L16: Reproductive Toxicology Flashcards
What is reproductive toxicity?
Describes an adverse effect on:
- any aspect of male or female reproductive structures or function
- the developing offspring
- lactation, that would interfere with normal offspring development
definition includes aspects of developmental toxicity, teratogenesis (formation of congenital malformations in embryo or fetus) and developmental neurotoxicity
What are the potential targets for reproductive toxicants? What is the range of physiological processes, behaviours and anatomical structures necessary for the birth of the next generation in humans?
- Gametogenesis
- release of gametes
- zygote formation
- embryonic/fetal development
- parturition
- lactation
How are reproductive toxicants identified?
- Clinical workups of people in infertility clinics
- people undergoing drug treatments (in particular for cancer treatment)
- epidemiological studies on general populations, in particular from workers who:
i) have industrial exposure in plants;
ii) use of chemical such as pescticides - animal studies
What is the aim of reproductive toxicology studies? What do they aim to study their effects on?
aim of repro tox is to reveal an effect of a substance on mammalian reproduction. They aim to study their effects on:
- reproductive competence of the adult animal
- the developing embryo or fetus before birth
- the development of the offspring
to detect immediate as well as latent effects, observations should continue through one complete life cycle (from conception in one generation through conception in the following generation
What are the advantages of studying reproductive toxicology in vivo models?
Advantages:
- most accurately depict the ‘real life’ situation
- picks up effects on reproduction (reproductive tract/HPG axis)
- metabolism of drugs can be considered (are compounds being detoxified?)
- effective
- can be used to study transgenerational effects
What are the disadvantages of studying reproductive toxicology in vivo models?
Disadvantages:
- time consuming
- costly
- compounds can persist in animal long after exposure
- requires more animal procedures than in vitro studies
- prenatal testing requires exposure to the mother - an animal that may not be of interest for the study
What are the advantages of studying reproductive toxicology in vitro models?
advantages:
- rapid/high throughput
- for repro tox studies it does not involve administration of drugs to an animal
- provides insight into tissues where in vivo studies are unethical or impractical
- permits investigation into whether drugs have direct effects on the gonads
- permits investigation into a specific cell type, structure or organ in isolation
- highly controlled (exposure window/dose/follicle stage)
- easy to manipulate culture conditions
- allows for examination of cell-cell signalling
- allows examination of a specific follicle type or stage
- cheaper than in vivo work which requires live animals or human participants
What are the disadvantages of studying reproductive toxicology in vitro models?
- doesn’t tell the whole story
- some of the tissue level barriers that might limit/prevent drug exposure are not present
- findings will still need to be confirmed by in vivo studies
- don’t fully recapitulate cellular pathways that occur in vivo
- excludes reproductive effects that occur through the HPG axis or on other tissues
When is a second mammalian species required for studies?
For embryotoxicity studies only, rabbit is usually the preffered choice
What is the classification of reproductive toxicity?
- category 1A: known human reproductive toxicant - largely based on human evidence, avoid
- category 1B: presumed human reproductive toxicant - largely based on animal evidence
- category 2: suspected toxicant, evidence from animal and/or human studies is limited
What are the examples of reproductive toxicants?
- animal toxins
- recreational drugs
- endocrine disrupting factors
- pesticides
- physical agents
- naturally occuring
- pharmaceutical drugs
- heavy metals
- plant toxins
- occupational chemicals
- biological agents
What are the side effects of chemotherapy?
- hair loss
- tiredness
- feeling sick
- risk of premature ovarian insufficiency (POI) and infertility – enter menopause 10 years earlier than they would have
What is the impact of cancer and cancer treatment on fertility?
- Women are ~38% less likely to fall pregnant after a diagnosis of cancer (Anderson et al. 2018)
- Males are 30% less likely to father children after a diagnosis of cancer (Chow et al. 2016)
How does chemotherapy affect follicle pool?
Risk of developing amenorrhea after chemotherapy:
- females at age 30: 25% risk
- females aged between 35-40 years: 50% risk
- females >40: 66-95% risk
How does chemotherapy affect ovaries?
- germ cell loss
- direct loss of primordial follicles
- primordial follicles activation
- inflammation
- stromal damage
- vascularisation
- radiation -> germ cell death through upregulation of p63, p63 is upregulated in response to damage caused
