EDCs & reproductive toxicology Flashcards
What does EDC’s stand for and what are they?
Endocrine disrupting compounds. EDCs are compounds that interfere with the hormonal (endocrine) system.
Endocrine signaling = signaling substance produced in one place, delivered through the bloodstream and have an effect in another place.
What is the definition of a EDC according to the European commission 2016, based on IPCS/WHO 2002?
“An endocrine disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations”
EDCs are very different from other toxicants, why?
Generally in toxicology, we say that “the dose makes the poison”, meaning that anything can be toxic in a high enough dose or that something incredibly toxic can be harmless in a low enough dose. This category of toxicants have clear and immediate effects.
With EDC’s that’s not the case, as they have very subtle and delayed effects (effects can for example apply to progeny but not the exposed individual) and the dose response curves are often non-monotonic, meaning that a higher doesn’t mean higher toxicity. All these characteristics makes them very hard to define and it’s also hard to verify if a compound is an EDC.
Many EDCs also have different modes of action, which make it even more complex!
What is the functions of the endocrine system in adults vs during development?
Endocrine system in adults:
- Regulation of metabolism
- Regulation of water, salt and nutrient uptake
- Stress response
- Reproduction
During development:
- Organ development, e.g. brain, sexual organs
- Growth and organisation
Which types of hormone signaling have been most studied in the context of EDCs?
EAT: estrogen, androgen, thyroid hormone signaling.
What does hormonal signaling depend on? Which of these can be affected by EDCs?
- Hormone production and secretion
- Transport in the blood by plasma proteins
- Receptor availability and activity
- Hormone metabolism and excretion
All of these can be affected by EDC’s! There are over a thousand identified EDCs out there, either stimulation or inhibition of hormonal pathways.
Where does steroidogenesis occur?
Steroidogenesis occurs in the endoplasmic reticulum and the mitochondria of hormone producing cells.
Which compound is the basis of all steroid hormones?
Cholesterol is the basis of all steroid hormones. Specialised enzymes
convert precursors to active hormones or one hormone to the other. Very complex!
Where are thyroid hormones produced and what compound is essential for their synthesis?
The thyroid hormones are produced in thyroid follicles, specialized cells in the thyroid gland. The production requires iodide, thyroid hormone
exists as T3 and T4 (3 and 4 iodides, respectively). T3 is much more active than T4.
Hormones often follow certain axis, name the three common axis in the body.
HPG: hypothalamus (GnRH: Gonadotropin releasing hormone) - pituitary (LH: Luteinising hormone) - gonads (FSH: follicle stimulating hormone)
HPT: hypothalamus (TRH: Thyrotropin releasing hormone) - pituitary (TSH: Thyroid-stimulating hormone) - thyroid (T4 & T3)
HPA: hypothalamus (CRH: corticotropin releasing hormone) - pituitary (ACTH: adrenocorticotropic hormone) - adrenal cortex (Glucocorticoids) Important in stress response.
All with built in negative feedback to self regulate hormone levels.
How are water vs lipid soluble hormones transported?
Water soluble hormones are transported freely in plasma. Lipid soluble hormones are bound to transport proteins like hormone binding globulin (SHBG), thyroxide binding globulin (TBG) or transthyretin.
Concentrations of free hormones in blood are low! E.g. 1-3% free sex hormones, 1% free thyroid hormone.
Which type of receptor does water soluble vs lipid soluble hormones bind to? Explain shortly how that work.
- Lipid soluble hormones such as steroids, thyroid hormones,
vitamin D, vitamin A can diffuse through membranes, so they bind to nuclear receptors. NRs are ligand- activated transcription factors that bind DNA at specific response elements to mediate transcription of
genes. Slower! - Water soluble hormones like insulin, oxytocin, growth hormone and adrenaline bind to membrane bound receptors, either G-protein coupled receptors (GPRs) or ion channels. Both trigger signaling cascade that cause the cell to change function (no change in gene transcription). Faster!
Hormones can interact with each other in three ways, which?
- Permissiveness: One hormone cannot exert its effect without another
- Synergism: More than one hormone can elicit the same effects in the cell
- Antagonism: One or more hormones oppose the action of another one
Does hormones have a monotonic dose-response curve?
No! They have an optimal range, so the dose-response curves are non-monotonic.
EDCs can have different modes of action, give one example of a EDC that have mixed modes of action.
DTT, a pesticide consisting of isomers with different properties:
- p,p´-DDT, metabolized to p,p’-DDE: androgen receptor antagonist
- o,p´-DDT: estrogen receptor agonist
BPA: Bisphenol A can act as estrogenic (which is what it was designed for) and also as an anti-estrogenic compound and has also been shown to act on the glucocorticoid, thyroid, and the androgen receptor.
