Tab. 3. Molecular Initiating Events and related key events of DNT AOP.
A literature review for the first five established human DNToxicants Lead (L), Methymercury (M), PCB (P), Arsenic (A), and Toluene (T)
| Molecular Initiating Event/Key events |
Cell Adverse Outcomes |
In vivo Correlate | Human (Histo-) Pathology |
|
|---|---|---|---|---|
| Oxidative stress (clear evidence for L, M, P, A) | Inhibition delta-aminolevulinic acid dehydratase: L (1) | Oxidative stress, ROS formation, lipid peroxidation of membrane (defense AP-1, NFkB): L (1,2,5,6), M (14) | Oxidative stress, brain damage, and impaired antioxidative defense (reduced GSH, induced defense AP-1, NFkB): L (1,2,5), M (14,15), P (17), A (18) | M is GSH-bound in erythrocytes, A leading to urinary 8 OHdG and plasma lipid peroxidation (21) |
| Inhibition of SOD, catalase, GSH peroxidase, GSH (via SH-binding) and Ca replacement at EF motifs and C2 domains): L (2,6), M (11,13), P (17), A (18) | ||||
| Mitochondrial accumulation and dysfunction: L (6), M (11,13) | ||||
| Membrane effects (likely secondary to oxidative stress) | Interaction with neg-charged membrane phospholipids: L (1) | Changed membrane biophysics (leading to iron-mediated lipid peroxidation): L (1) | Changed myelin membrane fluidity: L (1) | Membrane rigidity (erythrocytes): L (1) |
| Ca disturbance and replacement (clear evidence for L, M, P) | Electronegativity, binding to Sulfur and Oxygen (substituting for calcium and zinc): L (1,4), M (6,14,15) | Changed calcium fluxes (also leading to ROS from mitochondria), stimulation calmodulin and cAMP phosphodiesterase: L (1), M (13), P (17) | ||
| Interaction with glutamate (synergy on PKC): L (1,3), M (13), P (17) | ||||
| Inhibition of Ca-ATPase: L (6) | ||||
| Impaired Ca channels: M (11), P (17) | ||||
| Impaired neuro-transmission (clear evidence for L, M, P, T) | Competition with Ca at NMDAR and nNOS inhibition: L (1,2), P (17) | Reduced nNOS: L (1), increased NOS: M (13) | Reduced nNOS: L (1,2), increased NO (13) | |
| Impaired neuro-transmission (clear evidence for L, M, P, T) | Interaction with glutamate (excito-toxicity, inhibition of uptake): L (1,3), M (13), T (24) Inhibition of neuro-transmitter receptors (a-disintegrin and metalloprotease inhibition in membrane): M (11), T (24) |
Excitotoxicity: M (13) | Increased glutamatelevels: M (13) | |
| Competition with Ca at NMDAR and disturbed Ca transport as well as direct calcineurin and calmodulin stimulation: L (1,2,4,6) | Disturbed neuro-transmission (dopaminergic, cholinergic, glutaminergic): L (1,2,4), M (16), P (17), T (24) | Disturbed neuro-transmission (dopaminergic, cholinergic, glutaminergic): L (1,2,4), M (13,16), P (17), T (24) | ||
| Inhibition of voltage-dependent Ca channels: L (4,6) | ||||
| Impaired energy metabolism (clear evidence for L, M, P, A) | Interference with PKC phosphorylation: L (2,8), M (16) | Reduced cell proliferation: L (8), M (3,12,16), A (21) | ||
| Increased transendothelial permeability: L (2) | Edema, brain damage: L (2) | |||
| Neurite outgrowth impaired: M (3,16), A (19), T (24) | Altered neurogenesis and migration: T (24) | |||
| Impaired cytoskeleton: M (3,16), A (18,21) | ||||
| Accumulation in mitochondria (pore opening, depolarization, CytC and Ca release): L (6,8), M (13,14), A (21) | Impaired energy metabolism: L (6), M (3) | |||
| Apoptosis: L (3,8), M (3,11,14,16), P (17), A (21), T (22) | Apoptosis: M (14), T (22) | |||
| Reduced cell proliferation: M (3,16) | ||||
| Excitotoxicity by glutamate: L (8) | ||||
| Glia disturbance (Clear evidence for L, M, T) | Decrease in CNPase activity: L (8) | Oligodendrocyte toxicity and delayed development: L (8), M (12) | Hypomyelination: L (8) | |
| Astrocytic accumulation: L (8), M (15) | Astrocyte toxicity: L (8), T (23) | Loss of astrocytes: M (14), T (23) |
AOP span from exposure, chemico-physical properties to the initiating and adverse events depicted here and further to clinics and population effects. For the latter there is evidence for all substances: M (14,15), P (17), A (18) P (17), A (18), T (24).
Sources (mainly recent review articles):
1
Verstraeten, 2008
18
21