Midterm 1 Flashcards
The Barker hypothesis posits that bad genes are responsible for chronic disease (T/F).
False! Unhealthy womb environment, as well.
What did the Hertfordshire Cohort Study show?
1980’s study in England and Wales found a correlation between rates of heart disease and infant mortality. A U-shaped graph for birth weight vs. mortality from CHD. Fetal death rates went along with CHD mortality rates in the area.
What did the Helsinki Birth Cohort study show?
Adults with CHD tended to have poor growth from infancy to age 2, then a sharp weight increase (postnatal catch-up) from ages 8-10.
The Dutch Hunger Winter showed which effects at early, mid, and late exposure to famine?
Early: 3x higher risk of CHD + obesity in women.
Mid: Light birthweight + obstructive airway diseases in adulthood.
Late: Light birthweight + impaired glucose tolerance in adulthood.
LBW is like a _________ of fetal adaptation to adverse prenatal environment.
surrogate marker
How does inappropriate stimulus / incorrect developmental window affect disease risk?
Raises it such that the risk is higher earlier in life.
Developmental plasticity is the ability of an organism to develop in various ways depending on _____.
the particular environment or setting
The reaction norm is the range of _______ that can be induced in a given environment.
phenotypes
What are the three characteristics of developmental plasticity?
- The response is somewhat dependent on environmental cues.
- There are critical windows for systems’ plasticity where they’re more vulnerable to change.
- The duration is time-limited to organogenesis.
How does developmental programming operate within the context of plasticity?
A stimulus or insult applied at a critical period of development will have lasting effects on the structure/function of the body leading to higher risk of disease later in life.
Differentiate between the Developmental Constraints Model and Predictive Adaptive Response Model.
DCM is that organisms adjust their phenotype during development to avoid immediate death.
PAR is that organisms adjust their phenotype based on developmental cues to optimize later performance, but can lead to disease when the predicted environment is incorrect.
The Thrifty Phenotype Hypothesis is an example of which model?
Both?
What are two examples of evolutionary and developmental mismatch?
Evolutionary: IVF and formula diet.
Developmental: Unbalanced maternal diet, placental disease.
What is the Thrifty Genotype?
Repeated famine exposure has led to positive selection for efficient energy storage genes now leading to higher obesity rates. Evolutionary mismatch.
What is the Thrifty Phenotype?
Fetal reallocation of energy stores towards brain development, altering other development and creating insulin resistance. Developmental Mismatch.
What are examples of some stressors that can act as a “second hit” for pathogenesis?
Nutrition, disease, infection, and toxicant exposure.
Epigenetic marks control the expression of genes that function in ________.
embryonic development
Name 4 types of epigenetic programming.
Methylation marks, Genetic imprinting, X-inactivation, and somatic cell differentiation
Which genome undergoes rapid demethylation and histone modification right after fertilization?
The paternal.
How is the maternal genome marked following fertilization?
Gradual demethylation, eventually a new wave of embryonic methylation that establishes blueprint for developing tissues.
Imprinted genes are genes whose expression is determined by _______.
the parent that contributed them, contrary to normal rules of equal inheritance
Why are there lots of epigenetic defects in the majority of cloned embryos?
Inefficient reprogramming of the somatic cell to the epigenetic state of the embryonic nucleus for which it’s substituting.
Name 3 methyl-donating nutrients that can rapidly alter gene expression in early development.
Folic Acid, B vitamins, and SAM-e methionine
How does caloric restriction impact the Insulin/GF1 and DNA methylation pathways?
Lowers insulin resistance and causes hypo/hypermethylation of tumor suppressor and p16 genes to decrease incidence of disease.
How is epigenetic damage different from genetic damage?
Epigenetic patterns can be reversed.
Describe Fragile X Syndrome.
Too many CGG repeats in the FMR1 gene (200 vs. 6-50) methylate the gene. CpG island at the promoter turns the gene off. Associated with mental developmental conditions.
How are epigenetics associated with the immune response?
Shifts in both acetylation and methylation are needed to permit recombination for the immune response. Too much folic supplementation can lead to a loss of epigenetic control here —> autoimmune disease.
Desribe Systemic lupus erythematosus through the lens of epigenetics.
SLE has autoantibodies against nuclear antigens affecting all organs and tissues. Immune cells are hypomethylated, dysregulation of T-lymphocytes.
What modifications does RA involve?
Rheumatoid arthritis can have altered methylation status in T and B cells as well as synovial fibroblasts. Global hypomethylation.
How can dietary supplements aid in age-related neurological disorders?
Methyl donors can help restore cognitive performance for diseases in which genes develop gradual methylation. Like sequestration of synuclein protein into Lewy bodies in Parkinson’s.
What is the regulatory role of sirtuins?
They regulate fat and glucose metabolism through histone and transcriptional deacetylation in many cellular areas. Energy homeostasis, healthspan determination,
Name the 3 families of epigenetic proteins.
Readers, writers, and erasers
How can DNA methylation increase cancer risk?
Hypomethylation can activate oncogenes and initiate chromosome instability, hypermethylation initiates silencing of tumor suppressor genes.
Physical exercise modifies DNA methylation patterns in favor of _____.
tumor suppressor genes + decreases oncogene expression
Genes of colorectal cancer cells were substantially _____ in comparison with normal tissues.
hypomethylated
Fragile X syndrome is an example of which type of epigenetic modification?
Histone modification
Drugs exist targeting epigenetic ____ as well as analogues of epigenetic modifications for clinical use.
enzymes
The modification of histones can induce _______ leading to the introduction of _____.
epigenetic changes; non-coding RNAs
Describe the Histone Code Hypothesis.
Chromatin activity depends on the degree of chemical modification of histone tails
DNA demethylation is an active process (T/F).
False, can be active/passive or a combination of both.
Where are the majority of methylated cytosines in mammals?
Symmetrical dinucleotide 5’CPG3’. 70-90% of CpG dinucleotides are methylated. Islands, near promoters, have methylation variability.
How does methylation change gene expression?
Methylation of promoters and enhancers prevents RNA polymerase from binding.
What pathway does DNA methylation use?
One-carbon metabolism, dependent on several enzymes/cofactors like folate, choline, and betaine.
DNMT1 maintains DNA methylation patterns through division while DNMT3a/b establishes new patterns during development (T/F).
True
What do long non-coding RNA do?
Sequence specific molecules that guide protein complexes to sites in chromatin to orchestrate transcriptional repression.
What are circRNAs?
Covalently closed ncRNAs that are major regulators for pathogenesis. They can sponge microRNAs, bind proteins, or be translated themselves.
What are the most crucial stages for epigenetic reprogramming?
Pre-implantation (De-methylation, X inactivation, Tissue-specific implementation)
Gametogenesis (De-methylation, X activation, Imprinting)
A true transgenerational effect can only be proved of the effect of the exposure is transmitted ____.
to F3 on the maternal line when exposure occurs during pregnancy; F2 on either line if exposure was before conception
Ontogenesis runs from conception to ____.
old age
A term gestational period is ___-___ weeks.
37;42
At ~5 days following feritlizaton, what happens?
Morula (highly replicated zygote) becomes a blastocyst which will then implant in the uterus.
What is the cortical reaction?
When sperm penetration causes zona pellucida to become impermeable to other sperm.
How many chromosomes are in a zygote + cells in a morula?
46 and 16!
The blastocyst will go on to form the ______ and _____ which make up the embryo and placenta, respectively.
inner cell mass; trophectoderm
Pregnancy can be clinically detected at the _____ stage with presence of the _____ hormone.
implantation; hCG in the corpus luteum
Following implantation, in _____, the embryonic disk differentiates into the ectoderm, mesoderm, and ______.
gastrulation; endoderm
The ectoderm forms the nervous system and epithelium while the endoderm forms connective tissue (T/F).
False, endoderm forms GI organs and GI/respiratory epithelium.
When is the embryo most sensitive to environmental factors?
Organogenesis, weeks 4-8.
What differs parturition from labor?
Parturition is a set of sequential hormonal (progesterone) and physical changes in preparation of labor, which involves contractions and dilation.
What are the four stages of parturition?
Quiescence (progesterone, relaxin), Activation (Estrogen, Uterine stretch), Stimulation (Prostaglandins, oxytocin, cytokines for dilation), and Involution (Oxytocin, recovery).
Progesterone withdrawal —> _____ bioavailability —> responsiveness to ______ —> ____ —-> Uterine stretch
estrogen; prostaglandin/oxytocin; CRH
Which hormone maintains quiescence?
Progesterone
Which hormone promotes myometrial changes like receptor sensitization and cervical ripening?
Estrogen
Which parturition hormone can be activated by stress?
CRH
Symmetrical FGR makes up 25% of cases with late onset and 25% risk for chromosomal abnormalities and neurological sequelae (T/F).
False, onset prior to 32 weeks.
Asymmetrical FGR is _______.
brain-sparing
What is the leading cause of fetal and maternal morbidity around the world?
Preeclampsia
Proteinuria, edema and abnormal liver function (HELLP) are all signs of what?
Preeclammpsia
Name two common cooccurrences of preeclampsia?
Pre-term birth and fetal growth restriction
Leptin inhibits _____.
insulin
How does the placenta’s structure support its function?
Large SA and thin intrahaemal membrane separating circulations.
The maternal surface of the placenta is 15-20 _____. The fetal is a ______ covered by amniotic membrane and vessels converging towards the _____.
cotelydons; chorionic plate; umbilical cord
How does “hemomonochorial” describe the human placenta?
One layer of trophoblast cells between sides
What do trophoblast cells form?
As projections of the blastocyst they allow implementation in the uterine wall. They then differentiate into syncytio-trophoblast cells and cytotrophoblast cells.
Which cells form primary villi?
Cytotrophoblasts, while syncytiotrophoblasts connect to maternal sinusoids.
How do the placental chorionic villi develop?
Vasculogenesis and Angiogenesis. Angioblasts differentiate to form capillary like structures. Then sprouting, branching, and elongation.
Name 3 important factors for chorionic villi development.
FGF2, VEGF, and PLGF
What is the purpose of deciualization?
Mesenchymal-epithelial transition helps to lower stiffness, expand organelles, and increase lipid/glycogen storage. NK cells come in to regulate the uterine invasion process.
Define Decidua basalis, parietalis, and capsularis.
Basalis is the maternal component, parietalis is the rest, and capsularis is the inner loop on the back of the baby. The last two will eventually fuse.
What is the path of utero-placental circulation?
Low resistance spiral arteries (formed by extravillous sy-trophoblat cells) enter intervillous space, blood leaves then through endometrial veins going across the decidua.
What are the essential macronutrients for fetal growth?
Glucose, amino acids, free fatty acids, and cholesterol, all with their own transport systems.
How does glucose get transported to the fetus and placenta?
Facilitated diffusion along a concentration gradient through GLUT transporters (GLUT1 is abundant expressed)
How do amino acids come across the placenta?
Active transport, as [] is much higher on the fetal side. There are >15 transporters including System A (Na+ dependent for small, neutral AA’s and stimulated by insulin, leptin, IL6, IGF1) and System L (Na+ independent for large AA’s, stimulated by glucose or insulin.
How do essential fatty acids move across the placenta?
TG lipase breaks maternal triglyceride to FFA’s which use passive or facilitated diffusion.
Maternal hormones during pregnancy are regulated by the ______, pituitary, and fetal adrenal glands/gonads.
placenta
How is progesterone formed in the placenta and what all can it signal for?
STB and CTB synthesize P4 from cholesterol. It works to maintain quiescence in the myometrium before functional withdrawal. Also, appetite stimulant, and prevents mammary glands from activating before birth
What is the difference between estradiol and estriol?
Estriol is produced by the placenta from DHEA, regulated by fetal adrenal gland. Important for endometrial cell proliferation and mammary gland development.
What does placental lactogen do?
Promotes fetal growth by inducing lipolysis to FFA’s, maternal insulin resistance to increase fetal availability, fat deposition, appetite stimulant, protein synthesis, and milk production.
How does PGH support fetal growth?
Secreted by STB cells, stimulates glycogenesis, lipolysis, and anabolism in maternal organs. Promotes insulin resistance in the mom.
How does the role of leptin change in pregnancy?
This is the hormone that tells you you’re full. Creates a negative feedback loop for food intake, it increases along gestation to combat resistance caused by the other hormones.
How does leptin regulate fetal growth?
Alters nutrient transporter activity, promotes angiogenesis and very important pathways. Levels are super high in complicated pregnancies.
Name the three shunts of feta circulation.
Ductus venosus shunts oxygenated blood from placenta towards heart, bypassing liver.
Foramen ovale shunts blood from RA straight to LA, bypassing lungs.
Ductus arteriosus takes blood from pulmonary artery into aorta, bypassing lungs.
How does the glucocorticoid barrier work?
11BHSD-2 inactivates cortisol to cortisone to keep cortisol levels 10x lower on the fetal side.
Abnormal placental morphology has been linked to many _______ and ______ diseases.
cardiovascular; metabolic
The placenta, like other organs, has a critical window of _____.
plasticity
The nutrient sensor hypothesis, opposite to the adaptive compensatory, posits that fetal growth rate is matched to the _______.
availability of nutrients in maternal circulation
What does placental dysfunction usually refer to?
Compromised invasion of trophoblast cells to spiral arteries —> poor remodeling —> reduction in nutrient/oxygen delivery —> higher risk of preeclampsia, etc.
Altered glucose transport plays a role in fetal growth restriction (T/F).
True, hypoglycemia is implicated but no reduced uptake or expression of GLUT1. Late-term FGR does show more GLUT3 expression and increased consumption by the placenta.
How does placental dysfunction impact amino acid and fatty acid transporters?
Reduced expression/activity of System A and L transporters, less AA in umbilical cord blood. Reduced LPL activity means less fatty acid transport.
What are some reasons for GDM and maternal obesity?
Positive energy balance, net surplus of insulin, dysregulated growth factors.
Name the nutrient-sensing signaling pathway in the placenta.
mTOR, a serine/threonine kinase that controls cell growth and metabolism in response to maternal metabolic hormones and local nutrient levels.
What are some morphological changes in placenta for high altitude pregnancies?
Higher vascularization, thinning of villous membranes, more cytotrophoblasts, and reduced nutrient transport.
What are two oxygen sensors in placenta?
mTOR (reduced activity in hypoxic situations) and HIF (increased angiogenesis)
The glucocorticoid barrier is only damaged by maternal undernutrition (T/F).
False, maternal stress, as well!
Name 3 non-infectious inflammation insults to a placenta.
Maternal stress, placenta, hypoxia, or abnormal maternal metabolic status. Chronic inflammation!
What are the most common infections associated with congenital anomalies?
TORCH: Toxoplasmpsis, Other, Rubella, Cyotmegalovirus, and Herpes. Zika might make her way in there.
How does Zika impact fatty acid transport?
Hijack transport molecule to transform to virus factories, lack of essential lipids + massive inflammation
Which sex has less placental reserve capacity under adverse conditions?
Males
Male fetuses are more sensitive to early exposures while female are more affected from high fat diets (T/F).
False, it’s the opposite.
The ectoderm overlying the notochord will form the entire _______.
nervous system
What are the two major types of neural birth cells?
Neural stem cells, which give birth to progenitor cells which then differentiate.
How do neural cells migrate?
From the inner layer of the ectoderm to the outer layers of the neural tube. From ventral to dorsal.
Cell differentiation continues past birth for neural cells (T/F).
False, usually complete by birth. Maturation continues, though.
Synaptogenesis increases rapidly in the first _____ months of life before decreasing.
12
Myelogenesis begins after ____ and continues into _________.
birth; early adulthood
The amygdala is a mass of grey matter in the ______ of the temporal lobe, responsible for _____.
anterior/medial portion; integrating information
Which brain structure is involved in voluntary movement and rewards?
Basal ganglia
Prenatal inflammation is a risk factor for neurodevelopmental disorders (T/F).
True
Severe or UTI infection in pregnant mothers is a risk factor for ____ and ____.
post-partum depression; ASD
Chorioamnionitis is present in most cases of _____.
Pre-term birth <30 weeks
Infants born HEU don’t have the cognitive and developmental outcomes that HEI babies do (T/F).
False, they both face threats of poorer neurodevelopment. But, HEI is worse.
_____ can mediate HIV neuropathogenesis and also indicate neurocognitive decline.
Monocytes
Pro-inflammatory cytokines and monocyte activation are increased in ______ infants.
HEI
Highest risk of birth defects from Zika happens in which trimester of pregnancy?
First!
How does ZIKA impact neural development?
Infects neural progenitor cell proliferation + differentiation, causing cell death. Decreased cortical plate and subventricular zone thickness. Decreased brain weight and cognitive deficit (Y-maze)
How might COVID impact pregnancy?
Decreased oxygen transport, placenta integrity, proinflammation, and fetal brain infection.
Which part of the amygdala mediates the relationship between third trimester depression and male behaviour?
Mean diffusivity on the right amygdala
What makes up the HPA axis?
Hypothalamic-pituitary-adrenal
What is the general pathway of CRH?
Stimulus activates release in the PVN of the hypothalamus. CRH and AVP go through the hypophysial portal to bind to receptors on corticotropes of anterior pituitary. This stimulates ACTH release which stimulates GC secretion in adrenal cortex. GCs do negative feedback via GR in the hippocampus and PVN in pituitary.
Cortisol has a higher affinity for GC receptors than MC (T/F).
False, it’s the opposite.
Glucocorticoid is responsible for signalling _______ maturation in gestation.
organ
What is one maternal circumstance which lowers placental 11B-HSD-2 expression?
Maternal anxiety and depression
What are the main 3 causes of pre-term birth from most to least common?
Idiopathic, membrane rupture (PPROM), and medically indicated
Why are synthetic GCs administered to pregnant women?
For those at imminent risk of preterm delivery. GCs are a poor substrate for 11B, so they cross the placenta easily and bind to GRs to speed up organ maturation (esp lungs).
How do bile acids protect against pathogens?
They have antimicrobial properties
What are bacteriocins?
Short, toxic peptides that some bacteria produce which inhibit growth of other species. Many mechanisms but they disturb RNA/DNA and kill pathogenic cells.
Nutrient competition provides _______ resistance like our indigenous E. coli strains vs. pathogenic.
colonization
Half of the daily Vitamin B requirement is provided by gut bacteria (T/F).
False! Vitamin K
What is GALT?
Gut-associated lymphoid tissue. Microbes help it mature (PSA) by forming a full complement of T cells. Early microbe exposure prevents T cells associated with allergies and IBD while enhancing helper T set.
Bacteriodes PSA exposure induces a high inflammation response to pathogens (T/F).
False! Lower than non-exposed.
Bacteriodes thetaiotaomicron secretes _______ from Paneth cells to increase _______.
angiogenin-4; capillarization
How are SCFAs produced by the microbiota? What are the three main ones?
Produced by bacteria through fermentation of non-digestible carbs. Acetate, propionate, and butyrate.
Name four roles of SCFAs.
Renal arteria and peripheral nerve support, leptin activation in adipose tissue, fatty acid oxidation in liver + muscles, insulin production.
Butyrate promotes epithelial barrier function and is the main energy source of ____. They produce histone deacetylases for anti-______.
colonocytes; inflammation
Symbiont-containing mice had better ____ function.
brain
What are the main metabolites produced in the colon by fermentation?
SCFAs
Germ-free mice can complete intestinal development (T/F).
False, but they can initiate it.
What are the consequences of providing synthetic GCs?
In adults, there was some insulin resistance. In children, lower birth weight but nothing further that we know of.
What are the consequences of antenatal sGC exposure in animals and neonates?
We saw lower brain weight, altered myelination, and brain activity in animals. Decreased cortical volume and complex folding in human neonates, lower limbic and frontal lobe development.
What part of the brain regulates autonomic and endocrine function in response to emotional stimuli?
Limbic system
What did structural MRI scans show for antenatal sGC exposure?
Thinning of the ACC, which connects limbic to prefrontal cortex (ability to manage uncomfy emotions). Could result in mood disorders and avoidance, substance abuse issues.
Did antenatal sGC exposure in neonates impact the HPA system?
Yes, they found increased cortisol reactivity to acute stress, with a sex-dependent effect towards females. Suggests lasting effects of antenatal sGC exposure like stress-related disorders.
The guinea pig model for chronic maternal stress showed that sustained stress resulted in reduced _____ and ________ behaviour responses in male rodents.
postnatal growth; maladaptive
Describe an example of sexual dimorphism with prenatal stress exposure.
Mice exposed to a lot of stress in late pregnancy: males had more anxiety in a maze, females had reduced anxiety and improved learning.
The 1998 Ice storm saw negative ________ skills especially in second trimester exposure.
cognitive and language
What is serotonin important for in fetal development?
brain development, it’s a powerful vasoconstrictor.
How does the placenta regulate serotonin exposure?
It’s rich in MAO-A, which metabolizes serotonin.
What does too much serotonin exposure do to a fetus?
Impaired neurodevelopment!
Inattentive motherhood increased GR receptor methylation in the hippocampus (T/F).
True
High maternal care is associated with histone tail _____ and ______ binding.
acetylation; NGF-A
The gut comprises over 70% of our _______.
immune system
Which nerve mainly regulates internal organ functions?
Vagus
Inflammation inhibits signals sent through the Vagus nerve (T/F).
True
The gut is involved in direct production of _______ like GABA, norepi, and dopamine.
neurotransmitters
Gut microbes produce lots of SCFAs by digesting what?
fiber
What are some ways that SCFAs affect brain function?
Propionate can reduce appetite and regulate gluconeogenesis.
Butyrate helps form the blood-brain barrier and can induce apoptosis by colonocytes.
Acetate, the most abundant, is used for cholesterol metabolism and lipogenesis.
Lipopolysaccharide is an ______ toxin that can cause brain disorders when it leaks through the gut.
inflammatory
Microbiome diversity increases during pregnancy (T/F).
False, but some species like lactobacillus go way up.
Name 4 mechanisms behind gut dysbiosis influencing obesity.
Immune dysregulation, altered energy regulation (hunger signal), altered gut hormone regulation, and proinflammatory mechanisms (LPS endotoxins).
______ is a low-grade, chronic inflammatory disease. M1 macrophages are active and FFAs activate _____ in adipose tissue.
Obesity; TLR4
Which gut bacteria is helpful in lowering risk of asthma and allergies?
H. pylori
The well-known comorbidities of COVID-19 are all associated with _____.
dysbiosis
FODMAP (short-chain carbs) is a group of foods that reduce symptoms in _____ patients because they are easily ____ by gut bacteria into gas but poorly absorbed.
IBS; fermentable
CD seems to have greater dysbiosis than in UC, which may be responsible for its larger scope (T/F).
True
What is NOD-1?
A pattern recognition receptor that detects peptidoglycan segments and inflammatory signals. Activated after MAMPs are recognized, triggering an immune response. It mediates immunometabolic responses depending on the release of bacterial peptidoglycans.
What is the function of NOD2?
Works in the defensive barrier against bacteria + immune response to commensal bacteria. Deficiency increases risk of injury, inflammatory response, ileal disease, and higher levels of bacteria.
What is the difference between prebiotics and probiotics?
Prebiotics are fibers fermented by your gut that may reduce cortisol. Probiotics are active bacteria that can improve stress, anxiety, and depression.
Protiobacteria are prevalent in a healthy gut (T/F).
False
The effect of xenobiotics on development are dependent on gestational age, dose, and especially drug _________.
transport and efflux at the placenta barrier
The CTB layer progressively thickens across gestation, allowing less antibodies to cross (T/F).
False, it thins which allows an increase in fetal IgG with age.
