L4 DOHAD Flashcards
What is a teratogen?
Any agent that causes an abnormality following fetal exposure during pregnancy
Most sensitive period for teratogen-induced limb malformations
4th and 5th developmental week
What is fetal/prenatal programming?
A concept that suggests certain events (exposures) occurring during critical points of pregnancy may cause permanent effects on the fetus and the infant long after birth
Some of the most commonly studied exposures during pregnancy
- maternal hormonal changes e.g. stress
- maternal inflammation e.g. PE
- alterations in nutritional status
- exposure to toxins e.g. Thalidomide
- infection e.g. Zika virus
Risk factors for schizophrenia
- genetics (e.g. if a monozygotic twin develops schizophrenia, the other twin has a 50% chance of developing it too)
- children born during late winter/early spring: seasonality effect (higher risk of infections like RSV, depression, stress, nutrition status)
Example of a cytokine that affects axonal growth
IL-1β
What is psychoneuroimmunology?
Branch of neuroscience involved with interactions between environmental stimuli, nervous system & immune system
One line of research in neuroimmune interactions during nervous system development has focused on the impact of prenatal maternal infection on the development of childhood and adult neuropsychiatric disorders, particularly…
schizophrenia and ASD
2 extensively used models of maternal immune activation
- Maternal exposure to LPS (mimics G- bacterial infection)
- Maternal exposure to poly I:C (mimics acute-phase inflammatory response to viral infection)
What is the name of the first comprehensive study that investigated the interaction between genetic and environmental factors that influence ASD development?
The CHARGE Study (enrolled >500 children)
Dutch Famine Birth Cohort Study findings
- famine exposure associated with glucose intolerance in the children
- increased risk of CHD & obesity
- increased risk of brain disorders
- prenatal undernutrition permanently affected brain size
- prenatal undernutrition associated with premature brain aging during late adulthood
How is prenatal maternal stress measured?
- Objective stress (amount of hardship faced e.g. no. of days exposed to stressor)
- Subjective stress (personal reaction to stressor)
Which is easier to study: objective or subjective stress?
Objective, as it is more defined and can be quantified (objective measurements)
Prenatal maternal stress is associated with an increased risk of which brain disorders?
ASD and ADHD, but significant heterogeneity
How does the placenta protect the fetus from excessive cortisol exposure?
Blood is carried to the chorionic villi (composed of syncytiotrophoblast & cytotrophoblast) of placenta. HSD11β2, highly expressed in syncytiotrophoblast, converts maternal cortisol to inactive cortisone.
Cortisol stimulates fetal…
lung maturation and placental CRH
How is psychological stress measured?
using the 10-item Perceived Stress Scale (PSS)
How is maternal anxiety measured?
using the 6-item version of the State Trait Anxiety Inventory (STAI)
How are depressive symptoms assessed?
using the Edinburgh Postnatal Depression Scale (EPDS)
What effect did high levels of maternal stress have on placental HSD11β2 levels?
They had significantly lower levels of HSD11β2, thereby increasing cortisol exposure to the fetus
How does the placenta synthesise serotonin?
from maternally-derived tryptophan during pregnancy
How do alterations in 5-HT expression during development affect the brain?
patterns of brain wiring are affected, which could subsequently lead to impairment of neurodevelopmental processes
What is considered one of the most common gestational complications, affecting 3-10% of pregnancies?
Hypertensive disorders of pregnancy (HDP) - association between HDP exposure and neurodevelopmental disorders
Why doesn’t everyone who is exposed to prenatal perturbations develop a brain disorder?
Genetics
What is at the interface of the interaction between genes and the environment?
The epigenome
What is the name given to spontaneous base pair differences between individuals?
Single nucleotide polymorphisms (SNPs)
SNPs in coding regions cause…
missense mutations or silent mutations
How many SNPs does the average gene have?
4
A single base change in which gene is associated with a higher risk for Alzheimer’s?
APOE
What is 5-HTTLPR (serotonin transporter-linked polymorphic region)
A repeat polymorphism in the SLC6A4 gene that encodes the 5-HT transporter. This polymorphism occurs in the promoter region, thereby affecting gene function.
Individuals with the 5-HTTLPR long allele express…
high levels of the 5-HT transporter
How does the 5-HTTLPR genotype affect the amygdala?
by affecting its reactivity to environmental threat
The 5-HTTLPR short allele is associated with…
lower 5-HT transporter expression & function, as well as neuropsychiatric disorders such as anxiety in healthy individuals
How does 5-HTTLPR allelic variation affect ACTH levels?
Animals with short alleles had higher ACTH levels when exposed to stress, compared to animals with only long alleles.
How is 5-HTTLPR allelic variation associated with ASB?
Short allele carriers were more sensitive to a lack of parental support in predicting later ASB, which was not seen in the long/long genotype.
