Publications by authors named "Norman J Kleiman"

24 Publications

  • Page 1 of 1

Identification of newly formed toxic chemicals in E-cigarette aerosols with Orbitrap mass spectrometry and implications on E-cigarette control.

Eur J Mass Spectrom (Chichester) 2021 Apr 27;27(2-4):141-148. Epub 2021 Aug 27.

Department of Environmental Health Sciences, 33638Mailman School of Public Health, Columbia University, USA.

The increasing use of electronic nicotine delivery systems (ENDS) is of concern due to multiple emerging adverse health effects. Most analyses of the harmful chemicals of ENDS have targeted metals or carbonyls generated by thermal decomposition of carrier liquids such as propylene glycol. However, new complex compounds not routinely identified and with unknown health consequences could be formed. ENDS aerosol samples were collected by the direct aerosol droplet deposition method. Untargeted analysis was performed using Orbitrap mass spectrometry with high mass accuracy. We identified more than 30 "features" in the aerosol characterized by pairs of the mass-to-charge ratio "/" of the compound and the retention time. We identified several compounds containing nicotine and propylene glycol (NIC-PG), whose abundance relative to nicotine increased along with vaping power used. On the basis of the prediction by the Environmental Protection Agency Toxicity Estimation Software Tool, these compounds exert developmental toxicity. In addition, a nitrogen-containing compound, likely tributylamine (a known lung irritant), was identified based on the molecular weight. This compound has not been previously identified in ENDS e-liquids and aerosols. ENDS produce not only small toxic compounds such as aldehydes, but also large complex toxic compounds such as NIC-PG. Predicted development toxicity for NIC-PG is concerning for fetal development in pregnant women who use ENDS, children exposed to secondhand or thirdhand ENDS aerosols, and teenage ENDS users whose brains are still developing. The strong positive association between NIC-PG levels and ENDS power output supports regulating high-powered ENDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/14690667211040207DOI Listing
April 2021

Exposure to e-cigarette aerosol over two months induces accumulation of neurotoxic metals and alteration of essential metals in mouse brain.

Environ Res 2021 Jul 8;202:111557. Epub 2021 Jul 8.

Department of Environmental Health Sciences, Columbia University, New York, NY, 10032, USA; NIEHS Center for Environmental Health in Northern Manhattan, Columbia University, New York, NY, 10032, USA. Electronic address:

Despite a recent increase in e-cigarette use, the adverse human health effects of exposure to e-cigarette aerosol, especially on the central nervous system (CNS), remain unclear. Multiple neurotoxic metals have been identified in e-cigarette aerosol. However, it is unknown whether those metals accumulate in the CNS at biologically meaningful levels. To answer this question, two groups of mice were whole-body exposed twice a day, 5 days a week, for two months, to either a dose of e-cigarette aerosol equivalent to human secondhand exposure, or a 5-fold higher dose. After the last exposure, the olfactory bulb, anterior and posterior frontal cortex, striatum, ventral midbrain, cerebellum, brainstem, remaining brain tissue and spinal cord were collected for metal quantification by inductively coupled plasma mass spectrometry and compared to tissues from unexposed control mice. The two-month exposure caused significant accumulation of several neurotoxic metals in various brain areas - for some metals even at the low exposure dose. The most striking increases were measured in the striatum. For several metals, including Cr, Cu, Fe, Mn, and Pb, similar accumulations are known to be neurotoxic in mice. Decreases in some essential metals were observed across the CNS. Our findings suggest that chronic exposure to e-cigarette aerosol could lead to CNS neurotoxic metal deposition and endogenous metal dyshomeostasis, including potential neurotoxicity. We conclude that e-cigarette-mediated metal neurotoxicity may pose long-term neurotoxic and neurodegenerative risks for e-cigarette users and bystanders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2021.111557DOI Listing
July 2021

Microbial Contamination Risk and Disinfection of Radiation Protective Garments.

Health Phys 2021 02;120(2):123-130

Infection Prevention & Control New York-Presbyterian Hospital New York, NY 10032.

Abstract: Healthcare-associated infections are a major public health concern for both patients and medical personnel. This has taken on greater urgency during the current COVID-19 pandemic. Radiation Personal Protective Equipment (RPPE) may contribute to risks of microbial contamination. This possibility was tested in 61 personal or shared-use lead aprons and thyroid collars at Columbia Presbyterian Irving Medical Center. Fifty percent tested positive for either bacterial or fungal contamination, mostly around the neckline of lead vests and thyroid collars. Repeated testing of garments some weeks to months later confirmed continued presence of microbial contamination. The possibility that hospital-approved disinfection agents could degrade the radio-protective features of these garments was also examined. Samples of identical construction to garments in regular use were subjected to either daily or weekly wipes with hypochlorite or alcohol-based hospital-approved cleaning agents for 6 mo. A third group of samples was maintained in contact with the cleaning agents for 6 mo. All samples were fluoroscoped four times during the study. None demonstrated any degradation in radioprotection. All samples were photographed monthly. Physical degradation of the outer plastic covering by concentrated hypochlorite and limited mechanical damage around stitched seams of the samples cleaned daily with alcohol was noted. Based on the high prevalence of microbial contamination, regular cleaning and disinfection protocols should be implemented. Regular cleaning with medical-facility-approved cleaning and disinfecting agents is likely to be effective at reducing the microbial load and unlikely to result in significant reduction in radioprotective properties of these garments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HP.0000000000001387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872069PMC
February 2021

Transcriptomic responses in mouse blood during the first week after in vivo gamma irradiation.

Sci Rep 2019 12 4;9(1):18364. Epub 2019 Dec 4.

Center for Radiological Research, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA.

Due to limitations of available human models for development of gene expression based radiation biodosimetry, many such studies have made use of mouse models. To provide a broad view of the gene expression response to irradiation in the mouse, we have exposed male C57BL/6 mice to 0, 1.5, 3, 6 or 10 Gy of gamma rays, sacrificing groups of the mice at 1, 2, 3, 5, or 7 days after exposure. We then profiled global gene expression in blood from individual mice using Agilent microarrays. In general, we found increasing numbers of genes differentially expressed with increasing dose, with more prolonged responses after the higher doses. Gene ontology analysis showed a similar pattern, with more biological processes enriched among the genes responding to higher doses, and at later times after exposure. Clustering the timecourse expression data using maSigPro identified four broad patterns of response, representing different gene ontology functions. The largest of these clusters included genes with initially decreased expression followed by increased expression at later times, a pattern of expression previously reported for several genes following neutron exposure. Another gene cluster showing consistent down regulation suggests genes useful for biodosimetry throughout the first week after exposure can be identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-54780-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893039PMC
December 2019

A custom-built low-cost chamber for exposing rodents to e-cigarette aerosol: practical considerations.

Inhal Toxicol 2019 Sep - Oct;31(11-12):399-408. Epub 2019 Dec 4.

Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.

To (1) design and build a low-cost exposure chamber system for whole-body exposure of rodents to electronic cigarette aerosol, (2) provide detailed instructions with particular focus on automated e-cigarette activation, and (3) develop a simple mathematical model for aerosol levels in the exposure chamber. We built the system with standard laboratory equipment and an open-source electronics platform (Arduino) for e-cigarette activation. Arduino is used to control a solenoid, which pushes the activation button of so-called "Mod" e-cigarettes, and a pump to move the aerosol from the mouthpiece of the e-cigarette into the chamber. For "Pods" and "Cigalikes," the solenoid is not used as they are activated by the vacuum created by the pump. Aerosol concentrations were measured with a light-scattering laser photometer. The system allows varying the air exchange rate, monitoring aerosol levels, and programing arbitrary puff topography. Aerosol concentrations observed for different chamber operating conditions (puff time and period, e-cigarette power output, air exchange rate) were consistent with the mathematical model. Our low-cost exposure chamber can be used in animal experimental studies of the health effects of e-cigarettes. Our model allows estimating design parameters such as chamber volume, air exchange rate, and puff period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/08958378.2019.1698678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013998PMC
May 2020

Metal concentrations in electronic cigarette aerosol: Effect of open-system and closed-system devices and power settings.

Environ Res 2019 07 22;174:125-134. Epub 2019 Apr 22.

Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA. Electronic address:

Background: Electronic cigarettes (E-cigarettes) generate aerosol containing metal contaminants. Our goals were to quantify aerosol metal concentrations and to compare the effects of power setting and device type (closed-system vs. open-system) on metal release.

Methods: Aerosol samples were collected from two closed-system devices (a cigalike and pod) and two open-system devices (mods). Each open-system device was operated at three different power settings to examine the effect of device power on metal release. Concentrations of 14 metals in e-cigarette aerosol collected via droplet deposition were measured using inductively coupled plasma mass spectroscopy. Aerosol metal concentrations were reported as mass fractions (μg/kg) in the e-liquid.

Results: For open-system device 1 (OD1), median arsenic (As), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), lead (Pb), antimony (Sb), tin (Sn), and zinc (Zn) concentrations increased 14, 54, 17, 30, 41, 96, 14, 81, 631, and 7-fold when the device power was increased from low (20 W) to intermediate (40 W) setting. When the power was further increased from intermediate (40 W) to high (80 W) setting, concentrations of As, Cr, Cu, Mn, Ni, and Sb did not change significantly. For open-system device 2 (OD2), Cr and Mn concentrations increased significantly when device power was increased from low (40 W) to intermediate (120 W) setting, and then decreased significantly when power was further increased from intermediate (120 W) to high (200 W) setting. Among the four devices, aerosol metal concentrations were higher for the open-system than the closed-system devices, except for aluminum (Al) and uranium (U). For Cr, median (interquartile range) concentrations (μg/kg) from the open-system devices were 2.51 (1.55, 4.23) and 15.6 (7.88, 54.5) vs. 0.39 (0.05, 0.72) and 0.41 (0.34, 0.57) for the closed-system devices. For Ni, concentrations (μg/kg) from the open-system devices were 793 (508, 1169) and 2148 (851, 3397) vs. 1.32 (0.39, 3.35) and 11.9 (10.7, 22.7) from the closed-system devices. Inhalation of 0% and 100% of samples from OD1, 7.4% and 88.9% from OD2 by typical e-cigarette users would exceed chronic minimum risk levels (MRL) of Mn and Ni, respectively. No MRL exceedance was predicted for the closed-system devices. A large fraction of users of OD1 (100%) and OD2 (77.8%) would be exposed to Ni levels higher than those from reference tobacco cigarette 3R4F.

Conclusions: Our findings suggest that power setting and device type affect metal release from devices to aerosol which would subsequently be inhaled by users. Metal concentrations from open-system devices first increased with device power, and then leveled off for most metals. Open-system devices generate aerosol with higher metal concentrations than closed-system devices. These findings inform tobacco regulatory science, policy makers and health professionals on potential metal health risks associated with e-cigarette use, design and manufacturing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2019.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079580PMC
July 2019

Modifiers of radiation effects in the eye.

Life Sci Space Res (Amst) 2017 Nov 18;15:43-54. Epub 2017 Jul 18.

Center for Radiological Research, Columbia University, College of Physicians and Surgeons, 630 W. 168th St., New York, NY 10032, USA.

World events, including the threat of radiological terrorism and the fear of nuclear accidents, have highlighted an urgent need to develop medical countermeasures to prevent or reduce radiation injury. Similarly, plans for manned spaceflight to a near-Earth asteroid or journey to Mars raise serious concerns about long-term effects of space radiation on human health and the availability of suitable therapeutic interventions. At the same time, the need to protect normal tissue from the deleterious effects of radiotherapy has driven considerable research into the design of effective radioprotectors. For more than 70 years, animal models of radiation cataract have been utilized to test the short and long-term efficacy of various radiation countermeasures. While some compounds, most notably the Walter Reed (WR) class of radioprotectors, have reported limited effectiveness when given before exposure to low-LET radiation, the human toxicity of these molecules at effective doses limits their usefulness. Furthermore, while there has been considerable testing of eye responses to X- and gamma irradiation, there is limited information about using such models to limit the injurious effects of heavy ions and neutrons on eye tissue. A new class of radioprotector molecules, including the sulfhydryl compound PrC-210, are reported to be effective at much lower doses and with far less side effects. Their ability to modify ocular radiation damage has not yet been examined. The ability to non-invasively measure sensitive, radiation-induced ocular changes over long periods of time makes eye models an attractive option to test the radioprotective and radiation mitigating abilities of new novel compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lssr.2017.07.005DOI Listing
November 2017

At Arm's Length: Radiation Safety During Radial Percutaneous Coronary Intervention.

J Am Coll Cardiol 2017 05 18;69(20):2538-2541. Epub 2017 Mar 18.

Mailman School of Public Health, Columbia University, New York, New York.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2017.03.016DOI Listing
May 2017

Arsenite accumulation in the mouse eye.

J Toxicol Environ Health A 2016 ;79(8):339-41

a Department of Environmental Health Sciences , Columbia University, Mailman School of Public Health , New York , New York , USA.

Elevated arsenic (As) concentrations in drinking water are a major worldwide public health concern. Exposure to As is associated with carcinogenesis, skin lesions, cardiovascular disease, cognitive deficits, and other disorders. However, little is known regarding chronic As-mediated effects on the eye. Oxidative stress is believed to be an important factor in As-related pathology and is also implicated in certain eye diseases such as cataract. Thus, elevated exposure to arsenic could potentially be a contributing factor for ocular pathology. A pilot study was therefore initiated to determine whether As could be detected in eye tissue of mice exposed to sodium arsenite in drinking water. Total As concentrations were determined by inductively coupled plasma-mass spectroscopy in whole eyes, lens, liver, heart, lung, kidneys, spleen, brain, and hair from mice given 0, 10, 50, or 250 ppm sodium arsenite in their drinking water for 4 wk or 0, 10 or 50 ppm for 6 mo. Dose-dependent increases in As concentration were observed in all organs and tissues. Surprisingly, As concentrations in the eye and lens were significantly higher than those in liver, lung, heart, spleen, and brain and similar to that found in kidneys. The relatively high concentration in the eye, and the lens in particular, suggests As exposure may be a contributing factor in cataract formation in parts of the world where As in drinking water is endemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15287394.2016.1151392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982701PMC
May 2017

Formation of persistent hyperplastic primary vitreous in ephrin-A5-/- mice.

Invest Ophthalmol Vis Sci 2014 Mar 19;55(3):1594-606. Epub 2014 Mar 19.

Department of Chemical Biology, Susan Lehman-Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey.

Purpose: Primary vitreous regression is a critical event in mammalian eye development required for proper ocular maturity and unhindered vision. Failure of this event results in the eye disease persistent hyperplastic primary vitreous (PHPV), also identified as persistent fetal vasculature (PFV), a condition characterized by the presence of a fibrovascular mass adjacent to the lens and retina, and associated with visual disability and blindness. Here, we identify ephrin-A5 to be a critical regulator for primary vitreous regression.

Methods: Wild-type and ephrin-A5(-/-) eyes were examined at various developmental stages to determine the progression of PHPV. Eye tissue was sectioned and examined by H&E staining. Protein expression and localization was determined through immunohistochemistry. Relative levels of Eph receptors were determined by RT-PCR.

Results: Ephrin-A5(-/-) animals develop ocular phenotypes representative of PHPV, most notably the presence of a large hyperplastic mass posterior to the lens that remains throughout the lifetime of the animal. The aberrant tissue in these mutant mice consists of residual hyaloid vessels surrounded by pigmented cells of neural crest origin. Labeling with bromodeoxyuridine (BrdU) and detection of proliferating cell nuclear antigen (PCNA) expression shows that the mass in ephrin-A5(-/-) animals is mitotically active in embryonic and postnatal stages.

Conclusions: Ephrin-A5 is a critical factor that regulates primary vitreous regression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1167/iovs.13-12706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586972PMC
March 2014

Potential reduction of contralateral second breast-cancer risks by prophylactic mammary irradiation: validation in a breast-cancer-prone mouse model.

PLoS One 2013 20;8(12):e85795. Epub 2013 Dec 20.

Center for Radiological Research, Columbia University Medical Center, New York, New York, United States of America.

Background: Long-term breast-cancer survivors have a highly elevated risk (1 in 6 at 20 years) of contralateral second breast cancer. This high risk is associated with the presence of multiple pre-malignant cell clones in the contralateral breast at the time of primary breast cancer diagnosis. Mechanistic analyses suggest that a moderate dose of X-rays to the contralateral breast can kill these pre-malignant clones such that, at an appropriate Prophylactic Mammary Irradiation (PMI) dose, the long-term contralateral breast cancer risk in breast cancer survivors would be considerably decreased.

Aims: To test the predicted relationship between PMI dose and cancer risk in mammary glands that have a high risk of developing malignancies.

Methods: We tested the PMI concept using MMTV-PyVT mammary-tumor-prone mice. Mammary glands on one side of each mouse were irradiated with X-rays, while those on the other side were shielded from radiation. The unshielded mammary glands received doses of 0, 4, 8, 12 and 16 Gy in 4-Gy fractions.

Results: In high-risk mammary glands exposed to radiation doses designed for PMI (12 and 16 Gy), tumor incidence rates were respectively decreased by a factor of 2.2 (95% CI, 1.1-5.0) at 12 Gy, and a factor of 3.1 (95% CI, 1.3-8.3) at 16 Gy, compared to those in the shielded glands that were exposed to very low radiation doses. The same pattern was seen for PMI-exposed mammary glands relative to zero-dose controls.

Conclusions: The pattern of cancer risk reduction by PMI was consistent with mechanistic predictions. Contralateral breast PMI may thus have promise as a spatially targeted breast-conserving option for reducing the current high risk of contralateral second breast cancers. For estrogen-receptor positive primary tumors, PMI might optimally be used concomitantly with systemically delivered chemopreventive drugs such as tamoxifen or aromatase inhibitors, while for estrogen-receptor negative tumors, PMI might be used alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085795PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869887PMC
July 2014

Further analysis of the lens of ephrin-A5-/- mice: development of postnatal defects.

Mol Vis 2013 3;19:254-66. Epub 2013 Feb 3.

Department of Chemical Biology, Susan Lehman-Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.

Purpose: The cells of the mammalian lens must be carefully organized and regulated to maintain clarity. Recent studies have identified the Eph receptor ligand ephrin-A5 as a major contributor to lens development, as mice lacking ephrin-A5 develop abnormal lenses, resulting in cataracts. As a follow-up to our previous study on the cataracts observed in ephrin-A5(-/-) animals, we have further examined the morphological and molecular changes in the ephrin-A5(-/-) lens.

Methods: Wild-type and ephrin-A5(-/-) eyes at various ages were fixed, sectioned, and examined using histological techniques. Protein expression and localization were determined using immunohistochemistry and western blot analysis.

Results: Lens abnormalities in the ephrin-A5(-/-) animals are observed at postnatal stages, with lens opacity occurring by postnatal day 21. Structural defects in the lens are first observed in the outer lens fiber cell region where cells in the ephrin-A5(-/-) lens are severely disorganized. Ephrin-A5 and the Eph receptor EphA2 are expressed during early ocular development and continue to be expressed into postnatal stages. The cataracts in the ephrin-A5(-/-) mutants occur regardless of the presence of the CP49 mutation.

Conclusions: In this follow-up study, we have uncovered additional details explicating the mechanisms underlying ephrin-A5 function in the lens. Furthermore, elucidation of the expression of ephrin-A5 and the Eph receptor EphA2 in the lens supports a fundamental role for this receptor-ligand complex in lens development. These observations, in concert with our previous study, strongly suggest that ephrin-A5 has a critical role in postnatal lens fiber organization to maintain lens transparency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566898PMC
September 2013

Radiation-associated lens opacities in catheterization personnel: results of a survey and direct assessments.

J Vasc Interv Radiol 2013 Feb 28;24(2):197-204. Epub 2013 Jan 28.

Radiology Department, Hospital Clinico San Carlos, Complutense University, Martin Lagos sn, 28040 Madrid, Spain.

Purpose: To estimate ocular radiation doses and prevalence of lens opacities in a group of interventional catheterization professionals and offer practical recommendations based on these findings to avoid future lens damage.

Materials And Methods: Subjects included 58 physicians and 69 nurses and technicians attending an interventional cardiology congress and appropriate unexposed age-matched controls. Lens dose estimates were derived from combining experimental measurements in catheterization laboratories with questionnaire responses regarding workload, types of procedures, and use of eye protection. Lens opacities were observed by dilated slit lamp examination using indirect illumination and retroillumination. The frequency and severity of posterior lens changes were compared between the exposed and unexposed groups. The severity of posterior lens changes was correlated with cumulative eye dose.

Results: Posterior subcapsular lens changes characteristic of ionizing radiation exposure were found in 50% of interventional cardiologists and 41% of nurses and technicians compared with findings of similar lens changes in<10% of controls. Estimated cumulative eye doses ranged from 0.1-18.9 Sv. Most lens injuries result after several years of work without eye protection.

Conclusions: A high prevalence of lens changes likely induced by radiation exposure in the study population suggests an urgent need for improved radiation safety and training, use of eye protection during catheterization procedures, and improved occupational dosimetry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvir.2012.10.016DOI Listing
February 2013

Parallels between neuron and lens fiber cell structure and molecular regulatory networks.

Dev Biol 2012 Aug 26;368(2):255-60. Epub 2012 May 26.

Department of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, MSB H645, Newark, NJ 07103, United States.

Studies over the past fifty years have identified extensive similarities between neurons and elongated fiber cells that make up in the interior of the ocular lens. Electron micrographs showed parallels in the organization of their intracellular vesicle transport machinery and between lens fiber cell lateral protrusions and dendritic spines. Consistent with those observations, a number of gene products first characterized as highly neuron-preferred in their expression were also demonstrated in lens fiber cells. Going further, a fundamental network of regulatory factors with critical roles in determining the neuronal phenotype were also identified in lenses, and showed a corresponding mutually exclusive distribution of neural and non-neural factor isoforms in mitotic lens epithelial cells and post-mitotic fiber cells consistent with their interlocking functions in neural cells. These included REST/NRSF transcription factors, members of major RNA binding protein families, and "brain-specific" miRNAs that were each shown to have global roles in governing neural and non-neural gene expression and alternative transcript splicing in vertebrates. This review discusses these extensive parallels between neurons and fiber cells and implications regarding common themes in lens and neural cell physiology and disease, which may also suggest related evolutionary processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ydbio.2012.05.022DOI Listing
August 2012

GluA2 AMPA glutamate receptor subunit exhibits codon 607 Q/R RNA editing in the lens.

Biochem Biophys Res Commun 2012 Feb 10;418(2):273-7. Epub 2012 Jan 10.

Department of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, Newark, NJ, USA.

Regulated GluA2 AMPA receptor subunit expression, RNA editing, and membrane localization are fundamental determinants of neuronal Ca(2+) influx, and underlie basic functions such as memory and the primary brain disorder epilepsy. Consistent with this, AMPARs, and specifically GluA2, are targets of common antiepileptic drugs (AEDs) and antidepressants. Recently, epidemiological associations between epilepsy and increased cataract prevalence were found comparable to cataract links with diabetes and smoking. Similarly, use of AEDs and several antidepressants also showed links with increased cataract. Here, we demonstrated GluA2 in lenses, consistent with REST/NRSF and REST4 we described previously in lenses, as well as GluA1 and ADAR2 in the lens. Surprisingly, we found predominant neuron-like Q/R editing of GluA2 RNAs also occurs in the lens and evidence of lens GluA2 phosphorylation and STEP phosphatases linked with GluA2 membrane localization in neurons. This study is among the first to show GluA2 expression and predominant Q/R RNA editing in a non-neural cell. Our results suggest GluA2 AMPARs have related roles in lens physiology and disease processes, and provide evidence these anticonvulsant and antidepressant drug targets also occur in the lens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2012.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351098PMC
February 2012

Radiation and cataract.

Radiat Prot Dosimetry 2011 Sep 14;147(1-2):300-4. Epub 2011 Jul 14.

International Atomic Energy Agency, Vienna, Austria.

When this paper was about to go to press, the International Commission on Radiological Protection released a statement recommending a change in the threshold dose for the eye lens and dose limits for eye for occupationally exposed persons. It is clear that the earlier published threshold for radiation cataract is no longer valid. Epidemiological studies among Chernobyl clean-up workers, A bomb survivors, astronauts, residents of contaminated buildings, radiological technicians and recent surveys of staff in interventional rooms indicate that there is an increased incidence of lens opacities at doses below 1 Gy. Nevertheless, eye lens dosimetry is at a primitive stage and needs to be developed further. Despite uncertainties concerning dose threshold and dosimetry, it is possible to significantly reduce the risk of radiation cataract through the use of appropriate eye protection. By increasing awareness among those at risk and better adoption and increased usage of protective measures, radiation cataract can become preventable despite lowering of dose limits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rpd/ncr299DOI Listing
September 2011

Radiation cataract risk in interventional cardiology personnel.

Radiat Res 2010 Oct;174(4):490-5

Radiology Department, Complutense University, Madrid, Spain.

The lens of the eye is one of the most radiosensitive tissues in the body, and exposure of the lens to ionizing radiation can cause cataract. Cumulative X-ray doses to the lenses of interventional cardiologists and associated staff can be high. The International Commission on Radiological Protection recently noted considerable uncertainty concerning radiation risk to the lens. This study evaluated risk of radiation cataract after occupational exposure in interventional cardiology personnel. Comprehensive dilated slit-lamp examinations were performed in interventional cardiologists, associated workers and controls. Radiation exposures were estimated using experimental data from catheterization laboratories and answers to detailed questionnaires. A total of 116 exposed and 93 similarly aged nonexposed individuals were examined. The relative risk of posterior subcapsular opacities in interventional cardiologists compared to unexposed controls was 3.2 (38% compared to 12%; P < 0.005). A total of 21% of nurses and technicians had radiation-associated posterior lens changes typically associated with ionizing radiation exposure. Cumulative median values of lens doses were estimated at 6.0 Sv for cardiologists and 1.5 Sv for associated medical personnel. A significantly elevated incidence of radiation-associated lens changes in interventional cardiology workers indicates there is an urgent need to educate these professionals in radiation protection to reduce the likelihood of cataract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1667/RR2207.1DOI Listing
October 2010

Risk for radiation-induced cataract for staff in interventional cardiology: is there reason for concern?

Catheter Cardiovasc Interv 2010 Nov;76(6):826-34

Vinca Institute of Nuclear Sciences, Belgrade, Serbia.

Objectives: To examine the prevalence of radiation-associated lens opacities among interventional cardiologists and nurses and correlate with occupational radiation exposure.

Background: Interventional cardiology personnel are exposed to relatively high levels of X-rays and based on recent findings of radiation-associated lens opacities in other cohorts, they may be at risk for cataract without use of ocular radiation protection.

Methods: Eyes of interventional cardiologists, nurses, and age- and sex-matched unexposed controls were screened by dilated slit lamp examination and posterior lens changes graded using a modified Merriam-Focht technique. Individual cumulative lens X-ray exposure was calculated from responses to a questionnaire and personal interview.

Results: The prevalence of radiation-associated posterior lens opacities was 52% (29/56, 95% CI: 35-73) for interventional cardiologists, 45% (5/11, 95% CI: 15-100) for nurses, and 9% (2/22, 95% CI: 1-33) for controls. Relative risks of lens opacity was 5.7 (95% CI: 1.5-22) for interventional cardiologists and 5.0 (95% CI: 1.2-21) for nurses. Estimated cumulative ocular doses ranged from 0.01 to 43 Gy with mean and median values of 3.4 and 1.0 Gy, respectively. A strong dose-response relationship was found between occupational exposure and the prevalence of radiation-associated posterior lens changes.

Conclusions: These findings demonstrate a dose dependent increased risk of posterior lens opacities for interventional cardiologists and nurses when radiation protection tools are not used. While study of a larger cohort is needed to confirm these findings, the results suggest ocular radio-protection should be utilized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccd.22670DOI Listing
November 2010

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract.

Proc Natl Acad Sci U S A 2008 Oct 23;105(43):16620-5. Epub 2008 Oct 23.

Department of Chemical Biology, Susan Lehman-Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.

Cell-cell interactions organize lens fiber cells into highly ordered structures to maintain transparency. However, signals regulating such interactions have not been well characterized. We report here that ephrin-A5, a ligand of the Eph receptor tyrosine kinases, plays a key role in lens fiber cell shape and cell-cell interactions. Lens fiber cells in mice lacking ephrin-A5 function appear rounded and irregular in cross-section, in contrast to their normal hexagonal appearance in WT lenses. Cataracts eventually develop in 87% of ephrin-A5 KO mice. We further demonstrate that ephrin-A5 interacts with the EphA2 receptor to regulate the adherens junction complex by enhancing recruitment of beta-catenin to N-cadherin. These results indicate that the Eph receptors and their ligands are critical regulators of lens development and maintenance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0808987105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2575469PMC
October 2008

Mrad9 and atm haploinsufficiency enhance spontaneous and X-ray-induced cataractogenesis in mice.

Radiat Res 2007 Nov;168(5):567-73

Center for Radiological Research, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

Rad9 and Atm regulate multiple cellular responses to DNA damage, including cell cycle checkpoints, DNA repair and apoptosis. However, the impact of dual heterozygosity for Atm and Rad9 is unknown. Using 50 cGy of X rays as an environmental insult and cataractogenesis as an end point, this study examined the effect of heterozygosity for one or both genes in mice. Posterior subcapsular cataracts, characteristic of radiation exposure, developed earlier in X-irradiated double heterozygotes than in single heterozygotes, which were more prone to cataractogenesis than wild-type controls. Cataract onset time and progression in single or double heterozygotes were accelerated even in unirradiated eyes. These findings indicate that the cataractogenic effect of combined heterozygosity is greater than for each gene alone and are the first to demonstrate the impact of multiple haploinsufficiency on radiation effects in an intact mammal. These observations may help explain observed interindividual differential radiosensitivity in human populations and have important implications for those undergoing radiotherapy or exposed to elevated levels of cosmic radiation, such as the astronaut corps. These findings demonstrate that Mrad9 and Atm are important determinants of lens opacification and, given the roles of Atm and Rad9 in maintaining genomic stability, are consistent with a genotoxic basis for radiation cataractogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1667/rr1122.1DOI Listing
November 2007

Characteristics of tertiary butyl hydroperoxide and hydrogen peroxide conditioned cells withdrawn from peroxide stress.

Exp Eye Res 2004 May;78(5):1037-9

This laboratory has recently reported the preparation of immortal lens epithelial cell lines conditioned to survive in concentrations of peroxide sufficient to cause cataract with in vitro lens culture conditions. The cell conditioning process takes many months during which time the peroxide concentration is gradually increased. It was found that while the acquired resistance to H2O2 was permanent, if tertiary butyl hydroperoxide (TBOOH) was used the resistance was lost within 6-8 weeks of the withdrawal of the peroxide. We now report that resistance is lost within a few days but can be regained within 48 hr. Furthermore, cells resistant to H2O2 while vulnerable to TBOOH could also be rapidly conditioned to tolerate TBOOH in a manner similar to the reconditioning of cells that had lost their TBOOH resistance. The results suggest that a history of exposure to certain oxidative stresses produces a change in cell biology which allows the cell to rapidly respond to the same or other stresses and survive.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exer.2004.01.007DOI Listing
May 2004

The effect of stress withdrawal on gene expression and certain biochemical and cell biological properties of peroxide-conditioned cell lines.

FASEB J 2004 Mar;18(3):480-8

Department of Ophthalmology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.

Maturity onset cataract is a disease that afflicts >25% of the U.S. population over 65. Oxidative stress is believed to be a major factor in the development of this disease and peroxides are suspected to be prominent stressing agents. To elucidate mechanisms involved in the protection of cells against oxidative stress, immortal murine lens epithelial cells (alphaTN4-1) have been conditioned to survive lethal concentrations of either tertiary butyl hydroperoxide, TBOOH (a lipid peroxide prototype) (T cells), or H2O2 (H cells). It was found that T cells survived exposure to H2O2 but H cells were killed by TBOOH. In this communication, biological characteristics of the T cells are reported. It is shown that the T cell's ability to survive TBOOH is lost if the cells are grown in the absence of this peroxide (denoted as T- cells). By comparing the differential gene expression of 12,422 genes and ESTs from T and T- and the unconditioned control cells, 16 genes were found that may account for the loss of resistance to TBOOH. They include 5 glutathione-S-transferases, superoxide dismutase 1, zeta crystallin, a NADPH quinone reductase, as well as genes involved in detoxifying aldehydes, controlling iron metabolism, and degrading toxic lipoproteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.03-0732comDOI Listing
March 2004

Peroxide toxicity in conditioned lens epithelial cells--evaluation of multi-defense systems.

Exp Eye Res 2003 Dec;77(6):711-20

Department of Ophthalmology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.

Immortal murine lens epithelial cells which were conditioned to survive peroxide stress were found to have a remarkable increase in catalase activity as well as lesser changes in a number of other antioxidative defense systems [Invest. Ophthalmol. Vis. Sci. 43 (2002) 3251]. Furthermore, the gene expression of hundreds of other genes was altered. In order to determine the relative importance of catalase, other enzyme systems which maintain the reducing environment of the cell and the involvement of Fenton chemistry, an analysis of the effect of inhibiting catalase, disruption of the cells' reducing environment by inhibition of GSSG reductase (GR) and chelation of metal ion was investigated. It was found that inhibition of catalase caused peroxide resistant cells to die within 48-72 hr when exposed to normally tolerated concentrations of peroxide. If 1,10-phenanthroline (OP), an effective metal ion chelator was present, the cells were not affected by catalase inhibition and survived peroxide stress. Peroxide vulnerable unconditioned control cells were similarly protected by the chelator. The results demonstrate that H2O2 itself has minimal toxicity and that it is the products resulting from interaction with metal ion that produces lethal toxicity. In stark contrast, however, metal chelation did not protect the cells when GR was inhibited by BCNU. Examination of non-protein thiol (NP-SH), which is primarily GSH, indicated that rapid and extensive oxidation occurred almost immediately after exposure to peroxide under all conditions. However, NP-SH returns to the normal range in the conditioned cells even though later cell death is observed in some cases, suggesting fatal damage during the period when the cell is exposed to an oxidizing environment. Examination of DNA damage by alkaline elution indicated that H2O2 caused little observed strand breakage in peroxide resistant cells even if catalase is inhibited, suggesting that such cells have developed other systems to protect DNA and that H2O2 induced death is probably not related to DNA single strand breaks. In contrast, unconditioned cells (C cells) show extensive H2O2 induced DNA damage which is prevented by OP. Thus, depending on the conditions, DNA damage may contribute to cell death. The overall results indicate that the conditioned cell lines are not simply dependent on catalase activity but have developed a complex defense which includes GSH dependent systems and possibly more effective regulation of metal ion concentrations to resist oxidative stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exer.2003.08.004DOI Listing
December 2003

The effect of H2O2 and tertiary butyl hydroperoxide upon a murine immortal lens epithelial cell line, alphaTN4-1.

Exp Eye Res 2002 Nov;75(5):573-82

Department of Ophthalmology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.

The effect of comparable concentrations of H(2)O(2) and tertiary butyl hydroperoxide (TBHP) upon an immortal murine lens epithelial cell line was examined as part of an ongoing effort to delineate differences in the mechanism by which these peroxides cause cell death. Both compounds result in cell death of normal, unconditioned cells within 24hr. It was found that with similar conditions, TBHP conditioned alphaTN4-1 cells survive H(2)O(2) stress while H(2)O(2) conditioned cells are killed by TBHP. To better understand how these peroxides act, their effect upon unconditioned cells has been investigated. Both peroxides cause a rapid loss of GSH and disruption of pump activity as illustrated by (14)C-choline transport and (86)Rb uptake. While H(2)O(2) exposure resulted in extensive DNA damage, TBHP had a minimal effect. DNA damage caused by H(2)O(2) was shown to activate polyADP-ribosyl polymerase (PARP), leading to depletion of NAD and ATP. H(2)O(2) induced cell death could be delayed by addition of 3-aminobenzamide (3AB), an inhibitor of PARP. ATP levels in cells subjected to H(2)O(2) were also maintained by the presence of 3AB. H(2)O(2) stress also disrupted glycolysis and mitochondrial activity but these parameters were not affected by TBHP. TBHP induced cell death, under the relatively mild conditions used in this work, appears to be caused by membrane disruption and loss of a reducing environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1006/exer.2002.2045DOI Listing
November 2002
-->