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Perinatal exposure to lead (Pb) induces ultrastructural and molecular alterations in synapses of rat offspring
Magdalena Gąssowska1, Irena Baranowska-Bosiacka2, Joanna Moczydłowska1
1Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
Insights
Perinatal exposure to low-dose lead (Pb) causes synaptic damage and alters key synaptic proteins in developing rat brains, potentially impairing neurotransmission and cognitive function. This study reveals structural abnormalities and changes in protein expression linked to neurodevelopmental toxicity.
Area of Science:
- Neuroscience
- Toxicology
- Developmental Biology
Background:
- Lead (Pb) is a neurotoxicant affecting the developing central nervous system, impacting cognitive functions even at low doses.
- The precise mechanisms by which Pb impairs synaptic plasticity remain incompletely understood.
- Understanding Pb's effects on synaptic structure and protein expression is crucial for addressing neurodevelopmental toxicity.
Purpose of the Study:
- To investigate the impact of pre- and neonatal low-dose lead exposure on synaptic structure and protein expression in the developing rat brain.
- To analyze the levels of brain-derived neurotrophic factor (BDNF) following perinatal lead exposure.
- To elucidate the molecular mechanisms underlying lead-induced neurotoxicity in developing synapses.
Main Methods:
- Pregnant Wistar rats received lead acetate (PbAc) from gestation through weaning; offspring were analyzed at postnatal day 28.
- Ultrastructural analysis of synapses was performed in the forebrain cortex, cerebellum, and hippocampus.
- Expression levels of key presynaptic (VAMP1/2, synaptophysin, synaptotagmin-1, SNAP25, syntaxin-1) and postsynaptic (PSD-95) proteins, along with BDNF, were quantified.
Main Results:
- Low-dose lead exposure induced pathological synaptic changes, including nerve ending swelling, blurred synaptic clefts, and altered synaptic vesicle density.
- Synaptic mitochondria showed abnormalities (elongated, swollen, or shrunken) in lead-exposed rats.
- Lead exposure decreased levels of synaptotagmin-1, SNAP25, and syntaxin-1, while increasing synaptophysin; PSD-95 expression varied across brain regions, and BDNF levels were reduced globally.
Conclusions:
- Perinatal exposure to low-dose lead induces significant pathological changes in synaptic structure and alters the expression of critical synaptic proteins.
- These alterations can lead to synaptic dysfunction, impaired neurotransmission, and neuronal dysfunction.
- The findings highlight the detrimental effects of early-life lead exposure on neurodevelopment and synaptic integrity.
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.
