Toxicology of Metals

Cr, Ni, As, Cd, Hg, Pb

what are examples of some major environmental or occupational hazards

Be, Al, Mn, Zn

what are examples of some minor environmental or occupational hazards

electrophiles

generally, metals behave like what

no

are elements created or destroyed by biology

essential metals

Many toxic metals mimic these _____ for bioaccumulation

thiols

Direct coordinate/covalent interaction with critical protein targets, especially what

endogenous

Metal conjugates mimic _____ molecules

2-11 mg/day

what is daily adequate Manganese intake

0.3 to 2.9 ug/gram

Manganese is present in body tissues at what weight

cofactor

Manganese acts as a _______ in metalloproteins

yes

can too much Mn be toxic

not just by enzyme overload, but by damaging mitochondria, increasing oxidative stress, disrupting brain signaling, and causing inflammation

how do high Mn levels negatively affect an organism

optimum

for Mn, going even slightly above the _____ level can result in neurotoxicity by disrupting normal Mn-dependent proteins

CSF

when looking at plasma vs CSF (both exposed to Mn), which one retains it for longer

metal

high Mn levels disrupts what type of homeostasis

overloads transport systems, competes w/other essential metals (like iron), disrupts enzyme‑metal balance, provokes oxidative and organelle stress, and alters distribution of metals across tissues and cellular compartments, disrupting balance of multiple metals and harming cellular and neural health

how does excess Mn disrupt metal homeostasis

Mn blocks calcium entry into mitochondria, reducing ATP-induced Ca²⁺ influx → less mitochondrial activation, lower ATP production, impaired energy metabolism

How does Mn impair ATP-induced calcium currents in mitochondria?

Leads to reduced energy production and increased oxidative stress → neurotoxicity

Why is disruption of mitochondrial calcium by Mn important for neurons?

Dopaminergic neurons in the basal ganglia (striatum and globus pallidus)

Which type of neurons are most vulnerable in both Mn toxicity and Parkinson’s Disease?

By causing parkinsonian-like movement disorders (tremor, rigidity, bradykinesia) through overlapping mechanisms with PD

How does Mn exposure mimic Parkinson’s Disease symptoms?

Mn alters the phosphorylation and activity of IGF receptors and mTOR, disrupting downstream signaling (protein synthesis, autophagy, and cell survival) even at concentrations too low to cause mitochondrial dysfunction, priming cells for early stress.

Mechanistically, how does Manganese affect IGF/mTOR signaling?

pS6 signaling returns to homeostatic levels despite high cellular Mn. This adaptation suggests genetic or cellular changes enable homeostasis, but these changes may carry long-term toxic or health risks.

What happens to pS6/mTOR signaling during prolonged Mn exposure, and why is this significant?

Exposure duration (e.g., 6 hours vs 40 days), more than exposure level.

In PCA analysis of Mn exposure, what accounts for the majority of gene expression variance?

>50% of variance for certain genes

What percentage of variance is attributed to exposure duration for some genes in the study?

The length of exposure has a stronger influence on cellular gene expression, suggesting chronic vs. acute exposure may trigger different biological responses.

What is the implication of duration-dependent gene expression changes in Mn exposure?

minimal overlap; acute and chronic exposures trigger largely distinct sets of genes.

How do DEGs differ between acute and chronic Mn exposure?

Ingenuity Pathway Analysis shows minimal overlap; different biological pathways are affected depending on exposure duration.

How do pathways differ between acute and chronic Mn exposure?

Short-term studies cannot fully predict long-term effects; cellular responses differ depending on exposure duration.

What is the main implication of minimal DEG and pathway overlap between acute and chronic Mn exposure?

There is high overlap of DEGs across different chronic Mn concentrations.

In chronic 40-day Mn exposures, how do DEGs compare across different Mn concentrations (50 nM – 50 μM)?

Chronic exposure triggers similar gene expression changes regardless of the exact Mn concentration.

What does the high overlap of DEGs in chronic Mn exposure suggest?

Top IPA-detected pathways are largely shared across these concentrations, indicating consistent biological responses.

How do pathways compare across 40-day Mn exposures of 50 nM – 50 μM?

Minimata and Iraq

what are 2 Mercury poisoning events

Mercury

probably the most important metal public health hazard (due to its persistant enivronmental contaminance), principally exposured through diet (fish)

~2/3

What proportion of global mercury is anthropogenic (coming from human activity)?

Environmental cycling, biomethylation (to MeHg⁺), and redox reactions.

What environmental processes make mercury hazardous?

Methylmercury (MeHg⁺).

What is the major toxic form of mercury (toxicant)?

inhalation

How is mercury vapor best absorbed in the body?

poorly

How well are inorganic mercurials absorbed in the gastrointestinal (GI) tract?

well

How well is methylmercury (MeHg⁺) absorbed in the GI tract?

erythrocytes

How is mercury distributed in the blood?

Relatively efficient (~10%)

How efficiently does mercury distribute to the central nervous system (CNS)?

Cysteine conjugates

What helps methylmercury cross into the CNS and enter cells?

Methylmercury forms conjugates with cysteine that structurally resemble L-methionine.

What is the molecular mimicry mechanism of methylmercury in the body?

transported by the L-system neutral amino acid transporter (LAT1), which normally transports L-methionine.

How does the methylmercury-cysteine conjugate enter cells?

MeHg–cysteine conjugate mimics L-methionine; it uses LAT1 transporters to enter the CNS.

Why is methylmercury able to cross the blood-brain barrier efficiently?

chronic

What is the main toxicity of inorganic mercury vapor?

renal, ranging from immunologic glomerulonephritis to progressive nephropathy

What is the primary toxicity of inorganic mercury salts?

Paresthesia (tingling/pricking sensations) and ataxia (uncoordinated movement)

What are the main neurological symptoms of methylmercury toxicity?

Focal necrosis of neurons, leading to cerebral edema and brain atrophy

What histopathological changes occur in the brain with methylmercury toxicity?

methylmercury crosses the placenta, causing severe developmental neurotoxicity, as seen in Minamata, Japan

Why is the developing fetus highly susceptible to methylmercury?

Persistent effects can be observed for 50+ years, often with a delayed onset after exposure

How long can the effects of methylmercury exposure persist, and what is notable about their onset?

Faroe Islands study.

Which long-term study reported that low-dose prenatal MeHg exposure was associated with neurobehavioral deficits in children?

Attention, fine-motor function, confrontational naming, visual-spatial abilities, and verbal memory.

What neurobehavioral domains were affected in the Faroe Islands study?

It did not report significant associations between prenatal MeHg exposure and neurobehavioral deficits.

What did the Seychelles study find regarding low-dose prenatal MeHg exposure?

Both observed associations between prenatal MeHg exposure and developmental/neurobehavioral effects, despite smaller sample sizes

What did the New Zealand and Seychelles pilot studies observe?

Some studies show measurable developmental impacts, especially in attention and motor/visual-verbal skills, while others do not, indicating variability in susceptibility or study design.

What is the overall takeaway from these studies on low-dose prenatal MeHg exposure?

form strong coordinate bonds with thiol groups, leading to protein modifications.

How do Hg²⁺ and CH₃Hg⁺ interact with proteins in acute mercury toxicity?

it’s depleted, which contributes to oxidative stress

What happens to glutathione (GSH) during acute mercury exposure?

MAPK (Mitogen-Activated Protein Kinase) pathway.

Which stress signaling pathway is activated by acute mercury toxicity?

Cytoskeleton disruption, mitochondrial damage, and perturbed Ca²⁺ homeostasis.

Name some cellular structures or functions disrupted by acute mercury toxicity.

chelation approaches

How do we treat acute Hg poisoning?

Administration of –SH (thiol)-containing drugs

What is the systemic chelation approach for acute mercury poisoning?

Introduction of thiolated resins to the GI tract.

Specific for MeHg treatment

What is the enteric chelation approach?

similar to dialysis

What is the extracorporeal approach

Alters energy supply, neuronal activity, and pathways related to structure

What are the main effects of developmental methylmercury (MeHg) exposure?

T

T or F: effects persistent over time long after toxicant is no longer present

Pathways related to cellular function, aging, and energy metabolism.

Which pathways are persistently altered by developmental MeHg exposure?