Endocrine disrupting pharmaceuticals

Question 1

What are the main causes of infertility?

Answer 1

• Age is certainly a factor
  The gestation age is older now
• Lifestyle is a factor
  Calories – mainly in women
  Alcohol – mainly in men
  Chemicals/drugs

Question 2

What can lead to testicular dysgenesis?

Answer 2

• Environmental exposure
• Genetic defects and polymorphism
• Lifestyle factors
• Epigenic factors

Question 3

What is Testicular Dysgenesis Syndrome (TDS)?

Answer 3

Syndrome where the testicles are not moving correctly into the scrotum – undescended testicles

Question 4

How is the clinical expression of Testicular Dysgenesis Syndrome (TDS)?

Answer 4

Is expressed as mild, medium, and severe TDS.

Female base type developing into masculine phenotype

Question 5

What can Testicular Dysgenesis Syndrome (TDS) lead to?

Answer 5

Disturbed Sertoli cell function → Impaired germ cell differentiation
→ Reduced semen quality
→ Testicular cancer

Decreased Leydig cell (LD) function → Androgen insufficiency
→ Hypospadias
→ Testicular maldescent
→ Impaired LD function min adult life

Question 6

How is the steroidogenesis pathway operation different between animals and human?

Answer 6

The main route to testosterone is different.

Human → pregnenolone → 17OH-pregnonolone → DHEA → Androstenediol

Animals → pregnenolone → Progesterone → 17OH-progesterone → androstenedione → Testosterone

Question 7

What are H295R cell lines used for?

Answer 7

Used as an in vitro model for human adrenocortical and gonadal cell function

Question 8

Why can the H295R cell line be used for steroidogenesis?

Answer 8

It expresses all the key enzymes and receptors necessary for steroidogenesis.

Produces hormones from all three morphologically and biochemically different adrenocortical zones

Question 9

What is the therapeutic target for ketoconazole and what is the toxic mechanism?

Answer 9

Anti-mycelium used against local and systemic fungi infections.

Mechanism:
Inhibit all CYP enzymes. All of the secondary hormones are therefore decreased.
→ Endocrine disruptions

Question 10

What is the therapeutic target for genistein and what is the toxic mechanism?

Answer 10

Phytoestrogen is found in soya beans and other legumes.

Mechanism:
Inhibit the other enzymes (not CYP) in steroidogenesis.
→ Endocrine disruptions

Question 11

What is the therapeutic target for prochloraz and what is the toxic mechanism?

Answer 11

Imidazole fungicide is used against severe fungal infections in humans and animals and in agriculture and gardening.

Mechanism:
Inhibit all CYP enzymes except CYP11A1, which induces the first step of steroidogenesis.
→ Endocrine disruptions

Question 12

What is the mechanism behind testicular cancer?

Answer 12

Survival of a stem cell in the testis –> Teratoma –> Cell starts proliferation –> Envionic carcinoma –> Testicular cancer

Question 13

What biomarker is used to measure decreased testosterone levels in newborns?

Answer 13

anus genital distance (ASGC) – less testosterone lead to a smaller ASGC

Question 14

How does mild analgesics influence fetal development?

Answer 14

Paracetamol inhibits testosterone production during the fetal developing period

Paracetamol decreases the number of eggs/follicles in the ovaries

Paracetamol is stopping the stem cell (embryotic germ cells) proliferation. If exposed under fetal life this can lead to a reduction in fertility

Question 15

How does anillin have dual effects?

Answer 15

Aniline might be metabolized into acetaminophen/paracetamol

Aniline increases progesterones and is then converted into paracetamol and decreases androgens

Question 16

How does ibuprofen affect grown men?

Answer 16

Testosterone is steady after ibuprofen exposure in the adult man while LH increases.

LH induces negative feedback –> less testosterone is produced