M5-Lecture3

Question 1

is a process in which the neural plate bends up and later fuses to form the hollow tube that will eventually differentiate into the brain and the spinal cord of the central nervous system.

Answer 1

Neurulation

Question 2

More than 80 mutant mouse genes disrupt neurulation and lead to the development of NTDs

Answer 2

True

Question 3

Neurulation steps:

Answer 3

1. Neuroectoderm forms from the ectoderm and thickens into the neural plate, with the neural plate border separating it from the surrounding ectoderm.
2. The neural plate bends dorsally, and its two ends join at the neural plate borders, forming the neural crest.
3. As the neural tube closes, it disconnects the neural crest from the epidermis; neural crest cells later form most of the PNS.
4. The notochord degenerates but persists as the nucleus pulposus of intervertebral discs, while surrounding mesoderm cells form somites, which develop into the axial skeleton and skeletal muscle.

Question 4

Neural tube defects - Causes

Answer 4

• Neural tube not close properly
• Develop early during pregnancy
• Most common: SB & Anencephaly, see more
• ## Caused by multiple genes and GxE, complex

Question 5

Risk factors for NTDs

Answer 5

• Have had baby with NTD
• have close relative with NTD
• have type 1 (insulin dependent) diabetes
• Obese
• Take medications (sodium valporic acid)
• Low circulating folic acid levels

Question 6

is the generic name for a type of B vitamin. It’s found naturally in foods asfolate.

Answer 6

Folate (vitamin B9)

Question 7

is the manmade version sold as supplements and added to fortified foods.

Answer 7

Folic acid

Question 8

Folic acid is the fully oxidized monoglutamate form of the vitamin that is used in fortified foods and most dietary supplements.

Question 9

Folic acid - absorption

Answer 9

Passive diffusion also occurs when pharmacological doses of folic acid are consumed.

, the enzyme dihydrofolate reductase reduces the monoglutamate form to THF and converts it to either methyl or formyl forms before entering the bloodstream

Question 10

The main form of folate in plasma

Answer 10

5-methyl-THF

Question 11

Genetic polymorphisms in the population can affect folate metabolism

Answer 11

True

Question 12

can be found in probiotics is one of the significant beneficial bacteria in the human gut microbiota that is beneficial in regulating folate production.

Answer 12

Bifidobacterium

Question 13

also synthesized by colonic microbiota and can be absorbed across the colon, although the extent to which colonic folate contributes to folate status is unclear.

Answer 13

Folate

See diagram

Question 14

is essential for the synthesis of purine and thymidine nucleotides (RNA and DNA), which are needed for DNA replication and repair

Answer 14

Folate

Question 15

Folate is a methyl donor molecule and factor in synthesis of other methyl donor molecules for DNA methylation, which is a key mechanism of epigenetic regulation.

Answer 15

True

Question 16

Folate is important in the conversion of homocysteine to methionine in the synthesis of S-adenosyl-methionine (SAM),

Question 17

an important methyl donor for more than a hundred different methylation reactions fundamental to a wide range of metabolic functions.

Answer 17

SAM

Question 18

Folic acid - Functions

Answer 18

All these processes are particularly important to rapidly dividing cells in any tissue including those during pregnancy.

Question 19

Folate active form is:

Answer 19

Tetrahydrofolate (THF)

Question 20

5,10-methylenetetrahydrofolate is required for the synthesis of nucleic acid, and 5-methyltetrahydrofolate required for the formation of methionine from homocysteine.

Methionine is converted into SAM, essential to many biological methylation reactions, including DNA methylation.

Methylenetetrahydrofolate reductase (MTHFR) is a riboflavin (FAD)-dependent enzyme that catalyzes the reduction of 5,10-methyl… to 5-methyl.. See more

Question 21

About two-thirds of neural tube defects can be prevented through increasing folate (folic acid) intake at least a month before pregnancy and during the first 3 months of pregnancy.

Question 22

Adequate folate levels are critical during the early days of the developing embryo, particularly the 3rd and 4th week, the period in which neural tube defects occur and when many women won’t know they are pregnant

Question 23

choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk.

Question 24

Low levels of folic acid are associated with an increased risk of several health conditions, including

Answer 24

Elevated homocysteine.High homocysteine levels have been associated with an increased risk of heart disease and stroke.
Birth defects.Low folate levels in pregnant women have been linked to birth abnormalities, such as neural tube defects

Question 25

homocysteine can be converted into cysteine using co-factor vitamin b6, through a process called

Answer 25

transsulfuration

Question 26

Low levels of Folic Acid have also been implicated in increased risk for miscarriage, placenta abruption, reduced fetal growth, preterm birth and lip and palate cleft

Question 27

Demands for folate increase during pregnancy because it is also required for growth and development of the fetus

Question 28

A woman who is not planning to become pregnant may still take a prenatal folic acid supplement because neural tube defects (NTDs), such as spina bifida and anencephaly, can occur very early in pregnancy, often before a woman even knows she is pregnant. Folic acid is crucial in the early stages of fetal development, particularly during the first few weeks after conception when the neural tube is forming.

Question 29

Since about 50% of pregnancies in Canada are unplanned, women who are not actively trying to conceive may still be at risk of having a pregnancy during this critical window. Taking folic acid supplements ensures that, if pregnancy occurs, the woman’s body has adequate levels of folate to reduce the risk of NTDs.

Question 30

Mandatory fortification of foods (like bread and cereals) with folic acid has been shown to reduce the incidence of neural tube defects in countries like Canada and the U.S.

45% reduction

Question 31

Folic acid is potentially important in a number of crucial early stages of placental development

Answer 31

EVT invasion, angiogenesis, and secretion of Matrix metalloproteinases (MMPs).

Question 32

Only minimal effects of excess folic acid were observed on the primary indicators of placental health and function studied.

Question 33

Pregnancies exposed to folic acid antagonists have significantly higher rates of placenta-related pregnancy complications

Ex: drugs, medications for mental disorders.

Question 34

Sulfonamides interfere with folic acid synthesis
How?

Answer 34

Addition of PABA into the folic acid by competing for the enzyme dihydropteroate synthetase

Primarily bacteriostatic

Efficacy is enhanced when used with trimethoprim (antibiotic that interferes with the production of tetrahydrofolic acid)

See diagram

Question 35

is known to concentrate folate to the fetal circulation, leading to 2-4 times higher folate concentrations in the fetus

Answer 35

Placenta

Question 36

All three types of receptorshave been associated with folate transport across the placenta during pregnancy

Answer 36

• The folatereceptor (FOLR) in its -α (FOLR1) and β (FOLR2) forms
• The reducedfolatecarrier (RFC)
• The proton-coupledfolate transporter (PCFT)

Question 37

Folate transporter expression in placenta from pregnancies complicated with birth defects

Answer 37

Article title

The goal was to determine if altered expression of these transporters could be linked to insufficient folate supply to the fetus, potentially contributing to the development of birth defects.

The expression of PCFT was greater in placentas from pregnancies complicated with BD than in those from the control group (p < .01). The expression of FR‐α and RFC was not different between groups.

The expression of PCFT in placentas from BD-complicated pregnancies is increased, possibly as an adaptive response to increase the folate flux at the maternal-fetal interface.

Question 38

Another study examined how gestational diabetes (GDM) affects folic acid (FA) uptake by placental cells, comparing primary cytotrophoblasts from GDM-affected pregnancies (DTB cells) to those from uncomplicated pregnancies (NTB cells). It found that GDM altered FA uptake, with DTB cells showing greater sensitivity to acidic pH and 5-methyltetrahydrofolate inhibition, suggesting an increased involvement of the proton-coupled folate transporter (PCFT) in FA uptake.

Question 39

A Canadian study by Yi-Yung Chen et al. found that intrauterine growth restriction (IUGR) was associated with decreased folate transporter activity, specifically a 34% reduction in RFC protein expression in syncytiotrophoblast microvillous plasma membranes (MVM), leading to a 38% lower folate uptake in the IUGR group compared to controls. These findings highlight the importance of continued folate supplementation in the second and third trimesters for pregnancies affected by IUGR, and suggest that alcohol may impair folate transport across the placenta by reducing transporter protein expression.

Question 40

In a 2020 study by Piñuñuri et al., the epigenetic regulation of folate receptor-α (FOLR1) in the placenta of preterm newborns was explored, with a hypothesis that increased FOLR1 methylation is linked to lower cord blood folate and vitamin B12 concentrations. The study found that FOLR1 mRNA expression was lower in the placentas of preterm newborns compared to term newborns and was negatively associated with FOLR1 methylation in the chorionic plate (CP).

Question 41

is one of the most important and common complications during pregnancy and is one of the main causes of maternal and fetal mortality.

Answer 41

Preeclampsia

Question 42

Folic acid may decrease the risk of preeclampsia in different ways:

Answer 42

• reduces the plasma homocysteine
• improves the function of endothelial cells

Question 43

is a serious condition in which theplacentaseparates from the wall of the uterus before birth.

Answer 43

Placental abruption

Question 44

Placental infarction or abruption, recurrent pregnancy loss and pre-eclampsia due to defects in placenta.

Question 45

Deficiencies of vitamin B12 and folate, or other abnormalities within the methionine-homocysteine pathway have been implicated in the development of such placental diseases.

Question 46

Folate deficiency and altered folate metabolism are associated with adverse outcomes for male mice

Answer 46

Infertility and subfertility
Reduced sperm number
Increased sperm DNA damage
Embryo defects

Question 47

Folic acid may help boost sperm count by improving spermatogenesis, the process of sperm production, through its role in DNA synthesis and repair. It also works synergistically with other nutrients, like zinc and vitamin B12, to enhance sperm health and motility.

Question 48

Folate deficiency induces sperm mutations and chromatin fragmentation

Answer 48

There is a doubling of mutation frequency and a doubling in the DNA fragmentation – even though it is doubling, the frequency is so rare.
So increased sperm mutations due to low FA probably isn’t the causal mechanism underlying congenital defects in offspring

Question 49

A study by Kim et al. (2011) examined the effect of paternal folate deficiency on folate content and folate receptor α (FRα) expression in rat placental tissues. They found that while litter size and fetal weight were unaffected, the paternal folate deficiency group (PD) had a 10% reduction in placental weight and a 35% decrease in placental folate content, with a 130% increase in FRα expression compared to the paternal folate-sufficient group (PS). This suggests that paternal folate status can significantly impact placental folate metabolism and transport.

Question 50

A study by Lambrot et al. (2013) investigated the impact of low paternal dietary folate on the mouse sperm epigenome and its association with negative pregnancy outcomes. They found that paternal folate deficiency led to differential DNA methylation in genes related to development and chronic diseases such as cancer, diabetes, autism, and schizophrenia, and was linked to an increased incidence of birth defects in offspring, including craniofacial and musculoskeletal malformations.

Question 51

Folate essential for male reproductive health, as it helps reduce germline mutation frequency and chromatin instability, leading to improved fertility rates. Paternal folate status also plays a critical role in embryo development, placental growth, and protection from developmental delays and congenital anomalies, likely through alterations in sperm DNA and histone methylation.

Question 52

A study by Chaudhry et al. (2019) found that elevated maternal homocysteine concentrations in the early to mid-second trimester were associated with an increased risk of placenta-mediated complications, including small for gestational age (SGA), preeclampsia, placental abruption, and pregnancy loss. The results suggest that higher maternal homocysteine levels independently contribute to these pregnancy complications.

Question 53

in pregnantwomen has been associated with deep venous thrombosis, recurrent miscarriage, abruption placentae, preeclampsia, neural tube defects, and fetal growth restriction.

Answer 53

Hyperhomocysteinemia

Question 54

Homocysteine is an amino acid that, at elevated levels, has been implicated in the development of vascular diseases.

Answer 54

AD, depression, heart attack, stroke, birth defects, osteoporosis,

Question 55

A diet rich in folate, including foods like beans, oranges, asparagus, and dark leafy greens, is beneficial, but it can be difficult for women to meet the recommended daily intake through food alone. Folic acid, which is more bioavailable than natural food folates, may be necessary, as substances like catechins, polyphenols, and alcohol can hinder folate absorption and metabolism.

Question 56

Chronically elevated levels of unmetabolized folic acid may pose health risks, including an increased cancer risk and undetected vitamin B12 deficiency, particularly among the elderly. Some studies also suggest that maternal folic acid supplementation during pregnancy could be linked to childhood allergic diseases, such as asthma, potentially through DNA methylation changes in offspring, with a higher risk associated with folic acid exposure in the first trimester.

Question 57

is a source of methyl groups needed for many steps in metabolism. The body needs choline to synthesize phosphatidylcholine and sphingomyelin, two major phospholipids vital for cell membranes.

Answer 57

Choline

Question 58

functions as a cofactor for methionine synthase and L-methylmalonyl-CoA mutase. Methionine synthase catalyzes the conversion of homocysteine to methionine.

Answer 58

Vitamin B12

Question 59

in coenzyme forms performs a wide variety of functions in the body and is extremely versatile, with involvement in more than 100 enzyme reactions, mostly concerned with protein metabolism. Vitamin B6 also plays a role in cognitive development through the biosynthesis of neurotransmitters and in maintaining normal levels of homocysteine, an amino acid in the blood

Answer 59

Vitamin B6

Question 60

Omega-3 fatty acids, especially DHA, are crucial for brain development in babies, with DHA making up over 90% of omega-3s in the brain. Although ALA, a plant-based omega-3, can be converted into DHA, this conversion is highly inefficient. Iodine is essential for fetal growth, and severe deficiency can lead to serious complications like stillbirth, congenital anomalies, and mental impairments. Vitamin A deficiency during pregnancy has been linked to growth issues, preterm birth, low birth weight, placental problems, and higher maternal mortality.

Question 61

helps your body make blood to supply oxygen to the fetus. Helps prevent anemia, a condition in which blood has a low number of healthy red blood cells.

Answer 61

Iron

Question 62

See diagram

Question 63

Vitamin A

Answer 63

Vitamin A & Reproductive Health:

Essential for sperm production in males (via Sertoli cells).
Supports normal reproductive cycles in females with adequate intake.

Forms of Vitamin A:
Preformed Vitamin A (animal products).
Provitamin A carotenoids (e.g., beta-carotene, plant-based).

Conversion:
Carotenoids (like beta-carotene) convert to retinol (active form).
Fat-soluble, stored in the liver.

Embryonic Growth:
Crucial for development of heart, lungs, kidneys, eyes, bones, circulatory, respiratory, and nervous systems.

Postpartum:
Aids tissue repair after birth.

Other Benefits:
Maintains vision.
Supports immune system.
Helps fight infections.
Aids fat metabolism.

Precaution:
Avoid high-vitamin A foods and supplements (e.g., liver, fish liver oil) during pregnancy, unless prescribed.

Toxicity:
Excess preformed Vitamin A can cause teratogenesis and malformations (affects skull, face, limbs, eyes, and CNS).

Beta-carotene: No major adverse effects or reproductive toxicity, even in excess.

Answer 64

Essential Fatty Acids:
ALA and linoleic acid must be obtained from the diet.
Conversion:
ALA converts to EPA and DHA (less than 15% efficiency).
Direct Intake:
To boost EPA/DHA, consume fish or supplements.
Sources:
ALA: Flaxseed, soybean, canola oils.
EPA/DHA: Fish, fish oil, krill oil (from microalgae).
Body Role:
Omega-3s are crucial for cell membranes (especially DHA in retina, brain, sperm).
Omega-3 vs. Omega-6:
Both form eicosanoids; omega-6 is more inflammatory.
EPA/DHA:
Can reduce inflammation by competing with arachidonic acid for eicosanoid production.
DHA in Fetal Development:
Critical for fetal growth and brain development.
Omega-3 Functions:
Regulate blood pressure, clotting, nerve transmission, inflammation, and hormones.
Pregnancy:
Pregnant women may become omega-3 deficient as the fetus uses them for nervous system development.