M6-Lecture3

Question 1

agents that cause non-heritable birth defects.

Answer 1

Teratogens

2-5% born with abnormalities

testing is expensive

See diagram

Question 2

Wilson’s Principles of teratology

Susceptibility to the teratogenic effect of an agent depends on

Answer 2

on the genotype of the embryo
the genotype of the mother,

and the ways in which their genotypes allow mother and fetus to interact

Question 3

Wilson’s Principles of teratology

Teratogenic agents act in specific ways on genes, cells and tissues

Answer 3

Interfere with normal development

Question 4

The placenta does not completely protect the fetus as is seen with Rubella infections during the 1st trimester.

Question 5

Wilson’s Principle here emphasizes that while the placenta offers some protection, it is not a perfect barrier, and certain infections or teratogens can still harm the fetus, especially during sensitive periods of development like the first trimester.

Question 6

Wilson’s Principles of teratology

Several factors affect the ability of a teratogen to interfere with normal development.

Answer 6

Include the nature of the agent, the route and degree of maternal exposure, ability of mother to detoxify or block the agent, rate of transfer through the placenta, the rate of absorption by the embryo or fetus, and the genotype of the mother and her conceptus.

Question 7

Wilson’s Principles of teratology

There are four major manifestations of abnormal development

Answer 7

death, malformation, growth retardation, and functional defects

Question 8

Wilson’s principles of teratology

As teratogen dose increase, abnormal development increase in frequency an degree

Question 9

Teratogenesis - definitions

Answer 9

Congenital anomaly – birth defect- can be structural or functional

Functional = intellectual (cognitive), emotional physiological

Structural = malformations, disruptions, deformations or dysplasias

Question 10

Malformation – failure of tissue to initially form properly.

Disruption – Breakdown of a tissue that has initially formed properly.

Deformation- extrinsic mechanical forces on otherwise normal tissue.

Dysplasia – A lack of normal organization of cells in a tissue

Question 11

Most teratogens produce structural defects only during certain critical periods of development.

Answer 11

Embryonic period – Conception to 8 weeks
Fetal period – remaining time in utero

Question 12

Rare to have congenital anomalies before 3 weeks because teratogens damage either too many cells and it dies or too few cells and it recovers (pluripotent cells).

Answer 12

Pluripotent stem cells can differentiate into almost any cell type in the body, while multipotent stem cells can differentiate into a limited range of related cell types; totipotent stem cells can form all cell types, including extra-embryonic tissues, and unipotent stem cells can only produce one cell type, but retain the ability for self-renewal.

Question 13

Maximum susceptibility is between 3-8 weeks when organs start to form. Except for CNS which forms continuously until adolescence.

Question 14

teratogens can still be harmful even after organogenesis is complete, as exposure may lead to functional defects, growth issues, or long-term health problems. However, the risk of causing major congenital anomalies is lower after the organ has fully developed, as the critical periods of rapid development and differentiation have passed.

Answer 14

See diagram

Question 15

Types of teratogens

Answer 15

Drugs & chemicals (thalidomide, mercury, alcohol, retionic acid)
Ionizing radiation (x-rays)
Hyperthermia (fever)
Infectious microorganisms

Mother’s Metabolic conditions

Mechanical forces

Question 16

Thalidomide is a drug that was developed in the 1950s by the West German pharmaceutical company Chemie Grünenthal GmbH.

originally intended as a sedative or tranquiliser

For treating colds, flu, nausea and morning sickness in pregnant women.

But in 1960s was found to cause congenital mal.

Answer 16

Thalidomide

Question 17

Why the delay:

Answer 17

Due to wide range of changes to fetal development that included Limbs, internal organs including the brain, eyesight andhearingcould all be affected.
Some of its damaged resembled certain genetic conditions that affect the upper or lower limbs.

It did not show teratogenic effects in rodents.

Question 18

Thalidomide effects:

Answer 18

Phocomelia, along with a range of severe birth defects including disfigurements, ocular abnormalities, facial palsies, internal organ damage, congenital heart disease, and an increased risk of miscarriages, was caused by thalidomide, a teratogen that affected over 7,000 infants when taken between days 20-36 of pregnancy.

Question 19

Thalidomide is a very complex molecule, requiring metabolic breakdown to achieve activity and forming potentially over 100 by-products

Answer 19

The major functions of these by-products are anti-inflammatory, immunomodulatory, sedative or anti-angiogenic

These by-products can interfere with the normal formation of blood vessels, which are crucial for the paracrine signaling pathways needed for limb bud development, ultimately leading to teratogenic effects such as phocomelia.

Question 20

In angiogenesis, proteases break down extracellular matrix components to allow cell migration, while migrating cells proliferate to form vascular tubes that mature into functional blood vessels.

Question 21

When thalidomide is metabolized, it produces both potentially harmful (teratogenic) and harmless (non-teratogenic) metabolites

Question 22

once smooth muscle cells cover the newly formed blood vessels, thalidomide no longer has an impact.

Answer 22

thalidomide also has immunosuppressive properties, inhibiting the release of pro-inflammatory molecules like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) from immune cells, further contributing to its broad range of effects.

Question 23

IGF-1 (Insulin-like Growth Factor 1) and FGF-2 (Fibroblast Growth Factor 2) are signaling molecules that play key roles in cell growth, survival, and development. They can stimulate the expression of certain genes involved in angiogenesis (the formation of blood vessels).

Answer 23

These signaling molecules (IGF-1 and FGF-2) activate the transcription (the process of making RNA from DNA) of the genes that code for two subunits: αv and β3 } form dimerization and then are involved in blood vessel formation.

Thalidomide disrupts this process.

Question 24

Thalidomide is still a valuable drug for cancer treatment

Answer 24

Also other diseases. See examples

Question 25

Thalidomide exists in two forms: the R(+) enantiomer, which acts as a sedative, and the S(-) enantiomer, which is responsible for inhibiting the release of TNF-α and is the teratogenic form that causes birth defects. The S(-) form is the primary cause of thalidomide’s harmful effects on fetal development, including limb deformities.

Question 26

Industrial mercury can cause neurological abnormalities in nearly 10% of children born nearby, due to the conversion of mercuric sulfate into toxic methylmercury by microbes. This methylmercury then bioaccumulated in fish and shellfish, which were consumed by local populations, leading to widespread poisoning and birth defects

Answer 26

For pregnant women, mercury was selectively absorbed in regions of the developing cerebral cortex.

Mice given Hg during pregnancy had pups with small brains or eyes

Question 27

During the third week of gestation, the human nervous system begins to form in the embryo.

Answer 27

methylmercury has toxic effects on ns during ed.

readily crosses the placenta & bbb
- deposition in fetal brain can occur

In the brain, methylmercury causes focal necrosis of neurons and destruction of glial cells.

deficits in attention, behavior, cognition, and motor skills

Question 28

Children exposed to mercury may be born with symptoms resembling cerebral palsy, spasticity and other movement abnormalities, convulsions, visual problems and abnormal reflexes

Answer 28

neuron loss in the cerebellum and throughout the cerebral cortex.

preventing neurons from finding their appropriate place in the brain.

Question 29

Methylmercury, a toxic compound, causes Minamata disease by damaging the nervous system

Answer 29

Protein inhibition
Disruption of mitochondria function
Direct affect on ion exchange in a neuron
Disruption of neurotransmitters
Destruction of the structural framework of neurons

Cerebral hemispheres: Damage to both sides (left and right) of the brain, affecting movement (precentral gyrus), sensation (postcentral gyrus), hearing (temporal gyrus), and vision (occipital lobe).
Cerebellum: Affects balance and coordination.

Question 30

Mercury toxicity affect:

Answer 30

Motor system: weakness
NS: emotional instability, insomnia, memory loss, tremor
Immune system: decrease
Renal system: high plasma creatinine level (waste from muscle metabolism)

Question 31

Mercury has strong affinity for sulfur

Answer 31

interference of enzyme function and protein synthesis is primary mode of mercury’s toxic action

Question 32

Mercury absorption in tissue classified into:

Answer 32

Elemental mercury: poor gesta., abso. inhalation
- high lipophilicity

Inorganic mercury: poor gest. abso.
- low lipophilicity

Organic mercury: easily absorbed gest. skin, lungs, kidney, heart
- high lipophilicity

Question 33

Mercury (MeHg), or methylmercury, is a toxic, organic form of mercury

Answer 33

Methylmercury (MeHg) and mercury (Hg²⁺) toxic, accumulate in neurons and astrocytes, inhibiting key antioxidant enzymes (TrXR and Gpx), leading to increased reactive oxygen and nitrogen species (ROS and RNS). This oxidative stress disrupts glutamate regulation, impairing its reuptake by astrocytes and neurons, which can cause excitotoxicity and neuronal damage (cell death, apoptosis/necrosis) or neurodevlopmental disorders.

Question 34

Methylmercury (MeHg) forms when mercury (Hg²⁺) binds with methyl groups, often through microbial activity in the environment, while Hg²⁺ itself can form from the oxidation of elemental mercury (Hg₀) in biological systems.

Question 35

See diagram

Question 36

Probably the most devastating teratogen in humans

Answer 36

Alcohol
- FAS

see video

Question 37

FAS Categories

Answer 37

1. Have growth retardation and neurodeve. abnormalities, facial dysmorphology
2. FAS without confirmed maternal exposure
   - possible diagnose considering 1
3. Partial FAS with confirmed maternal exposure
   - some of facial anomalies, GR, NA
4. FAS with confirmed exposure & alcohol-related birth defects
   - some congenital anomalies
5. FAS with confirmed exposure and a-r ND
   - NA, maybe not obvious physical changes

See facial changes and brain.

Question 38

Intellectual defects and behavioral abnormalities from alcohol exposure during pregnancy can occur even without obvious physical changes, with effects varying based on the dosage and timing of exposure, and mice models show that these impacts can occur at multiple developmental stages.

Answer 38

Alcohol-induced craniofacial and brain anomalies in mice

Question 39

Alcohol disrupts fetal development by

Answer 39

triggering neural crest cell differentiation, affecting migration-related genes, killing cells in brain regions, and cell death through superoxide free radicals, with antioxidants potentially mitigating some effects

Question 40

Alcohol disrupts fetal development by down-regulating Sonic Hedgehog (essential for brain and facial development), blocking neuroblast differentiation through Sox5 and Ngn1, increasing DNA methyltransferase activity (without affecting histone transacetylase), and inhibiting L1-mediated cell adhesion, which impairs neuronal migration and axon guidance.

Question 41

Ethanol and acetaldehyde disrupt the metabolism of carbohydrates, proteins, and fats, and also reduce the transfer of essential nutrients leading to fetal growth impairment due to nutrient deprivation.

Question 42

Mutations in the ALDH2 gene, involved in alcohol metabolism, cause DNA damage, leading to developmental defects like embryonic resorption and lethality, but bone marrow failure can be rescued, preventing complete embryonic death.

Question 43

Functions of dopamine:

Answer 43

movement
memory
pleasurable reward
behavior and cognition
attention
inhibition of prolactin production
sleep
mood
learning

Question 44

During adolescence, the brain experiences significant structural and functional changes, particularly in the dopamine and GABA neurotransmitter systems, both of which are altered by alcohol consumption.

Question 45

GABA, the brain’s primary inhibitory neurotransmitter, reduces brain cell activity and is enhanced by alcohol, leading to relaxation and sleepiness, while glutamate, the main excitatory neurotransmitter, also undergoes changes during adolescence, interacting with receptors like the NMDA receptor to regulate brain function.

Question 46

Alcohol can damage the hippocampus, a brain region essential for learning and memory, leading to difficulties in learning new information and potential long-term cognitive impairments.

Question 47

Retinoic acid

Answer 47

is an essential compound for development, role in the formation of the anterior-posterior axis, heart, and jaw in mammals, but if present in excessive amounts or at inappropriate times, it can disrupt normal development

Question 48

sotretinoin (Accutane) - 13-cis–retinoic acid, can cause a wide range of birth defects, by altering HOX gene expression, inhibiting neural crest cell migration, and activating enzymes that degrade retinoic acid, leading to developmental disruptions.

Question 49

Retinoic acid (RA) is a significant public health concern due to its teratogenic effects, especially as women of childbearing age often use acne medications like Accutane, which requires pregnancy testing before use; excessive vitamin A intake can increase malformations, and exposure to glyphosate herbicides may exacerbate these risks by upregulating endogenous RA activity, disrupting Sonic hedgehog (Shh) signaling and leading to developmental defects.

Question 50

Tobacco smoke harms fetal development, causing growth issues, brain and lung damage, and reduced oxygen supply.

Question 51

Nicotine disrupts fetal lung development, lowers sperm count, alters gene methylation, and affects brain neurotransmitters.

Question 52

Cannabinoids like THC can impair brain development, functions and interfere with the endocannabinoid system, potentially causing addiction and cognitive issues.

Question 53

THC exposure before or during adolescence can impair memory, reduce IQ, and disrupt the endocannabinoid system, leading to long-term cognitive and mental health issues.

Question 54

A 2010 review by van Gelder et al. identified several mechanisms causing structural defects from prescription drugs taken by women of reproductive age, including folate antagonism, neural crest disruption, endocrine disruption, oxidative stress, vascular disruption, and receptor or enzyme-mediated effects.

Question 55

ACE inhibitors can cause fetal growth restriction, death, and defects mainly due to hemodynamic effects, with low teratogenic risk in the first trimester.

Question 56

Warfarin can cause CNS defects, hearing loss, and miscarriage risks, while vitamin A disrupts gene regulation, leading to autism-like symptoms, neural tube defects, and skeletal abnormalities.

Question 57

Viruses are also teratogenic.
Rubella virus makes a protein which stops mitosis by blocking kinases required needed for cell division.
First 5 weeks are the most critical.

Question 58

CMV and Herpes are almost always fatal in early embryos.
In late embryos – cause blindness, deafness, cerebral palsy and mental deficiencies.

Answer 58

An extended maternal temperature of 102F (38.9 C) or higher during the first 6 weeks may affect closure of the neural tube.

Question 59

Neonatal herpes, though rare, can be fatal to the fetus if the mother contracts genital herpes late in pregnancy,

while toxoplasmosis and cytomegalovirus (CMV) pose risks to the unborn if contracted during pregnancy, with potential for brain damage, eye issues, and hearing loss in the baby.