Developmental toxicology Flashcards
What is a birth defect?
Birth defects = congenital anomalies, disorders, malformations, or abnormalities. It’s an umbrella term for all conditions of prenatal origin that are present at birth, potentially impacting an infant’s health, development and/or survival.
What causes birth defects?
- Genetics 10%
Monogenic diseases – e.g. cystic fibrosis, fragile X syndrome, sickle cell anemia, Chromosomal abnormalities – e.g. Down syndrome (47,XX or XY,+21), Klinefelter syndrome (47,XXY) - Environment 15%
Maternal pathologies – e.g. diabetes, obesity, infections, Exposure to chemical agents (particular medicines, drugs, pesticides) or physical agents (radiation) - Multifactorial 25% (genetics x environment) – e.g. cleft lip and cleft palate
- Unknown 50%
At what point during gestation does the embryo change to a fetus?
Week 0-9 = embryo, after that we call it fetus.
Account for all the steps from fertilization until implantation.
Fertilization of the egg (haploid) occur somewhere in the fallopian tube.
1. Zygote formation (diploid) that is totipotent
2. cleavage, cell proliferation without growth until it forms the morula (you can no longer see different cells) at this stage all cells are equal, no differentiation.
3. Early blastocyst = cells start to differentiate into two germ layers, the trophoblast, which later forms external structures and inner cell mass (which later forms the the hypo- and epiblast).
4. A lot of proliferation until the blastocyst implants into the uterine wall within the first 10 days post-conception.
Deviation in any of these processes leads to death of the embryo.
After implantation (10 days at the most), the embryo develops in the uterine wall. What happens during the second week of gestation?
- First, a bilaminar disk is formed from the inner cell mass, comprised of the hypoblast and the epiblast (which later forms the ecto-meso- and endoderm) –> blastula.
- A number of extraembryonic structures are formed from the hypoblast, like amniotic cavity, yolk sac, connecting stalk, chorion
- The trophoblast invades the mothers circulation to establish a utero-placental circulation (lacunar networks).
During the third week of gestation a landmark differentiation occurs, what is the process called and what happens?
Gastrulation occurs during the third week of gestation and it is the process by which the bilaminar embryonic disc undergoes reorganization to form a trilaminar disc. The primitive streak appear and cells start to migrate from the top layer towards the streak and then to the location where the head will form. The tre three layers are
the ectoderm (upper layer), mesoderm (middle layer) and endoderm (lower layer) –> gastrula.
During this process, the notochordal process connects to the yolk sac and notochord form from the mesoderm.
Give two examples each for what tissues the ecto-, meso- and endoderm give riste to.
Ectoderm:
CNS, PNS, skin, pigment etc.
mesoderm:
muscle, blood, bone, kidney etc.
endoderm:
Gi-tract, lungs, thyroid etc.
What is the process that marks the beginning of the formation of the nervous system called and what happens?
The process forms the NS is called neurulation happens in the 3-4 week of gestation. The notochord sends signals that cause folding of the of the ectoderm which forms the neural tube, which will later go on to form the entire CNS. At this point a new population of cells (neural crest cells) form from the ectoderm which later becomes the PNS.
When does organogenesis occur and which two organs start to develop first?
Organogenesis occurs throughout week 3-9, the brain first and then the heart (both are needed to sustain life) and then other organs, in order: limbs, ears, eyes, teeth, palate and external genitalia.
Some milestones: Somewhere around week 17-20 movements can be felt by mother, week 26-29: hearing is fully developed, fetus responds to stimuli and changes position often, week 34-38: coordinated reflexes, can blink, close the eyes, turn the head, grasp firmly.
What is teratology?
The science dealing with the causes, mechanisms and manifestation of developmental deviations of either structural or functional nature.
Wilson’s six principles of teratology are very long, what are the basic takeaway from them?
- Species matter, a teratogen can be toxic to one species but safe to another.
- Stage and timing of exposure matter, a compound can be teratogenic one week but safe another week.
- Mechanisms of action for a teratogen can differ between adult and fetus. A mechanism can be used for different things in the adult vs fetus, so the effects can differ a lot.
- The properties of the toxin/teratogen determine it’s effects.
- The four manifestations of deviant development are death, malformation, growth retardation and functional deficit and all are possible in response to a teratogen.
- There is dose-response differences between teratogens. Manifestations of deviant development increase in frequency and degree as dosage increases for most teratogens.
What are the effects of thalidomide exposed children?
Thalidomide was marketed 1957 – 1961 initially as a sedative and sleeping tablet and subsequently used to treat nausea and vomiting
during pregnancy. It was so ”non-toxic” that the LD50 dose in animals
could not be determined. Used in Australia, Germany, Japan, Britain, Brazil, Sweden and Italy.
Exposure to the drug in early pregnancy resulted in severe limb, eye and ear malformations in nearly 10000 children. Effects depended on the time of exposure during gestation.
The mechanism is still not fully understood but the proposed mechanism is that thalidomide binds to cereblon and makes it target the wrong proteins for destruction.
What effect is most common for teratogen exposure during week 3-8 of gestation?
Since week 3-8 is the period or organogenesis, toxic insults during this period likely lead to major structural malformations, while insults that occur later are more likely to lead to functional or growth deficits.
When did we start developmental toxicity testing? Account for the basics of it.
- Developmental toxicity testing was started after the thalidomide disaster.
- Performed according to regulatory guidelines by the OECD (Organization for Economic Cooperation and Development) and adopted internationally. The requirements can depend on the type of chemical and its intended use (e.g. food additives, pesticides, pharmaceuticals etc).
- Today, devtox testing is always performed on animals, mainly rats and rabbits but other animals too and it often require A LOT of animals. There are some suggestions for non-animal models being worked on.
- Over 150 different tests
- A lot of factors are described, like housing and feeding conditions, administration period, dose and dose-frequency, if animals need to be killed (often) - both offspring and adults, one-generational or multigenerational, tests on offspring, tests during life and after death, biochemical and histopathological examinations are performed, often with attention to the gonads.
What does DNT stand for and what is it?
DNT stand for developmental neurotoxicology and it is the study of adverse effects on the structure or function of the nervous system resulting from exposure to a toxicant at any time during the period of central nervous system (CNS) development and maturation (i.e., prior to birth through adolescence).
