title: Perinatal exposure to lead (Pb) induces ultrastructural and molecular alterations in synapses of rat offspring.
abstract: Lead (Pb), environmentally abundant heavy-metal pollutant, is a strong toxicant for the developing central nervous system. Pb intoxication in children, even at low doses, is found to affect learning and memorizing, with devastating effects on cognitive function and intellectual development. However, the precise mechanism by which Pb impairs synaptic plasticity is not fully elucidated. The purpose of this study was to investigate the effect of pre- and neonatal exposure to low dose of Pb (with Pb concentrations in whole blood below 10μg/dL) on the synaptic structure and the pre- and postsynaptic proteins expression in the developing rat brain. Furthermore, the level of brain-derived neurotrophic factor (BDNF) was analyzed. Pregnant female Wistar rats received 0.1% lead acetate (PbAc) in drinking water from the first day of gestation until weaning of the offspring, while the control animals received drinking water. During the feeding of pups, mothers from the Pb-group were continuously receiving PbAc. Pups of both groups were weaned at postnatal day 21 and then until postnatal day 28 received only drinking water. 28-day old pups were sacrificed and the ultrastructural changes as well as expression of presynaptic (VAMP1/2, synaptophysin, synaptotagmin-1, SNAP25, syntaxin-1) and postsynaptic (PSD-95) proteins were analyzed in: forebrain cortex, cerebellum and hippocampus. Our data revealed that pre- and neonatal exposure to low dose of Pb promotes pathological changes in synapses, including nerve endings swelling, blurred and thickened synaptic cleft structure as well as enhanced density of synaptic vesicles in the presynaptic area. Moreover, synaptic mitochondria were elongated, swollen or shrunken in Pb-treated animals. These structural abnormalities were accompanied by decrease in the level of key synaptic proteins: synaptotagmin-1 in cerebellum, SNAP25 in hippocampus and syntaxin-1 in cerebellum and hippocampus. In turn, increased level of synaptophysin was noticed in the cerebellum, while the expression of postsynaptic PSD-95 was significantly decreased in forebrain cortex and cerebellum, and raised in hippocampus. Additionally, we observed the lower level of BDNF in all brain structures in comparison to control animals. In conclusion, perinatal exposure to low doses of Pb caused pathological changes in nerve endings associated with the alterations in the level of key synaptic proteins. All these changes can lead to synaptic dysfunction, expressed by the impairment of the secretory mechanism and thereby to the abnormalities in neurotransmission as well as to the neuronal dysfunction.
authors.affiliation: Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland. Electronic address: magy80@gmail.com.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gąssowska
authors.affiliation: Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland. Electronic address: ika@pum.edu.pl.
authors.forename: Irena
authors.initials: I
authors.lastname: Baranowska-Bosiacka
authors.affiliation: Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Moczydłowska
authors.affiliation: Electron Microscopy Platform, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Frontczak-Baniewicz
authors.affiliation: Electron Microscopy Platform, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gewartowska
authors.affiliation: Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
authors.forename: Lidia
authors.initials: L
authors.lastname: Strużyńska
authors.affiliation: Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24, 71-460 Szczecin, Poland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Gutowska
authors.affiliation: Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Chlubek
authors.affiliation: Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland. Electronic address: agataadamczyk72@gmail.com.
authors.forename: Agata
authors.initials: A
authors.lastname: Adamczyk
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000254:growth & development; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D005260:Female; D007774:Lactation; D007854:Lead / Q000378:metabolism / Q000633:toxicity*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009942:Organometallic Compounds / Q000633:toxicity; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure*; D013572:Synaptic Vesicles / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D009942:Organometallic Compounds; D007854:Lead; C008261:lead acetate
keywords: Lead (Pb) neurotoxicity; Synaptic dysfunction; Synaptic proteins; Synaptic ultrastructure