Final Flashcards
(152 cards)
1
Q
How can weight from a first pregnancy alter the metabolic status of a second pregnancy?
A
A mother with normal weight at conception might gain excessive weight during her first pregnancy and fail to lose it, resulting in overweight at her second conception.
2
Q
What is meant by the double burden of malnutrition?
A
An individual born into too little or poor quality food is now growing up into a world of excessive, high fat food environment.
3
Q
How does a high fat maternal diet alter maternal behaviour?
A
Results in inadequate maternal care in mice (spend less time caring for their offspring independent of a variety of other factors) resulting in obesity in offspring, early onset or puberty in female offspring, and an increased ACTH and corticosterone response to restraint stress.
4
Q
How does maternal high fat alter the early growth trajectory of the offspring?
A
The pups had a lower birth weight but grew much faster, displaying catch-up growth. They also showed increased fat mass before puberty in showed signs of increase adiposity.
5
Q
How does maternal high fat nutrition alter the reproductive functioning of their offspring?
A
Offspring of these mothers show advanced pubertal onset that is exacerbated with a high fat postnatal diet and in girls. This early puberty is linked to obesity and ovarian reserves in girls are effected, aging earlier, altering menstrual cycle and altering the ability to become pregnant.
6
Q
What is the relationship between perinatal nutrition and MetS risk in adulthood?
A
Adults offspring of HF-fed moms are obese, hyperleptinemic, hyperinsulinemic, and hypertensive even when fed normal diet through out their lives.
7
Q
What is the arcuate nucleus?
A
It is a hypothalamic nuclei. An arc-shaped collections of neuronal cell bodies, they express receptors for many hormones and neuropeptides known to regulate feeding. The ARC interacts with the peripheral circulation through semipermeable capillaries in the underlying median eminence, thus its in an ideal position to integrate hormonal signals for energy homeostasis. It regulates the signals coming in from the gut with the median eminence regulating hormone release.
8
Q
What is the paraventricular nucleus?
A
Hypothalamic nuclei. It is the main site of corticotrophin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH). It is richly innervated by neuronal protections from the ARC, allowing communication. It plays a role in the integration of nutritional signals with the thyroid and HPA axes.
9
Q
How do the ARC and the PVN interact?
A
Projection pathways from the ARC into the PVN allow for the neural control of food intake. When you are full, adipose tissues release leptin, it causes POMC release in the ARC which causes MC4R to be released from PVN. This causes ACTH to be released from the median eminence causing an increase in cortisol release from the adrenal gland, decreasing food intake. When you are hungry, the leptin released triggers NPY release in the ARC, limiting cortisol release and decreasing satiety.
10
Q
What hormone is key in hunger regulation?
A
Leptin. It targets neurons in the ARC to decrease food intake and increase energy expenditure.
11
Q
How does HF effect leptin?
A
High fat results in increased leptin release but is altered by leptin resistance. The brain doesn’t sense the high leptin levels so the signal to shut down hunger and stop eating never comes. The brain actually believes you don’t have enough leptin so it tells your body to eat more and causes food to look more appetizing.
12
Q
What occurred when a leptin deficient mouse was treated with leptin in the neonatal period?
A
Leptin is critical for hypothalamic neuronal circuit formation and the treatment caused an increase in the innervation of PVH by axons form the ARC in neonates, essentially giving leptin back.
13
Q
What occurred when a leptin deficient mouse was treated with leptin in the late postnatal period?
A
Found that this did not reverse the phenotype (disruption of A gRR) and the alphaMSH pathway in adults, indicating the critical window of leptin exposure was earlier in pregnancy.
14
Q
What is the neonatal leptin surge?
A
Occurring in rodents only, it is the spike in leptin seen after birth that corresponds with the post-natal hypothalamic circuit formation.
15
Q
How does post-natal nutrition alter hypothal programming?
A
A large litter saw less milk available and therefore lower neonatal growth but resulted in rapid post weaning weight gain, increased adiposity, and glucose intolerance. It also say a decreased density of alphaMSH and NPY/ArgR fibres (projecting between 2 neurons) in the hypothalamus.
16
Q
How is leptin related to the HPA axis?
A
When leptin is in high levels, it inhibits CRH and AVP release from the hypothalamus and cortisol release from the adrenal gland. Cortisol also increases leptin secretion, so as leptin increases, it inhibits cortisol, reducing cortisol and therefore reducing leptin, keeping homeostasis in place.
17
Q
How are orexic (appetite) mechanisms developed in utero? What does this mean for the fetus?
A
The development of hypothalamic feeding circuits occur in utero and postnatally. Because of this, adverse perinatal nutrition and hormonal cues can act directly on the brain to regulate activity and development, resulting in altered hypothalamic development, particularly in ARC.
18
Q
What stimulates swallowing?
A
Central NPY injection stimulates swallowing of the amniotic fluid in late gestational fetal sheep
19
Q
What regulates the dipsogenic mechanisms?
A
The OVLT. It lacks a BBB, therefore the neutrons can respond to osmotic pressure factors present in systemic circulation. They interact with a variety of nuclei in the hypothalamus that are regulating thirst.
20
Q
How may an adverse intrauterine environment programme appetite or thirst?
A
Altered development of the orexic or dipsogenic (thirst) centres during critical periods of development may affect normal set points for regulation of appetite and osmoregulation. This may contribute to the programming of hyperphagia or salt preferences, obesity.
21
Q
How is inflammation related to the HPA axis?
A
Peripheral and central inflammatory factors can alter HPA function. MetS and obesity are associated with chronic, low grade inflammation, which circulates in the periphery, causing insulin resistance, glucose intolerance, nutrient excess, and finally more cellular inflammation. GCs are important in mitigating these adverse effects.
22
Q
How can perinatal nutrition effect MetS risk in adulthood?
A
Whether high or low perinatal nutrition, it results in altered maternal body weight during pregnancy, and therefore altered levels of maternal hormones (GCs). Low nutrition will lead to a premature leptin surge, a lack of leptin, and an increased exposure to GCs. High nutrition will result in maternal hyperleptinemia, leptin resistance, and an increased exposure to GCs. Both result in an increase in NPY and a decrease in POMC, resulting in potentially permanent alteration in hypothalamic wiring. Changes show in cell number, reduced leptin sensitivity, and altered projection development.
23
Q
In what order to taste responses appear in sheep?
A
Acid taste by mid
Salt and sweet by late
24
Q
What is flavour learning?
A
We learn about flavour by building on the familiar flavour through repeated exposure and increasing complexity (variety) of flavours to which we are exposed. During pregnancy, maternal dietary flavours are transmitted to and flavour the amniotic fluid. Fetal experience of the flavours leads to heightened preferences for these in early postnatal period. Exposures to flavours in breast milk also influence an infant’s liking and acceptance of that flavour as a food. The flavours of weaning foods and subsequently adult foods also affect our flavour preferences.
25
What occurs with a child's flavour preference when the mother consumes a high fat diet?
Perinatal exposure to HF, high sugar diet results in preference for palatable food in the offspring resulting in preference for fat, CHO, and protein. In rodents, that has been linked to permanent changes within the central reward (dopaminergic and opioid) pathways that increase the subsequent drive to over consume palatable foods.
26
Describe the development of the central reward system in humans.
Development of the DA system begins are early as 6-8 weeks of gestation with the opioid system beginning to develop slightly after.
27
How are preferences for sugars or high fats programmed?
Poor maternal diet causes an increase in transplacental or breastmilk transport of hormones, specifically leptin, insulin, and endogenous opioids, to the offspring. The increase in levels during a critical window will alter the reward system. The DA and opioid signalling pathways may be permanently altered with an increased preference for a suboptimal diet. This leads to consistent or over-consumption, resulting in obesity.
28
How can preferential perinatal flavour learning be altered?
Breastfed and formula fed infants can learn to like flavours of different foods depending on what and to the degree they are exposed to something.
29
What is the predictive adaptive response?
Adaptations in utero are done with the assumption that the infant will be born into the same stressful environment. This often results in a mismatch with sufficient/excessive ex-utero environment and places babies at increased risk for developing metabolic diseases in adulthood.
30
What is the mismatch hypothesis?
Individuals are more likely to suffer from disease if a mismatch occurs between their in utero environment and their postnatal environment. The degree of the mismatch determines the risk of later disease.
31
Why do not all children exposed to poor pre- or post-natal environments develop disease?
Genetics has a lot to do with this. they may be additive (or protective) to the influence of the early life environment. There is evidence that polymorphisms within genes act as primary contributors of an individual's risk of disease.
32
How are genetics associated with obesity?
There is an association between the A allele in the Fat Mass and Obesity Related Locus (FTO) and MBI in childhood. They often show a low BMI in infancy, an early adiposity rebound, and a greater BMI during childhood. This rebound is known to be associated with a risk of adult fat mass and metabolic disease (T2DM). Interestingly, breastfeeding mitigates the impact of these adverse genetics.
33
Why is breast milk protective against some genetic issues?
Human milk contains nutrients and bioactive molecules. The milk composition changes from the first milk to the end of lactation, with changes in maternal diet, disease state, preterm birth, genetics, and environment. It contains nutrients that are important for brain and gut development that might be missing in formulas.
34
How do feeding environments effect a childs developmental trajectory?
Programming factors such as milk composition, introduction of complementary feeds, and feeding practices can shape the infants phenotypes. Those that are breast fed gain weight slower and have a lower adiposity than those that use formula or receive early complementary feeding. The difference in hormonal cues from BM may also influence hypothalamic development and connections between the brain and the gut, which can influence distal sites including adipose tissue. The differences in growth and susceptibility to metabolic diseases in breast vs. formula fed infants could arise from different responses of these infants to these types of feeding, or difference exposures to bioactive compounds in BM.
35
What is the importance of leptin in breast milk?
The BM [leptin] correlates with maternal and infant plasma [leptin]. The BM derived leptin may cue the infant to eat less, slowing weight gain as the leptin binds to receptors in the gastrointestinal epithelium, resulting in satiety signals.
36
What is the importance of adiponectin in breast milk?
Works opposing leptin and is protective against obesity. It is important in glucose and fatty acid oxidation, although less is known about its role in BM as a postnatal growth factor. It is highly glycosylated in BM, which may protest it from breakdown in the stomach, increasing bioavailability in the infant.
37
What is the importance of ghrelin in breast milk?
Important in hunger signals. The BM [ghrelin] correlates with the infant serum [ghrelin]. This is unregulated in the infant during periods of rapid growth and correlates with weight and weight gain in the first month of life. This may promote increased appetite and increased E intake, leasing to increase adipose tissue deposition in early infancy. These levels are higher in formula-fed babies.
38
Why does feeding behaviour matter?
Hormonal cues from breast milk may programme appetite regulation, therefore differences in feeding behaviours and type may influence hypothalamic circuitry development and connections between the gut and brain which can influence distal sites including adipose tissue. Difference in growth and susceptibility to metabolic diseases may arise from responses to different feeding types or exposure to bioactive compounds in breast milk.
39
What are HOX genes?
Transcription factors that regulate patterning of embryos into regions along the AP axis. This includes some factors that regulate development as well as the gut. Some are expressed in the mesoderm in overlapping patterns whilst some are expressed in the endoderm.
40
Aside from HOX genes what else are involved in gut patterning?
Some molecules have opposite functions in different areas of the gut, or functions that can change with time even in the same area.
41
What does the gut come from?
The endoderm.
42
How do the 3 germ layers form?
Through gastrulation, the 3 germ layers are formed from the epi and hypoblast. The embryo forms an indentation called the primitive streak along the dorsal surface of the epiblast. A node at the end emits growth factors, direct cells to multiply and migrate, flowing the mesoderm and the endoderm, cells remaining in the middle form the ectoderm.
43
What is gut rotation?
The twisting and movement of the digestive tube during development. The stomach first begins to form along with the small intestine. The pharynx ascends first followed by the descent of the stomach from around the neck to the higher areas. The elongation of the midgut then continues quicker than the rest of the body and the midbrain herniates into the EEC. This allows for the development of the midgut loop in line with the superior mesenteric artery. The stomach twists counter clockwise along the longitudinal axis with the midgut going opposite, causing twisting. At around 6 weeks, the midgut forms cycal buds and begins rotating. At around 10 weeks, everything descends into the final locations and the midgut returns into the cavity.
44
What types of stem cells are in the intestines?
Putative stem cells. Residing in the crypts, just above the paneth cells. These give rise to all the cells of the gut.
45
What are the 4 types of cells that putative stem cells give rise to?
Enterocyte, panted, goblet, enteroendocrine cells
46
What are the secretory cells of the stomach?
Mucous cells: secrete mucous and bicarbonate
Parietal: cells secrete gastric acid (HCl) intrinsic factor
Chief: secrete various enzymes for food breakdown
Endocrine: secrete serotonin, gastrin, glucagon, somatostatin, and other hormones
47
What is the function of enterocytes?
Columnar cells with apical microvilli that perform hydrolytic and absorptive functions. They also express receptors and other singling molecules involved in the innate immune response.
48
What is the function of goblet cells?
Located in the middle of the crypt to the tip of the villas, they secrete mucus to protect the stem cells at the base of the crypts.
49
What is the function of paneth cells?
Columnar epithelial cells with apical granules that hold an innate immune function and are associated with microbial defence by secreting antimicrobial peptides that combat bacteria.
50
What is the function of endocrine cells?
They produce gastro-intestinal hormones that influence GI secretion, motility, or postprandial satiety.
51
What triggers the functional development of the gut?
An increase in GCs before and during parturition triggers this as well as several environmental cues during the neonatal period that signal adaptive changes in gut function to facilitate post-weaning survival.
52
What are the different aspects of gut functional maturation?
```
Regulation of amniotic fluid volume
Motor activity
Digestive and absorptive activity
Immunity
Nutrition
```
53
Describe the act of swallowing during gestation.
As the fetus grows, the volume of amniotic fluid swallows increases, starting at around 11 weeks and peaking at about 34 weeks.
54
How often does amniotic fluid turn over?
The volume turns over every 24 hour. IT is cleared via swallowing.
55
What is hydramnios?
An inability to swallow that leads to excess amniotic fluid volume.
56
What occurs if swallowing is prevented?
The gut development becomes delayed. By preventing the passage of injected fluid in sheep during late gestation, it retards the development of the small intestinal mucosa whilst sparing the non-mucosal elements. Although it has no effect on fetal weight, you see reduced SI volume and a lack of fluid in the stomach. Peristalsis is less motile and there is a decrease in mucosal epithelium growth, with shorter villi and an increased villus density.
57
What occurs if saline is swallowed as opposed to amniotic fluid?
The constituents of the amniotic fluid are trophic for the fetal gut. Saline was less effective at promoting intestinal development. Amniotic fluid in mice has promoted villus growth, crypt development, and premature differentiation of paneth cells.
58
How does maternal nutrition effect gut development?
Nutrition is a potent trophic stimulus for GIT growth. It supplies nutrients for growth and oxidative metabolism of mucosal epithelial cells as well as indirectly triggering release of growth factors, gut hormones, and activating neural pathways.
59
What occurs to the gut with improper maternal diet?
Maternal malnutrition and neonatal starvation cause diseases in gut tissue mass, shortened willing, increased catabolism, and decreased protein synthesis.
60
What is required for proper motor development of the gut?
Integrated neural input
Muscular contractions
Effective peristalsis
Coordination of these with enteral intake
61
What are migrating motor complexes?
Generate peristalsis, the facilitate the transportation of indigestibles substances through the GIT, transport bacteria for SI to LI and inhibit migration of colon bacteria into terminal ileum.
62
What is the function of peristalsis?
Spatial organization, something essential for proper function of GIT. It comes online when the function of the motor gut is required.
63
Describe the development of the MMC.
Initially short closers of rhythmic activity coordinated with the development of the enteric nerve system that progressively increase but are fairly unorganized (24w). Clear intervals appears at 32 weeks and is known as the classical fetal pattern. By 36 weeks, the mature MMC is in place, showing quiescence state and regular and irregular waves. Similar to adult but periods are much shorter.
64
What is found in the gut during fetal life?
Swallowed amniotic fluid, secretions from the intestinal glands, bile, swallowed tracheal secretions, and cellular debris.
65
When does the gut enzymatic function develop?
The brush borders are present early in gestation, around 10 weeks.
66
Describe the development of immunity.
Intraepithelial lymphocytes are present in the 2nd trimester but immature until term. Also have mucosal protection by gastric acid and gastrointestinal motility clears microorganisms, other toxic substances from prolonged contact with G!.
67
How does the micro biome effect pregnancy?
In germ free mice from T3, it was found that they had an increased adiposity and greater response to rising levels of blood glucose. This suggested from permissive effects of he microbes in T3.
68
How does the mode of delivery effect gut micro biome of an infant?
Vaginally delivered babies have micro biomes similar to maternal vagina where as C/S delivery babies are more similar to maternal skin.
69
What are some factors that have been showed to be associated with variance in the micro biome?
Maternal BMI, maternal probiotics, birth mod, breast milk, solid food, probiotics, vitamin D, geographical location, household sibling, pets, living on a farm, and antibiotics.
70
What is the most important factor in determining variation in the gut micro biome?
Breast milk exposure in the first 14 months. Bottle fed macaques had less rich and diverse micro biomes compared to breast fed macaques, still very different at 6mo. Had radically different immune systems by 1 year of life.
71
What are the different functions of the featl gut?
```
Regulates amniotic fluid volume
Motor actiivty
Digestive activity
Absorptive activity
Nutrition
Excretion
Immunity
```
72
What factors affect gut growth/developemtn?
Swallowing
Growth factors
Nutrition
Blood supply (placenta)
73
Describe the postnatal gut development.
We have substantial GIT growth after birth, increasing in length and crypt complexity as the cells come online, facilitated but hormones secreted in maternal milk. Passive immunity is also acquired via the gut as IgA in the breast mild is absorbed and confers immunity to infections.
74
How does the function of the gut change post-birth (by enteral feeds)?
Gastric pH is significantly higher after birth and is then lowered through buffering. There is a dramatic change in the hormonal profiles with enteral feeding, there is a decrease in the efficacy of bile acid metabolism, and the blood flow is profoundly effected by the release of vasoactive hormones.
75
What is th role of gastrin in the gut, the postnatal changes, and the implications?
It regulates gastric secretions in the stomach and has an affect on gastric mucosa. After birth, the levels remain high for several weeks and increases further with first feeding, flowed by a drop at 3-4 weeks. The gastric acid levels are low despite high gastrin due to a lack of receptors or inhibitory effects of peptide yy and neurotensin, which allows gastrin to stimulate gastric muscousal maturation without excess acid secretion.
76
What is th role of secretin in the gut, the postnatal changes, and the implications?
In the duodenum, it neutralizes acidic chyme entering. At birth we see higher basal levels with more marked increases with feeding in the first 3 weeks. It may protect the mucosa using malnutrition and occurs even in the absence of feeding.
77
What functional changes occur in the neonatal gut with enteral feeding?
```
Increase in gastric pH first few days after birth
Hormonal changes
Blood flow
Growth
Passive immunity acquired.
```
78
What failures can occur in gut development?
```
Structures to separate
Rotation
Gut return into abdomen
Recanalisation
Grow
Mature
```
79
What occurs when separation of the gut fails?
The proximal and distal esophagus fail to separate. resulting in part of the esophagus attached to the trachea. Can result in esophageal atresia, where the path is closed or absent or tracheoesophageal fistula, an abnormal connection.
80
What occurs when rotation of the gut fails?
Failure of any of the gut rotations will lead to malposition of the gut. This results in an increased risk of twisting the bowel around the mesenteric stalk, leading to compromised blood supply, as opposed to normally lining up with artery. This may also be associated with malnutrition (maybe a HOX gene defect in patterning or timing)
81
What is microgastria?
Failure or arrest of appropriate development of caudal portion of foregut = smallness of stomach. It is associated with large esophagus and incomplete gastric rotation.
82
What occurs when the gut fails to return to the abdominal cavity?
Omphalocele: covered by sac of peritoneum and amnion
Gastroschisis: no sac
No midgut rotation
83
What is a recanalisation failure?
Duodenal atrasia (DA): failure of recnaalisation during duodenal development from solid stage to tube-like structure. Prevents stomach contents from passing and often seen as secondary to other malformations of abnormal rotation. Results in what looks like two separate cavities as the tube of the stomach develops in two different parts.
84
Define developmental programming.
A stimulus or insult operating at a critical/sensitive period of development could result in long-term effects on structure or function of the organism.
85
How does the gut effect IUGR
The increased permeability of the epithelium and decrease in mucosal immunity increases IUGR rates. IUGR and preterm infants also take longer to establish enteral feeding.
86
Could we bypass the placenta for treatment of IUGR?
Yes. Since IGUR normally results from placental abnormality, by passing it my treat IUGR. Evidence shows that an amniotic infusion of IGF-1 can partially improve growth of IUGR in offspring. As a regulator of fetal growth, we see a decease in IGF-1 in IGUR kids. It is found in the amniotic fluid. When sheep were treated with IGF, they were able to recover and fix their growth rate due to IGF bypassing the placenta and going tinto the gut. It also altered placental characteristics, improving its ability to improve the direct administration of IGF, with a longer treatments increasing overall growth.
87
Why are babies born at term with gastroscisis (GS) smaller than premies with GS?
Preterm babies are still earlier in their development where the fetal gut is not yet required to supplement placental nutrient supply for normal fetal development. As the pregnancy progresses in the last few weeks, growth requires a functioning investing to supplement the placental supply.
88
Why are babies born with proximal intestinal atrisia (IA) smaller than babies with distal IA?
Figure out
89
Why are babies born with proximal IA smaller than premature babies?
Figure out
90
Why are premature babies at risk for reduced nutrition?
Immature digestive function as the final maturation occurs shortly before and after term. It is also associated with other complications such as problems transitioning from parenteral to enteral nutrition, taking longer to establish enteral feeding although require optimal feeding as premies. Many also experience postnatal growth failure.
91
How does the environment differ between fetus and preterm infant and how does this effect their nutrition?
After birth, premies receive more fat and CHO that age-matched fetus in utero, leading to accelerated post-natal growth. This can increase visceral adiposity in preterm infants, potentially due to a protein:energy imbalance. The question is whether it would be more beneficial to match premies nutrition to age-matched in utero.
92
How are GI hormones and enteric peptides in the gut problematic for premies?
The initiation of feeding is followed by an increase in plasma levels of endocrine factors (Implications?). The intestinal immune function is also immature in preterm infants with a greater permeability to macromolecules than in normal kids.
93
What is necrotizing entoercolitis (NEC)?
Inflammation that causes destruction of the bowel. It affects preterm infants after initiation of enteral feed, occurring in the first 2 weeks of postnatal life. Risk factors include preterm, low birthweight, feeding (esp. formula), patent ductus arterioles, and hypotension.
94
Why is NEC so common in premies?
Gut bacterial colonization in premies is altered due to less diversity that can result in pathogenic proliferating causing mucosal injury (also metabolic programming). When combined with enteral feeding, (breast milk reduces, formula increases NEC risk) and the abnormal physical barriers, immune cells, biochemicals, and MMC in premies results in bacterial overgrowth and increased endotoxin exposure.
95
How can we prevent NEC?
```
Can be prevented by altering the gut micro biome through:
Probiotics
Probiotics
Breast milk only
Growth factor supplementation
```
96
How is gut micro biome linked to obesity?
In rats, when TLR-5 was knocked out, it caused obesity. They then took the stool and gave it to germ free mice, casing these mice to become obese, showing a direct causative association between TLR-5 and metabolic syndrome. When the KO mouse was give antibiotics to wipe out microorganisms, the syndrome was corrected.
97
How does diet alter the gut micro biome?
A diet high in fat showed a reduced number of microbes in their gut micro biome. However, some were found to be sensitive to high fat diets and stayed lean but had an identical micro biome. Their diet was associated with the change. Similarly, it was found that normally nourished kids had different micro biomes that those on the same diet but were undernourished. When hey preformed the fecal transfer to GF mice, the undernourished ones gained less weight and had decrease in their lean mass, typical of malnourished infants.
98
How could microbes alter the ability to remedy malnutrition?
In a study, they took animals with UN and normal micro biomes and mixed them in a cage. After consuming poo of moral mice, the UN were able to recover their lean mass. They then took the top five bacteria that differed from healthy to UN poo, and created a cocktail. When fed back to the UN mice, they were able to regain the weight.
99
How might the gut micro biome alter our stress?
They took mice and stressed them out. They measured the stress in normal, GF, and pathogen free mice and found that the micro biome can alter the stress hormone output. GF mice had increased stress compared to normal and controls. They found that you can treat with a bacterium to prevent that increase in HPA axis response to stress by transferring faces at an early age, partially reversing this response to stress.
100
What is total parentral nutrition (TPN) and what is it associated with?
Feeding intravenously, bypassing the gut and thus, digestion and absorption. The formula contains various nutrients but decreases growth and causes atrophy of the intestinal mucosa. Also associated with decreased gut DNA, protein mass, cell proliferation, protein synthesis,and secretion of gut peptide hormones and growth factor, as well as increased gt apoptosis and proteolysis.
101
What are some causes of sub/infertility?
Problems producing eggs - phenotype: irregular/no menstrual cycle
Low sperm quality or quantity
Hormones - abnormal function of the HPA and HPG axes or exposure to endocrine disruptors ex. BaP
Obesity - often associated with hormonal dysfunction which can impact production and release of sex hormones required for reproduction
Other chronic illnesses and treatments (diabetes)
STIs
Drugs (prescription or illicit)
Advanced paternal or maternal age
102
What are some structural or disease based causes of sub/infertility?
Polycystic ovarian syndrome - cysts in ovaries prevent follicle development and egg release
Uterine fibroids or polyps
Endometriosis - endometrium tissue grows outside uterus
Fallopian tube blockage or damage - prevents sperm+egg contact or egg movement
Early menopause
103
What causes the age related decline in fertility seen in women?
There is a decrease in monthly odds of conception begins at age 40 as well as an increase in the odds that pregnancy will terminate after conception or implantation.
104
How does paternal age affect their sperm?
See declines in seman volume and sperm performance with increases in malformed and DNA-damaged sperm.
105
How did they discover woman do not have a finite number of eggs?
When looking at mouse ovaries, they found cells that resembled the stem cells normally found in fetal mouse ovaries. When looking for MSG gene expression (normally expressed in germ line cells), it was detected, indicating germ line cells that underwent high proliferation and mitosis. Had found a stem cell population in follicles in ovaries. When looked at in humans, they identified a rare cell with cell surface expression of DDX4, indicating adult oogonial stem cells (OSCs) that can generate oocytes when implanted into mice.
106
How might oocytes generated in adulthood contribute to fertility?
Using YFP, they tracked germ cells in adult follicles and found that stem cells made new eggs and produced offspring, meaning they were functionally active.
107
Describe IUI.
Intrauterine injection. Involves injecting sperm directly into the uterus to avoid the clerical music in the cervix, as this is a protective barrier that makes fertilization difficult. Typically performed through two inseminations across two days before and after ovulation, this works well for low sperm count, unexplained infertility, and the presence of anti-sperm antibodies.
108
Describe IVF.
The eggs are fertilized outside the uterus them implanted via IUI. A woman is given a hormone treatment to induce ovulation of multiple eggs which are then harvested from the ovaries. The eggs and sperm are mixed in a dish then fertilized eggs are incubated for 48 hours to allow embryo development. 1-2 fresh embryos are them implanted into the uterus. This is good for damaged or blocked fallopian tubes, low sperm count, advanced maternal age, reduced ovarian reserve, severe endometriosis, PCOS, or idiopathic infertility.
109
Describe ICSI.
Intra-cytoplasmic sperm injection. This is used in conjunction with IVF. The eggs are collected but this time the sperm are collected and assessed for quality. The cumulus cells are then removed from the eggs and assessed for maturity. A single sperm is injected into the cytoplasm of a mature egg which is then incubated and checked for fertilization, implanted once an embryo is present. This is good for couples with unsuccessful IVF, men with poor sperm morphology, motility, or low count, obstruction preventing sperm release, or anti-sperm antibodies.
110
What are three parent babies?
Babies that have undergone mtDNA screening and IVF. Mothers with inherited mt disorders have the defective mt replaced by a donor mt. The material DNA remains as the nuclei is transferred to the donor egg, which is then fertilized with father's sperm and implanted into the mother via IVF. Although still only in trials, does hold promise. However, involves freezing and thawing oocytes several times as well as lots of oocytes to be collected in order to have a hope of working (ex. out of 29 oocytes retrieved, 5 were usable, 4 developed into blastocysts, and only one was euploid). Another issue is that some maternal mt DNA still remained, therefore not completely preventing disease transmission.
111
How might mt screening increase fertilization with IVF?
High levels of mtDNA in embryos are associated with implantation failure, therefore some trials are now screening blastocysts for mtDNA levels and selecting and implanting only those with appropriate levels. This is believed to increase IVF efficacy and success rates.
112
Ho is mtDNA screening achieved?
The patient is insects with hormones and eggs are collected (IVF) which are fertilized with sperm. At 5 days, 5 cells are removed from the embryos and tested for mtDNA levels. The embryos that did the optimum threshold will be implanted.
113
What is egg rejuvenation?
The mt in some eggs contributes to poor embryo viability. This process harvests younger mt from egg precursor cells and injects it into older eggs to replacing the aging mt. This si believed to improve embryo quality and viability.
114
Explain the process of egg rejuvenation.
The eggs are taken from a small biopsy of the ovaries. Precursor cells are cultured and frozen with their mt being injected with sperm into the IvF egg.
115
What are sperm bots?
They are a motorized apparatus to assist with sperm delivery and fertilization used for male infertility.
116
Compare natural and ART conception.
Maternal age: 20-30 vs 30-40
Gonadotropins: endogenous, variable, [modest] vs. exogenous, as ordered, [higher]
Steroids: natural vs. [higher]
Ovulation: natural after LH surge vs. natural (IUI) or various triggers with egg retrival (no ovulation)
Follicles and oocytes: several mature with a single dominant one vs. increased numbers with many co-dominant
Uterine interaction: after passage through fallopian tube vs. after incubation in media and deposited through cervix (usually significant steroid exposure precedes)
Insemination: vagina to oocyte vs. cup to tube to dish or cytoplasm
117
How might oviductal fluid effect development?
Early embryo undergoes massive DNA meth. reprogramming of it's genome as it travels in oviduct, factors in the fluid impacting this methylation. Bovine embryos cultures in the presence of oviductal fluid show changes in blastocyst DNA meth. and mRNA expression in genomic regions of developmentally important genes.
118
What might impact the pregnancy rates of ART?
Intercouse during IVF could improve pregnancy rates potentially through improved embryo development and/or implantation. Exposure to seman around the time of embryo transfer increases the proportion of viable embryos at 6-7 weeks post-ET. Exposure to seminal plasma around the time of egg retrival improves IVF pregnancy rates.
119
What is found in seminal plasma?
Hormones (E2, PGs, testosterone), signalling molecules (TGF-B), cytokines, bacterial polysaccharides.
TGF-B is the primary component and its concentration in SP is amongst the highest measured in biological fluids.
120
What are some of the roles of seminal plasma?
When the female immune system is first exposed to SP, it exposes to paternal antigens, resulting in an inflammatory-like response, activating immune changes in the female and promoting fertility. The SP interacts with the cervix and endometrium while embryo proceeds pro-inflammatory cytokines, supporting implantation. TGF-B is key to the post-intercourse inflammatory response and likely initiates the process of immune tolerance to seminal antigens, priming the female immune system for implantation.
121
Why is it hard to judge the quality of artificial environments for ART?
Protocols have changed with little consensus over the years and minimal testing for safety. This includes ovarian stimulation vs natural, use of recombinant FSH or urinary FSH for ovulation induction, various methods of oocyte fertilization, different medias for culture, duration of culture, and fresh vs. frozen gametes and embryos.
122
What are some outcomes associated with single pregnancy outcomes with ART?
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Prematurity
Low birth weight and very LBW
SGA
Perinatal mortality
Birth defects
(ex. cerebral palsy)
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123
Why might frozen embryos be better than fresh for ART?
Believed they may reduce the rates of PTB and LBW by reducing the amount of hormonal change in the environment of the embryo as well as less hyper stimulation of the microenvironment.
124
How does ART media effect pregnancy outcomes?
In a study, it was found that birth weights in babies cultures in two common medias had a difference of 200g, similar to the difference seen in smokers and non-smokers, indicating a link between media and pregnancy rates and birth weights.
125
How does ART result in programming?
Mouse embryo culture and embryo transfer is associated with hypertension, increased endothelial dysfunction, vascular stiffness, and arterial blood pressure in adulthood. Systemic vascular function also decreased, overall indicating a general vascular dysfunction in otherwise healthy kids that were conceived with ART. There was also a difference in blood pressure and fasting glucose levels between IVF and control children, indicating alterations in metabolic outcome. Body composition was also different. HPA axis was also altered, with a decrease in awakening cortisol levels in pubertal ICSI females, indicating that ART conception may reprogram HPA development and function.
126
How does a low protein paternal diet alter sperm, SP, and maternal preimplantation uterine environment in mice?
LPD testes decrease DNA meth. and folate cycle enzymes, sperm lowers DNA meth. and seman blunts maternal uterine cytokine and immunological responses.
127
How does paternal LPD alter offspring metabolic phenotype via sperm and SP in mice?
It results in increase weight postnatally, response to glusoce challenge test and gondola fat:body weight, indicating changes in body composition and growth trajectory postnatally.
128
How does a high fat diet effect ART conceived offspring?
Reduced lifespan.
129
Can ART programme the next generation?
In this study, a male ART derived mouse was mated with female control mice. When vascular function and blood pressure were measured in the male offspring, they were found to be comparable to the levels observed in their ART fathers (increased).
130
What are some outcomes associated with increased paternal age (>45)?
Increased preterm, low birth weight, and seizures as well as gestational diabetes. Decreased ATGAR scores. Overall, increased paternal age was increased with an increased rate of adverse birth defects.
131
What are the mechanisms behind adverse outcomes with paternal age?
High number of germ cell divisions in aging fathers combined with epigenetic changes in spermatocytes of older men leads to an increased number of genetic changes with age, which could affect fetal growth and maternal pregnancy health/outcomes.
132
How is autism affected by paternal age?
In swedish study, found that autism risk increase with paternal age. Those born to men 50 or older were 2.2X more likely to have autism than those born to less than 29. Was seen in siblings as well. Even travelled across generations with granddaughters having 1.79X more likely and grandsons 1.67X more likely compared to fathers of 20-24 years. Increased even more if father and grandfather were of advanced paternal age.
133
How is schizophrenia effected by paternal age?
Found that kids with dads 30 or over have increased risk of schizophrenia compared to 25-29 as well as those <25.
134
Compare spontaneous and induced mutations.
Spontaneous: due to errors associated with normal processes, reaction with metabolites (ROS) that induce damage, or sites of endogenous damage that don't get repaired.
Induced: exposure to a mutagen resulting in damage to the DNA or alterations in cellular processes that can result in genetic damage either directly or indirectly.
135
What is the difference between mutations in germ-line and somatic cells?
Germaine: a mutation occurs in the egg or sperm that are inherited and occur in the testes or ovaries
Somatic: a mutation occurs in the body cells after fertilization that are not inherited but can affect an individual through lifetime.
136
What is somatic mosaicism?
Only certain cells in the body carry the mutation. Mainly seen in skin diseases.
137
How are germ line mutations and somatic mosaicism related to ASD?
ASD brain has deleterious mutations in candidate ASD genes as well as somatic mutation only in parts of the brain. Suggests that combination of these two mutations contributes to ASD risk.
138
What is copy number variants?
Abnormal number of copies of a section of the DNA. Results in neuropsychiatric disorders, cognitive disabilities, and cancer.
139
What de novo genetic mutations are maternally linked? Paternally?
Maternal: Autosomes (13, 18, 21)
Paternal: Turner (XY), Klinefelter (XXY), XYY
140
How does paternal age affect mutation rate?
There is a great risk of negative outcomes with increase in paternal age due to an increase in mutation transmission.
141
How does the presence of maternal stem cells alter how we think about maternal age and fertility?
Eggs produced later in life could be generated from stem cells that underwent multiple additional cell divisions, with increased chance of mutation accumulation.
142
Why are sperm more likely to have mutations?
Spermatogenesi is ongoing throughout life, resulting in a large number of divisions in the stem cells and creating lots of opportunity for mutations to occur, resulting in an enhanced effect with maternal age.
143
What are the critical windows of genetic damage?
Gametogensis
Fertilization
Embryogenesis
144
What are tandem repeat mutations?
Mutations that result in gains/losses of repeat until
Microsatellites: 1-6bp, associated with fragile X syndrome, due to replication issue.
Mini satellites: 10-100kb, very high mutation rate, mostly due to issues in recombination process during mitosis
145
What are some different mutagens that can cause mutations in germ cells?
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Ionizing radiation
ENU
Smog
Smoking
Air pollution
FolicAcid deficiency
Chemotherapy drugs
```
146
Do paternal lifestyle factors influence minisatelite mutation rate?
Yes. Fathers who smoke 6mo prior to conception saw a dose response relationship between smoking and mutation rate in offspring.
147
How does BaP effect sperm?
Mice stem cells were exposed to BaP and left to become sperm. The sperm were collected and used to either mate with females of analyzed using next generation sequencing. They found that BaP increased micro satellite mutations at specific loci in a dose-response relationship, depending on the loci. This was shown at multiple loci, concluding that BaP caused it. Proved that chemicals can induce micro satellite mutations which can be used to monitor for environmental chemicals. Can be used to analyze exposure at a population level.
148
What are some critical windows of vulnerability in spermatogenesis?
Ideally, we would want BaP exposure to occur in the dividing spermatogonia (most sensitive) but can also occur in the stem cells or the sperm. Found that the dividing spermatogonia had that highest rate of mutations after exposure due to their rapid divisions although stem cells were also effected, which allowed it to be passed onto offspring.
149
Do germ cells and somatic cells differ in their response to mutagens?
Spontaneous mutations G to A are more common in sperm than bone marrow and BaP-induced mutation spectra differs between sperm and bone marrow, responding differently to the exposure. Bone marrow sees more substitutions, where as sperm see more deletions. Suggests that germ cells and somatic cells have different mutation mechanisms.
150
Is the in utero environment important in the context of mutations?
Embryonic/fetal periods are critical to optimal tissue and organ development as a single cell may be a progenitor for a larger tissue or organ and changes can therefore impact many cells, leading to somatic mosaicism. This can impact both somatic and germ line cells, affecting both the individual and the individual's offspring/fertility.
151
Can chemicals induce mutations in utero?
Pregnant mice were treated with BaP through transplacental exposure, covering a major period of fetal organogenesis. They examined tissues from the major cell linages in the offspring and found that although there was no difference in the litter size or post-natal body weight, there was a decrease in testes weight, [sperm] and motility at higher [BaP] (impacted germ line cells) and decreases in primordial and primary follicles at every dose in females meaning something about oogenesis caused increased sensitivity. They also saw an increase in mutation frequency across all three germ layers (somatic cells such as bone marrow, brain, liver) in males. The mutation frequency in testes, sperm, and ovaries also increased with increased dose.
152
How does in utero BaP exposure compare to adult exposure?
Cells in the brain and liver were seen to sustain more mutations in utero as they are rapidly dividing during development. Bone marrow cells were seen to sustain more mutations with exposure in adulthood as that is when they are dividing. Indicates that the developing tissues have higher rates of mosaicism, seen only in bone marrow and sperm in adult hood but in bone marrow, liver, brain, sperm and ovary in utero. Therefore the more active a tissue is after birth, the more likely mutations occurring in utero are to expand.
