Supranormal electroretinogram in a 10-year-old girl with lead toxicity

Nagpal, Agnieszka G.

doi:10.1007/s10633-008-9144-7

Cited by 12 publications

(8 citation statements)

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“…Our results show that GLE in mice with [BPb] at the current low level of concern (CDC 1991) produced persistent retinal alterations characterized by proportional increases in rod and rod BC neurogenesis that likely underlie the observed scotopic ERG supernormality (Fox et al 2008; Lilienthal et al 1994; Nagpal and Brodie 2009; Rothenberg et al 2002). In concert with our previous work (Fox and Boyes 2008), these findings stress the importance of examining developmental-stage–dependent and dose-dependent effects in human and animal toxicology studies.…”

Section: Resultsmentioning

confidence: 66%

“…After postnatal lead exposure, rod photoreceptor-selective apoptosis, persistent rod-mediated (scotopic) electroretinographic (ERG) subnormality, and scotopic behavioral deficits occur in humans, monkeys, and rodents (Fox and Boyes 2008; Fox et al 1997; He et al 2003). In contrast, children, monkeys, and rats with low-dose (LD) to moderate-dose (MD) gestational lead exposure (GLE) exhibit novel scotopic ERG supernormality (Fox et al 2008; Lilienthal et al 1994; Nagpal and Brodie 2009; Rothenberg et al 2002). …”

mentioning

confidence: 99%

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Low-Level Gestational Lead Exposure Increases Retinal Progenitor Cell Proliferation and Rod Photoreceptor and Bipolar Cell Neurogenesis in Mice

Giddabasappa¹,

Hamilton²,

Chaney³

et al. 2011

Environ Health Perspect

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BackgroundGestational lead exposure (GLE) produces novel and persistent rod-mediated electroretinographic (ERG) supernormality in children and adult animals.ObjectivesWe 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.ResultsBlood 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.ConclusionsOur 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.

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Section: Resultsmentioning

confidence: 66%

mentioning

confidence: 99%

Low-Level Gestational Lead Exposure Increases Retinal Progenitor Cell Proliferation and Rod Photoreceptor and Bipolar Cell Neurogenesis in Mice

Giddabasappa¹,

Hamilton²,

Chaney³

et al. 2011

Environ Health Perspect

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“…For example, the dopaminergic neurotoxin 6-hydroxydopamine selectively kills DA ACs and produces supernormal scotopic ERGs (Oliver et al, 1986; Skrandies and Wässle, 1988) similar to those observed in children, monkeys and rats with GLE (Fox et al, 2008; Lilienthal et al, 1988, 1994; Nagpal and Brodie, 2009; Rothenberg et al, 2002). Furthermore, placental insufficiency reduces the number of TH-IR DA ACs and retinal DA content, but does not affect other retinal ACs (Loeliger et al, 2004).…”

Section: Discussionmentioning

confidence: 86%

“…Low-level (blood lead concentration [BPb] ≤10 µg/dL) to moderate-level ([BPb] 11–39 µg/dL) developmental lead exposure produces cognitive, auditory, retinal and visual-motor dysfunction in children and experimental animals (Altmann et al, 1998; Canfield et al, 2003; Fox et al, 1997; Fox and Boyes, 2007; Fox et al, 2008; Giddabasappa et al, 2011; He et al, 2003; Nagpal and Brodie, 2009; Osman et al, 1999; Rothenberg et al, 2000, 2002; Wasserman et al, 2000). Children, adult monkeys and rats with gestational lead exposure (GLE) exhibit novel rod photoreceptor-mediated (scotopic) electroretinogram (ERG) supernormality characterized by increased a-wave and b-wave amplitudes (Fox et al 2008; Lilienthal et al 1988, 1994; Nagpal and Brodie 2009; Rothenberg et al 2002). Moreover, adult rats and mice with GLE have a selectively increased number of late-born rod photoreceptors and bipolar cells (Fox et al, 2008; Giddabasappa et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Gestational lead exposure selectively decreases retinal dopamine amacrine cells and dopamine content in adult mice

Fox

Hamilton

Johnson

et al. 2011

Toxicology and Applied Pharmacology

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Gestational lead exposure (GLE) produces supernormal scotopic electroretinograms (ERG) in children, monkeys and rats, and a novel retinal phenotype characterized by an increased number of rod photoreceptors and bipolar cells in adult mice and rats. Since the loss of dopaminergic amacrine cells (DA ACs) in GLE monkeys and rats contributes to supernormal ERGs, the retinal DA system was analyzed in mice following GLE. C57BL/6 female mice were exposed to low (27 ppm), moderate (55 ppm) or high (109 ppm) lead throughout gestation and until postnatal day 10 (PN10). Blood [Pb] in control, low-, moderate- and high-dose GLE was ≤1, ≤10, ~25 and ~40 µg/dL, respectively, on PN10 and by PN30 all were ≤1 µg/dL. At PN60, confocal-stereology studies used vertical sections and wholemounts to characterize tyrosine hydroxylase (TH) expression and the number of DA and other ACs. GLE dose-dependently and selectively decreased the number of TH-immunoreactive (IR) DA ACs and their synaptic plexus without affecting GABAergic, glycinergic or cholinergic ACs. Immunoblots and confocal revealed dose-dependent decreases in retinal TH protein expression and content, although monoamine oxidase-A protein and gene expression were unchanged. High-pressure liquid chromatography showed that GLE dose-dependently decreased retinal DA content, its metabolites and DA utilization/release. The mechanism of DA selective vulnerability is unknown. However, a GLE-induced loss/dysfunction of DA ACs during development could increase the number of rods and bipolar cells since DA helps regulate neuronal proliferation, whereas during adulthood it could produce ERG supernormality as well as altered circadian rhythms, dark/light adaptation and spatial contrast sensitivity.

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“…Developmental lead exposure produces cognitive, behavioral, auditory, retinal, and visual-motor dysfunction as well as neuropsychiatric alterations ( Canfield et al 2003 ; Fox and Boyes 2013 ; Goyer 1993 ; Nagpal and Brodie 2009 ; Osman et al 1999 ; Rothenberg et al 2000 , 2002 ; Wasserman et al 2000 ). Many Chinese scientists contributed to this research and helped elucidate sites and mechanisms of lead neurotoxicity.…”

Section: Resultsmentioning

confidence: 99%

The History, Status, Gaps, and Future Directions of Neurotoxicology in China

Cai

Luo

Ruan

et al. 2016

Environ Health Perspect

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Background:Rapid economic development in China has produced serious ecological, environmental, and health problems. Neurotoxicity has been recognized as a major public health problem. The Chinese government, research institutes, and scientists conducted extensive studies concerning the source, characteristics, and mechanisms of neurotoxicants.Objectives:This paper presents, for the first time, a comprehensive history and review of major sources of neurotoxicants, national bodies/legislation engaged, and major neurotoxicology research in China.Methods:Peer-reviewed research and pollution studies by Chinese scientists from 1991 to 2015 were examined. PubMed, Web of Science and Chinese National Knowledge Infrastructure (CNKI) were the major search tools.Results:The central problem is an increased exposure to neurotoxicants from air and water, food contamination, e-waste recycling, and manufacturing of household products. China formulated an institutional framework and standards system for management of major neurotoxicants. Basic and applied research was initiated, and international cooperation was achieved. The annual number of peer-reviewed neurotoxicology papers from Chinese authors increased almost 30-fold since 2001.Conclusions:Despite extensive efforts, neurotoxicity remains a significant public health problem. This provides great challenges and opportunities. We identified 10 significant areas that require major educational, environmental, governmental, and research efforts, as well as attention to public awareness. For example, there is a need to increase efforts to utilize new in vivo and in vitro models, determine the potential neurotoxicity and mechanisms involved in newly emerging pollutants, and examine the effects and mechanisms of mixtures. In the future, we anticipate working with scientists worldwide to accomplish these goals and eliminate, prevent and treat neurotoxicity.Citation:Cai T, Luo W, Ruan D, Wu YJ, Fox DA, Chen J. 2016. The history, status, gaps, and future directions of neurotoxicology in China. Environ Health Perspect 124:722–732; http://dx.doi.org/10.1289/ehp.1409566

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Supranormal electroretinogram in a 10-year-old girl with lead toxicity

Abstract: Lead toxicity with significant visual and cognitive dysfunction, and supranormal ERG, can persist at lead levels below those recognized for lead poisoning.

Cited by 12 publications

References 8 publications

Low-Level Gestational Lead Exposure Increases Retinal Progenitor Cell Proliferation and Rod Photoreceptor and Bipolar Cell Neurogenesis in Mice

Low-Level Gestational Lead Exposure Increases Retinal Progenitor Cell Proliferation and Rod Photoreceptor and Bipolar Cell Neurogenesis in Mice

Gestational lead exposure selectively decreases retinal dopamine amacrine cells and dopamine content in adult mice

The History, Status, Gaps, and Future Directions of Neurotoxicology in China

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