title: Exposure to As, Cd and Pb-mixture impairs myelin and axon development in rat brain, optic nerve and retina.
abstract: Arsenic (As), lead (Pb) and cadmium (Cd) are the major metal contaminants of ground water in India. We have reported the toxic effect of their mixture (metal mixture, MM), at human relevant doses, on developing rat astrocytes. Astrocyte damage has been shown to be associated with myelin disintegration in CNS. We, therefore, hypothesized that the MM would perturb myelinating white matter in cerebral cortex, optic nerve (O.N.) and retina. We observed modulation in the levels of myelin and axon proteins, such as myelin basic protein (MBP), proteolipid protein, 2'-, 3'-cyclic-nucleotide-3'-phosphodiesterase, myelin-associated glycoprotein and neurofilament (NF) in the brain of developing rats. Dose and time-dependent synergistic toxic effect was noted. The MBP- and NF-immunolabeling, as well as luxol-fast blue (LFB) staining demonstrated a reduction in the area of intact myelin-fiber, and an increase in vacuolated axons, especially in the corpus-callosum. Transmission electron microscopy (TEM) of O.N. revealed a reduction in myelin thickness and axon-density. The immunolabeling with MBP, NF, and LFB staining in O.N. supported the TEM data. The hematoxylin and eosin staining of retina displayed a decrease in the thickness of nerve-fiber, plexiform-layer, and retinal ganglion cell (RGC) count. Investigating the mechanism revealed a loss in glutamine synthetase activity in the cerebral cortex and O.N., and a fall in the brain derived neurotrophic factor in retina. An enhanced apoptosis in MBP, NF and Brn3b-containing cells justified the diminution in myelinating axons in CNS. Our findings for the first time indicate white matter damage by MM, which may have significance in neurodevelopmental-pediatrics, neurotoxicology and retinal-cell biology.
authors.affiliation: Academy of Scientific and Innovative Research, India; Developmental Toxicology, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), India.
authors.forename: Nagendra Kumar
authors.initials: NK
authors.lastname: Rai
authors.forename: Anushruti
authors.initials: A
authors.lastname: Ashok
authors.forename: Asit
authors.initials: A
authors.lastname: Rai
authors.forename: Sachin
authors.initials: S
authors.lastname: Tripathi
authors.forename: Geet Kumar
authors.initials: GK
authors.lastname: Nagar
authors.forename: Kalyan
authors.initials: K
authors.lastname: Mitra
authors.forename: Sanghamitra
authors.initials: S
authors.lastname: Bandyopadhyay
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001151:Arsenic / Q000633:toxicity*; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000473:pathology*; D002104:Cadmium / Q000633:toxicity*; D005260:Female; D007854:Lead / Q000633:toxicity*; D009186:Myelin Sheath / Q000187:drug effects* / Q000473:pathology; D009900:Optic Nerve / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D012160:Retina / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology
chemical_list: D002104:Cadmium; D007854:Lead; D001151:Arsenic
keywords: Brn3b; CNS-disruption; Demyelination; MBP; Metal mixture; NF