early environmental and biological impacts of lifelong health Flashcards
what challenges can fetus face in utero that might have a lasting impact on its health
fetal infection in utero
maternal nutrition (under or over)
maternal illness
maternal stress
maternal medication
enviromental factors or exposires
dohad programming adult health in early life concluded what
on average adults who had a coronary event had been small at birth and thin at 2 years of age
thereafter put on weight rapidly
the risk of coronary event was more strongly related to the rate of change of childhood bmi rather than to bmi attained at any particular age of childhood
what increases risk of metabolic syndrome (barker et all hypothesis)
undernutrition in utero or overnutrition as a child increases risk of metabolic syndrome which causes an increase in cardiovascular events
mechanism of DOHaD
Idea of PROGRAMMING in utero
Leads to changes which influence development and physiology
These changes might include predictive adaptive responses (PARs)
PARs are proposed to be developmental adaptations taken to prepare the fetus for its future environment
PARs don’t benefit the fetus immediately, but are taken in anticipation of the environment they will be exposed to.
what does a mismatch between PAR and actual environment cause
may contribute to disease risk later in life
If a fetus acquires PARs in anticipation of a particular post-natal environment, but then encounters a different environment to that predicted, it will be mal-adapted, potentially raising the risk of ill-health in later life.
how do we link DOHaD to biology
Associations between early environmental exposures and:
Cardio-vascular disease
Type 2 diabetes
Lung disease
Cancer risk
Neurological, special sense and intellectual development
Allergic and auto-immune diseases
what are the 3 major mechanisms of challenges that fetus face in utero
Thought to be three major mechanisms:
Hormonal effects (especially glucocorticoid exposure)
Epigenetic modifications (fetal gene expression)
Irreversible developmental changes in organ size/structure
linking mechansims of dohad to biology
foetal gene expression—->maternal health and environment/endocrine millieu,placental vascular supply,foetal nutrient demand greater than supply—>foetal developmental responses including alternered endocrinology and metabolism,changes in fetal bone lean and fat mass,altered blood flow/vascular loading,altered immune response—>expsoure as an adult or amplification in infancy—>cardio/metabolic/lung and immune mediated disease/neurodevelopmental disorders
glucocorticoid exposure and dohad
fetal glucocorticoid usually regulated by placental 11BHSD2 enzyme (fetal shielded)
reduction in 11BHSD2 expression or increased GCs may lead to greater fetal gc exposure (increased glucocorticoid growth)
this in turn programmes fetal growth development and metabolism
glucocorticoid exposure occurs how
environmental factors such as undernutrition stress and infection–>increased maternal stress–>increased release of glucocorticoids and decreased 11BHSD2 expression–>increases fetal glucocorticoid load—>in the fetus this can induce growth,organ structure,cell numbers,gene expression,neuro/endocrine function or metabolism—>adult disease
epigentic mechanism
epigenetic changes modify expression of dna without modifying dna sequence
includes dna methylation post translational (protein) modification of histones and non coding rnas
in utero exposures can modify the types or levels of epigentic marks leading to altered or dysregulated gene expression
epigenetic mechanism in detail
maternal/placental stress–>fetal epigenomic changes—>fetal growth restriction, increased capacity to store energy( causing obesity) ,adaptations in metabolic pathways ( causing diabetes mellitus) ,adaptation in terminally differentiated cell numbers—-> causes cardiomyocytes/nephron/vascular myocytes leads to hypertension or cariovascular disease///or altered neurons and other brain cells causing risk of stroke schizophrenia cognitive dysfunction depression and other behavioural disorders
key windows of epigenetic programming during developments
these are points of vulnerabilitiy
gametogenesis (writing the gametic epigenome via maternal/paternal environment
early development (erasure of gametic identity) maternal environment
organogenesis and foetal growth (writing the epigenome in each cell type during organ or cell differentiation for the acquisition of a specific expression profile and cell identity) maternal
post natal period maternal and paternal environment
adulthood and ageing causes health and disease
3 major windows of epigenetic programming
gametogenesis-parent specifice epigenetic marks are estabilished development of sperm and oocytes
early development-very early embryos undergo widespread erasure and repatterning of epigenetic marks during which these gamete-specific marks are erased and new epigenetic profiles established
organogenesis-epigenetic marks influence the timing and onset of cell type-specific gene expression influencing how cells differentiate.
in utero programming
environmental stimuli have been shown to impact the development of key organ systems pre disposing to adult disease
eg fetal hypoxia causes reduced nephron numbers which causes an increased risk of hypertension or renal disease in adulthood
fetal undernutrition causes reduced beta cell mass or altered muscle insulin sensitvity causes impaired glucose in adulthood
implications for later generations of in uero exposures
primordial germ cells are the embryonic precursor cells of oocytes and spermatazoa
PGCs undergo epigenetic reprogramming during embryogenesis
these cells give rise to sperm and egg which transmit these epigenetic marks to the next generation ie the exposed fetus’ offspring
experimental data shows that fetal germ cell development is sensitive to environmental impacts for exmaple diet and pharmaceuticals
influences on mebryo development
TE/ICM cell number (trophoectoderm and inner cell mass)
metabolic status
epigenetic remodelling
influences on uterine environment
maternal environmental stressors
seminal plasma mediated interactions
inflammatory and immunological responses
vascular remodelling
influences on fetal growth
predictive adaptive responses
organ biometry
placental function and adaptations
maternal response to pregnancy
influences to adult health
cardiometabolic disease risk
reproductive fitness
gamete quality
inter/transgenerational programming
influecnes on gamete quality
dna integrity
ROS generation
lipid composition
spindle integrity
epigenetic status
seminal plasma composition
