15. Reproductive toxicology Flashcards
What are the latest examples of commonly found agents causing infertility?
A few common stories:
- olaplex
- pesticides containing infertility causing agents
- BPA in plastic boxes etc
In animals:
- excreting chemicals into oceans causes more development of male fish than female
What is the current trend of male fertility in the western world?
Declining sperm counts - higher percentage requiring fertility treatment (in 2004 12.4% -> in 2017 21.3%) - don’t know if there is a causation link
What are the recent trends concerning fertility?
Global decline in fertility rates + increase in av maternal age
Why are other factors than genetics suspected to play a bigger role in current decline of fertility?
Current fertility decline rates can’t be explained by genetics alone because too short time-frame for genetics to be at such significant play -> growing suspicion of:
- social + economic changes in the Western world
- lifestyle choices and environmental substances negatively impacting fertility
Explain what is reproductive toxicology
Reproductive toxicology studies 3 areas of adverse effects:
- male / female reproductive structures / functions
- developing offspring
- lactation
What are the range of physiological / behaviour and anatomical structures involved in reproduction?
Range of physiological / behaviour and anatomical structures involved in reproduction - vulnerable to toxins - studied for toxicity effects:
- gametogenesis
- release fo gametes
- zygote formation
- fetal development
- parturition
- lactation
How are reproductive toxins identified?
Reproductive toxins identified by:
- clinical workup on infertility patients
- people undergoing drug treatments (ex cancer)
- epidemiological studies on particular populations (ex factory workers)
- animal studies
What are the points to be considered when studying a reproductive toxin?
In studying reproductive toxins it is essential to consider:
- reproductive competence of adult
- effect on developing fetus
- development of offspring
- combination studies involving all stages of development until adulthood
- concider immediate and latent effects - all life observation
What are the two classes of experiments carried out in studying reproductive toxicology?
Experiments in reproductive toxicology:
- in vitro
- in vivo
What are the advantages and disadvantages of in vitro experiments in reproductive toxicology?
Adv:
- precise and direct structure / stage examination
- cell-cell signalling examination
- easy to culture / manipulate / control
- high throughput
- more ethical
Disadv:
- excludes effects on other structures - less contextual
- findings need to be confirmed by in vivo studies
- doesn’t account for drug metabolism effects
- don’t fully resemble all necessary pathways
=> with in vitro studies - in vivo studies need to be complimentary performed
What are the advantages and disadvantages of in vivo experiments in reproductive toxicology?
Adv:
- more closely resembles real situations
- direct effects on reproduction
- drug metabolism can be considered
- effective
- transgenerational effects can be studied
Disadv:
- time consuming
- costly
- compounds persist in animals long after exposure
- more ethical concerns
- prenatal testing requires the mother - which may not be of interest to the study
What is special about embryotoxicity studies?
In embryotoxicity studies a second animal species is required in the study - rats + rabbits
Are naturally occurring agents generally less reprotoxic?
No, a common misconception - both man-made and naturally substances can be equally reprotoxic
What are the substances which are commonly though to have reprotoxic effects?
What is a pharmaceutical drug which is commonly conciderred to be reprotoxic?
Chemotherapy agents have been widely found to be reprotoxic - ex doxorubicin
What are the side effects of chemotherapy treatment?
Chemotherapy side effects:
- hair loss
- fatigue
- feeling sick
- risk of POI and infertility
What is the extent of chemotherapy impact on fertility in men and women?
After chemotherapy:
- women -38% less likely to fall pregnant
- men -30% less likely to father children
What are the chemotherapy effects on ovarian reserve depletion rates?
Chemotherapy increases ovarian reserve depletion
How does chemotherapy induce higher ovarian reserve depletion rates?
Chemotherapy increases ovarian reserve depletion - increases PMF atresia via:
- direct loss of PMFs
- PMF activation
- loss of vascularisation in the ovary
Explain the chemotherapy induced pathway by which PMFs are killed
DNA damage response - p63 pathway
How does cigarette smoking affect women’s fertility?
Negatively:
- accelerated menopause
- lower rates of natural conception
- higher miscarriage risk
- lower IVF success chances
Explain the experimental design which aimed to assess if cigarette smoking affects follicle development in the ovary
In vivo mouse studies: continuous exposure to cigarette smoke -> ovarian histology -> decreased ovarian volume/weight + lower PMF levels
What are the endocrine disrupting chemicals?
Endocrine disrupting chemicals are ones which mimic / block / interfere with hormones in endocrine system -> increase adverse health outcomes - cancer / reproductive impairment:
- dioxins
- phthalates
- flame hydrants
- phenols
- pesticides
- phytoestrogens
Explain how endocrine disruptors work
Endocrine disruptors disrupt normal hormone function with their receptors -** induce identical / altered cellular response** in endrocrine system -> disbalance in the system => adverse negative outcomes
Give an example of an endocrine disruptor and how it acts
Bisphenol A (BPA) - found in plastics - ex: food packaging / industrial materials / personal hygiene products - weakly estrogenic, anti-androgenic, anti-thyroid activities + accumulates in tissues -> disrupts signalling
Affects not only reproductive system
Explain how BPA effects were tested on mice and what were the results
Mice exposed to environmentally relevant BPA levels - found adverse effects on testicular function - decreased testosterone production
Explain how BPA effects were tested on humans and what were the results
Human fetal testicular tissue grafts exposed to BPA levels - reimplanted into SCID mice as xenografts - no effect observed on testosterone production
