogenesis in mice.
BACKGROUND
Gestational lead exposure (GLE) produces novel and persistent rod-mediated electroretinographic (ERG) supernormality in children and adult animals.


OBJECTIVE
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.


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. 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.


CONCLUSIONS
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.
Giddabasappa
Anand
A
Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-2020, USA.
Hamilton
W Ryan
WR
Chaney
Shawntay
S
Xiao
Weimin
W
Johnson
Jerry E
JE
Mukherjee
Shradha
S
Fox
Donald A
DA
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004785:Environmental Pollutants / Q000097:blood / Q000633:toxicity*; D005260:Female; D007854:Lead / Q000097:blood / Q000633:toxicity*; D008297:Male; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D055495:Neurogenesis / Q000187:drug effects; D012160:Retina / Q000187:drug effects* / Q000254:growth & development; D051245:Retinal Bipolar Cells / Q000187:drug effects* / Q000502:physiology; D017948:Retinal Rod Photoreceptor Cells / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology
D004785:Environmental Pollutants; D007854:Lead