Reproductive toxicity and endocrine disruption exam preparation

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Previous exam 2023

  1. In your own words, describe what an endocrine disruptor is, according to the WHO/IPCS definition. (3p)
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Endocrine disruptors are exogenous substances that alter function(s) of the endocrine system and consequently cause adverse health effects in an intact organism, or its progeny, or (sub)populations.

From slides

  1. Describe briefly and in general terms how exposure to endocrine disrupting chemicals may have adverse effects on fertility and give one example of a negative effect on male fertility and one example of a negative effect on female fertility. (3p)
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Endocrine-disrupting chemicals (EDCs) interfere with the hormonal systems that regulate reproductive functions. These disruptions can alter hormone production, signaling, or receptor function, potentially leading to adverse effects on fertility.

- Male fertility example: EDCs like phthalates can reduce testosterone levels, leading to decreased sperm production and quality.  
- Female fertility example: Diethylstilbestrol (DES) can increase rate of miscarriage, preterm birth, low birth weight, and primary infertility, increased trend of cancer and testicular abnormalities in the offspring.

From ChatGPT except female example is from slides.

  1. Chemical exposure during development (i.e. during embryonic and fetal stages and in childhood) is of particular high concern. Wilson’s 5th principle of teratology states that there are four general manifestations of deviant development, list these four manifestations. (2p)
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death, malformation, growth retardation and functional deficit

From slides

  1. Chemicals may interfere with the normal function of the endocrine system in different ways, for example by interacting with hormone receptors (receptor agonism or antagonism) and thereby affecting gene transcription.
    a) Affinity and potency are important aspects of ligand-receptor interactions. Define affinity and potency and describe the main differences of these aspects. (2p)
    b) How can an endocrine disruptor activate gene transcription via the classical genomic nuclear-receptor mediated pathway. It is sufficient to list the main steps. (2p)
    c) Give two examples of how chemicals can cause endocrine disruption other than interacting with hormone receptors and affecting gene transcription. (1p)
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a)
- Affinity: Affinity refers to the strength of the binding between a ligand (e.g., a hormone or chemical) and its receptor. A ligand with high affinity binds tightly and is more likely to remain bound to the receptor.  

- Potency: Potency refers to the ability of a ligand to produce a biological response at a given concentration. A highly potent ligand elicits a significant effect at a low concentration.  

Main difference: Affinity is about how well a ligand binds to the receptor, while potency is about the magnitude of the biological response elicited by that ligand after binding. High affinity does not necessarily correlate with high potency, as other factors (e.g., downstream signaling efficacy) contribute to potency.

b)
1. Binding to the receptor: The endocrine disruptor enters the cell and binds to a nuclear receptor in the cytoplasm or nucleus, mimicking a natural hormone.  

2. Receptor activation: Ligand binding activates the receptor, causing a conformational change that allows it to dimerize (if required) and bind co-regulators.  

3. DNA binding: The activated receptor-ligand complex binds to specific hormone response elements (HREs) on DNA in the promoter region of target genes.  

4. Recruitment of transcription machinery: The complex recruits coactivators and transcription factors to initiate gene transcription.

c)
1. Inhibiting hormone synthesis: Chemicals like bisphenol A (BPA) can interfere with enzymes like CYP11A1 and CYP19 involved in hormone production, altering the normal sex hormone ratio.

2. Altering hormone metabolism or clearance: Chemicals such as TCDD can active AHR then increase biliary excretion of T4, causing decreased levels of thyroid hormones.

From ChatGPT and slides (c2).

  1. The endocrine system is complex and endocrine disruptors consequently exhibit complex toxicity, which poses challenges to testing and assessment.
    a) Describe two different aspects that make endocrine disruption complex. (1p)
    b) Give an example of an in vitro assay that can be used to investigate endocrine activity and describe the endocrine mechanism it investigates. (2p)
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a)
1. There are many different hormones and tissues involved in endocrine system which make endocrine disruption complex.
2. Hormones have maximum effect well below receptor saturation, a very low concentrations can take significant effects.
b)
estrogen receptor transactivation assay
This assay measures the ability of a chemical to activate or inhibit a nuclear receptor (e.g., estrogen receptor). The chemical's effect on receptor activity is detected by the expression of a reporter gene (e.g., luciferase), which produces a measurable signal like luminescence or fluorescence.
  1. Developmental toxicity of endocrine disruptors can be studied both in animals (in vivo toxicity testing) and in epidemiological studies. State one strength and one limitation with studying developmental toxicity in animal studies, and one strength and one limitation with studying developmental toxicity in epidemiological studies. (2p)
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Animal studies:  
- Strength: Controlled environment allows precise determination of dose-response relationships and causality.  
- Limitation: Results may not fully translate to humans due to species differences in physiology and metabolism.  

Epidemiological studies:  
- Strength: Direct relevance to human populations and real-world exposure levels.  
- Limitation: Difficulty in establishing causality due to confounding factors and reliance on observational data.

From ChatGPT

  1. Explain why timing of exposure is a critical aspect of endocrine disruption. (2p)
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Timing of exposure is critical in endocrine disruption because the endocrine system plays specific roles at different stages of development and life. Disruptions during sensitive periods can have profound and irreversible effects:
Developmental stages: During fetal development, infancy, and puberty, hormones regulate critical processes like organ formation, growth, and maturation. Exposure to endocrine disruptors during these windows can lead to permanent structural or functional abnormalities.
Hormonal programming: Early-life exposure may reprogram hormonal pathways, leading to latent effects that manifest later in life, such as reproductive disorders, metabolic issues, or cancer.

From ChatGPT