toxicology c3.3 reprod and nephron

explain the HPG axis

• hypothalamus-pituitary-gonadal axis

• Hypothalamus → releases GnRH

• Pituitary gland → releases LH & FSH

• Gonads (testes/ovaries) → produce sex hormones & gametes (sperm/ova)

causes:

• opiate drugs (morphine, heroin, codeine) suppress hypothalamus

• toluene and organochlorines (DDT) suppress hypothalamus

explain male reproductive system toxicity

Structure	Function	Toxicity Effect
Leydig cells	Make testosterone	↓ testosterone → infertility, low libido
Sertoli cells	Support and nourish sperm development	Abnormal sperm, ↓ sperm count
Germ cells	Make sperm via spermatogenesis—>spermatozoa	Easily damaged → reduced sperm formation

Why germ cells are VERY sensitive to toxicants?

Because:

• They divide rapidly

• They have high metabolic activity

• They undergo many DNA replication cycles

how lead affect MRS

1. Vascular disruption in testes

   • Lead interferes with the blood vessels in the testes.

   • Seminiferous tubules (where sperm is made) are damaged due to poor blood supply.

2. HPG axis interference

3. Direct effects on sperm

   • ↓ sperm count

   • ↑ malformed sperm

   • reduced fertility

how cadmium affect MRS

• Testicular vascular system damage

  • Reduces blood flow → hypoxia → tissue damage

• Cellular damage

  • Sertoli cells die → cannot support germ cells

  • Germ cells damaged → poor spermatogenesis

  • Testicular tissue necrosis

how Plasticizers like Phthalates (diethylhexyl phthalate aka DEHP) affect MRS

• if exposed during pregnancy, it affects testosterone production in fetal testes

• if exposed in adult, it damages sperm DNA → reduced fertility

• HPG axis disruption, ↓ testosterone and estrogens

describe the cell types in FRS and the effect of toxicants towards those cells

1. thecal cells (=leydig cell)

• LH stimulates thecal cells to make androgens → granulosa cells converts androgen to estrogen

• effect of toxicants: Inhibit androgen production → ↓ estrogen → menstrual problem, poor follicle maturation

2. granulosa cell (=sertoli cell)

• Convert androgens from thecal cells into estrogen

3. germ cells

• Induce formation of the ovary and eventually become oocytes (eggs) via mitotic division

list out the toxicants that affect FRS

1. smoking (nicotine/heavy metals/carbon monoxide/Benzo[a]pyrene

2. diethylstilbestrol (DES)

3. pesticides (organochlorine like DDT aka Dichlorodiphenyltrichloroethane)

4. bisphenol A

how smoking affect FRS

• Premature menopause → accelerated depletion of oocytes.

• Reduced fertility → disrupted ovulation, oocyte maturation, implantation

• Chromosomal abnormalities in oocytes → lower conception rates.

• Effects on offspring → compromised fertility

how DES affect FRS

• DES is a Synthetic estrogen, formerly given to prevent miscarriage.

• in DES daughters:

  • Cervicovaginal cancer

  • Uterine malformations

  • ectopic pregnancy

  • Breast cancer

  • Premature menopause & decreased fertility

• in DES granddaughters as well

how OC pesticides affect FRS

disrupts estrogen signaling → endocrine disruption.

breast cancer/lactation problem/menstruation problem/early pregnancy loss/preterm birth

how BPA affect FRS

mimics estrogen → binds to estrogen receptors.

• Accelerated puberty

• Abnormal ovarian follicles

• breast cancer

Why the renal system is mostly targeted by toxicants (4 factors)

Factor	Why Kidney is Vulnerable	Result
High renal blood flow	Kidney receive 25% cardiac output	High delivery of toxicants to renal cortex
[toxicants] in intraluminal fluid	Water reabsorption by nephrons concentrates toxicants [toxicant]=2000 mM in collecting duct	Tubular injury, crystal precipitation, obstruction
Active tubular transport	Proximal tubules actively reabsorb and secrete chemicals. Active transport causes toxicant accumulate inside cells	Proximal tubular cell damage
Renal bioactivation	CYP enzymes bioactivate protoxicants into reactive metabolites	intrarenal injury (oxidative stress, necrosis, cellular damage)

list out 5 examples of nephrotoxicants

1. chloroform

2. ethylene glycol

3. cadmium

4. melamine and cyanuric acid

5. paracetamol aka acetaminophen

explain the toxicity mechanism of chloroform

1. In proximal tubule, chloroform is bioactivated by CYP450 enzymes.

2. This metabolism produces phosgene, a highly reactive toxic metabolite.

3. Phosgene reacts with glutathione (GSH) and cysteine for detoxification.

4. When phosgene too much, it binds to cellular proteins, causing:

   • Cellular injury

   • Proximal tubular necrosis

explain the toxicity mechanism of ethylene glycol

1. Ethylene glycol metabolized into oxalic acid.

2. Oxalic acid causes renal toxicity by:

   • Direct cytotoxicity on renal tubular cells

   • Combine with calcium to form calcium oxalate crystals

3. These crystals:

   • Deposit in renal tubules

   • Lead to nephrolithiasis (renal stones)

explain the toxicity mechanism of cadmium

1. Cd found in fertilizers, pesticides, and environment.

2. In blood, cadmium binds to metallothionein (MT).

3. The Cd–MT complex is filtered and reabsorbed by proximal tubular cells.

4. Inside the cells:

   • The complex accumulates in lysosomes

   • MT is degraded

   • Free Cd is released, which persists in cells

5. causes proximal tubule dysfunction / impaired absorption / proteinuria

explain the toxicity mechanism of melamine and cyanuric acid

• Melamine + cyanuric acid → form insoluble crystals

• Crystals deposit in renal tubules

explain the toxicity mechanism of acetaminophen (paracetamol)

1. A small fraction of acetaminophen is metabolized by CYP enzymes into NAPQI, a toxic intermediate.

2. if NAPQI too much

   • Glutathione (GSH) becomes depleted

   • NAPQI accumulates

3. Excess NAPQI binds to proteins in the S3 segment of the proximal tubule.

4. NAPQI causes:

   • Oxidative stress

   • Lipid peroxidation (↑ MDA)

   • Renal tubular cell death

5. Cell death—>inflammation—>renal impairment