Lead and Mechanisms

Exposure to lead can lead to:

  • damage to the brain and nervous system development

  • slowed growth development

  • motor development deficits

  • learning and behavioral issues

  • hearing and speech deficits

Sources of Lead:

  • mining

  • manufacturing of ceramics and glassware

Timing of Critical: effects of lead on development may differ depending on time, length of exposure, and source of exposure

Adverse health effects of Pb in children at leass than 5 µg/dL of blood lead levels can include developmental delays, lower IQ, and increased behavioral problems.

Effects differ between children and adults, with childrenf acing the most severe developmental effects

Lead during preganancy will enter through the blood in the mother, through the placenta and eventually reach the BBB

Lead is a substitute for calcium and zinc, and mimics Ca2+ binding sites and is an NMDA antagonist. Lack of Ca2+ signaling, triggers cytochrome C release and leads to apoptosis

Motor Development:

  • delayed motor milestones, both infant and toddler fine or gross motor coordination deficits

Verbal Communication:

  • Hearing deficits - auditory processing in time and space

  • Poor speech aritculation

  • delayed language

  • Poor language understanding or usage

Learning in School and at Home:

  • Difficulty with learning and remembering new information

  • Difficulty with reading, language, math and writing

  • difficulty maintaing attention

  • Hyperactivity, ADHD, solving abillities

Social Interactions:

  • Anti-social, deliquent

  • difficulty controlling behavior; aggressive and impulsive

Blood Brain Barrier: formed by endothelial cells lining the cerebral microvasculature. The BBB limits the passage of pathogens or toxins capable of disturbing neural function

Lead effects on the BBB:

  • Lead increases the permeability of the BBB by disrupting protein kinase C (PKC) which regulated tight junctions (TJ). Lack of PKC will lead to leaky TJ, allowing diffusion of water in the CNS

  • Water in CNS leads to Edema and Encaphalopathy

  • Neuronal injury due to Pb activates microglia and causes oxidative stress

  • PB also affects calcium release, leading to signaling dysfuntions

Astrocytes and the BBB

  • Astrocytes support the integrity of the BBB and neurons in the brain.

  • Astrocytes are targeted bu Pb

  • They function as mini kidneys of the CNS, regulating the composition of interstitial fluid

  • Astrocytes take in lead quicker than neurons, but neurons are more sensitive to the lead

Pb Pathway of Destruction:

Microglia: targets inflammatory cytokineswhich then lowers TJ function and increases ROS leading yo BBB dysfucntion, neuron damage and LTP inhibition

Astrocyte: targts different cytokines, and follows a similar path as microglia dysfunctions

Neurons: increases cellular calcium and leads to signaling dysfunction , leading to LTP inhibition and neuron damage

Caspases

Initiator Caspases

8, 9, 10

Effector Caspases

1,2,3,4,5,6,7,11,12,13

  • Caspase 3

    • Morphological changes

    • nucleosomal DNA fragmentation

    • Breakdown of nuclear envelope

    • formation of apoptotic bodies

Neurotoxic Effects of Pb

  • Apoptosis: mostly observed at the cerebrum, thalamus, caudate/putamen, dentate gyrus

  • Excitoxicity: abnormal mitochondrial dysfucntion, glutamate induced apoptosis

  • Synapse Formation and Function

  • Protein Formation and Function

  • Glial Effects

Oxidative Stress

  • Proteins: protein oxidation altering the function

  • Lipid: lipid peroxidation disrupting the membrane

  • DNA: nucleic oxidation causing cancer/mutations

Dendritic Spines

  • speacialized for synaptic transmission and are the location of receptors

  • Mushrooms have larger PSDs and more receptors, thought to be memory spines

  • lead decreased the # of mushroom spines

  • impaired synaptic plasticity

  • lower expression of NDR kinase, Arc/Arg3.1

  • increased risk of neurodegenerative diseases