General Toxicology Exam 3

Mechanism of toxicity of metals

Inhibition of critical enzymes

Oxidative damage to DNA

Mimics

Adducts with DNA or protein

Lead

Exposed through paints, food, and water

Lead to vomiting, dizziness, anemia, hypertension

Treated with chelation

Toxicity: bind to -SH groups, inhibit antioxidant enzymes, compete with Ca2+, and increase ROS production

Cadmium

Exposed through food and inhaled through emissions

Lead to vomiting, impairment of vitamin d metabolism, pulmonary edema

Treated with chelation

Toxicity: protein degradation, genotoxicity, protein synthesis inhibition, apoptosis

Mercury

Exposed through diet (fish), occupational, and accidental exposure

Toxicity: bind to sulfhydryl groups, interrupt protein/DNA synthesis, ROS

Lead to bronchitis, proteinuria, vision/hearing loss

Thimerosal

Mercury containing component that presents the growth of dangerous microbes/fungus in multi-dose vials of vaccines

Ethylmercury

.1-.3 ug/kg/day

Broken down and excreted faster

Not linked to neurodevelopmental outcomes

Methylmercury

.02-.2 ug/kg/day

Accumulates in tissue

Causes severe health effects

TRH

TSH

Thyroid

GnRH

LH and FSH

Gonads

CRH

ACTH

Adrenal cortex

GHRH

GH (liver and fat, muscle, bone) →IGF

IGF (fat, muscle, bone)

Pituitary toxicity

Uncompensated hormonal dysregulation leads to increased synthesis of hormones, absence of negative feedback inhibition lead to hyperplasia and neoplasia

Adrenal gland

Consists of cortex and medulla

Adrenal cortex

Secretes corticosteroids (hormones made in the cortex)

Toxicity: Inhibition of cholesterol synthesis, activation of CYP P450 (increase ROS), inhibition of hormone synthesis (atrophy), inhibition of secretion of hormones

Adrenal medulla

Tumors caused by nicotine, beta blockers, antihypertensive, etc

Thyroid hormone

Thyroglobulin and I- are transported out of cell and oxidized to couple Thyroglobulin to MIT and DIT which converts to T3 and T4 through thyroid peroxide, then processed through endocytosis back to the cell and degraded to release T4, T3, MIT, and DIT. T3 and T4 are released into circulation and I is salvaged from MIT and DIT

Thyroid toxicity

Interference of hormone synthesis leads to increased secretion of TSH and leads to proliferation of follicular cells (hypertrophy, hyperplasia, neoplasia), inhibition of hormone release, increased hormone biotransformation/excretion (decrease in T4 and T3)

Feedback loops

Negative feedback loops have an inhibitory effect and positive feedback loops have a stimulatory effect

C cells

Secrete calcitonin (CT, increase calcium deposition and decrease osteoclasts)

Parathyroid gland

Release parathyroid hormone (PTH, regulates blood Ca2+)

Ozone leads to hypertrophy and hyperplasia

Aluminum leads to inhibition of PTH secretion

Male hypothalamus-pituitary-gonadal

GnRH (anterior pituitary) → FSH → ABP (spermatogenesis) → Cells

GnRH (anterior pituitary) → LH → testosterone or other tissues → cells

Female hypothalamus-pituitary-gonadal

GnRH (anterior pituitary) → FSH and LH (ovary) → Estradiol and progesterone (secondary sex organs and libido)

HPC

Altered by PCB, heavy metals, etc

Ovarian toxicity

From sex cords and/or stroma

Result from overstimulation from decrease in estrogen that causes an increase in GnRH, FSH, and LSH