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Environmental Impacts, Postnatal and Child Development Vanathi Pugalendhi vp822@ic.ac.ukTILO'S COVERED II. Mechanisms of early I. Early life impacts life programming III. Postnatal growth & IV. Developmental Hormonal changes in domains Childhood and PubertyLECTURE TIMELINE 1. Developmental 2.Linking DOHaD 3.Transition from 4.Developmental origins of health to Biology Prenatal to domains and and disease Postnatal growth, Developmental (DOHaD) Phases of growth delayDevelopmental Origins of Health and Disease (DOHaD) HypothesisDevelopmental Origins of Health and Disease (DOHaD) Hypothesis Undernutrition in utero + Overnutrition as a child Increased risk of ‘Metabolic syndrome’ Increased risk of Cardiovascular events Possible Mechanism of DOHaD: Predictive Adaptive Responses (PARs) PARs are proposed to be developmental adaptations taken to prepare the fetus for its future environment – they don’t benefit the fetus immediately but are taken in anticipation of the environment they will be exposed to.Developmental Origins of Health and Disease (DOHaD) Hypothesis Mis-match between PAR and Fetus is mal-adapted Potentially increases risk of ill- external environment health later in lifeLinking DOHaD to biology There is an association Challenges faced by the fetus in utero can have a between early environmental lasting impact on its health (DOHaD hypothesis) exposures and: • Cardio-vascular disease Thought to be three major mechanisms • Type 2 diabetes (by which fetuses are programmed): • Lung disease • Cancer risk • Neurological, special Hormonal effects Epigenetic Irreversible sense and intellectual (especially Glucocorticoid modifications developmental development overexposure) (Fetal environmental changes - in organ • Allergic and auto-immune exposure DOES NOT size/structure diseases change DNA!) Linking DOHaD to biology – Glucocorticoid exposure and DOHaD Fetal glucocorticoid exposure is regulated by placental 11BHSD2 enzyme Reduction in Increased maternal 11BHSD2 expression stress Increased stress hormone release Increased Fetal Glucocorticoid (GC) Load Wider HPA axis dysregulation + Changes in GC receptor expression FETUS’ OVERALL SENSITIVITY TO GC ALTERED + INDIVIDUAL PREDISPOSED TO DISEASE IN FUTURE LIFELinking DOHaD to biology – Epigenetic mechanisms Epigenetic mechanisms: • DNA methylation • Post-translational (protein) modification of histones • Non-coding RNAs In utero exposures can modify the types or levels of these epigenetic marks, leading to altered/dysregulated gene expression. e.g. Changes in gene expression that increase your capacity to store energy anticipating a nutrient-poor environment -> High-nutrient environment after birth -> Predisposed to obesityLinking DOHaD to biology – Key windows of epigenetic reprogramming during development are points of vulnerability 3 major windows of developmental vulnerability when epigenetic reprogramming occurs: Gametogenesis: Parent-specific Early development: Very early embryos Organogenesis and fetal growth: epigenetic marks are established undergo widespread erasure and re- Epigenetic marks influence timing and during the development of sperm and patterning of epigenetic marks during which onset of cell-type-specific gene oocytes these gamete-specific marks are erased and expression, influencing how cells new epigenetic profiles established. differentiate (This is BEFORE fertilisation has even occurred -> Health of mother and father has an impact on the epigenetic marks of the gametes)Linking DOHaD to biology – DOHaD and in utero programming of organ systems Environmental Impact the development of key Pre-disposing to stimuli organ systems adult disease Examples: Fetal hypoxia Reduced no. of renal Reduced nephron Increased risk of progenitor cells numbers (at birth) HTN/renal disease in adulthood Reduced Beta cell Increased glucose Impaired glucose Fetal mass/Altered muscle undernutrition exposure after birth control in adulthood insulin sensitivityDOHaD - TILOs 1. What are early life impacts? • External stimuli/influences acting to alter fetal development or physiology • Direct (on fetus) or indirect (via mother) - can be biological, social or environmental • Developmental Origin of Health and Disease (DOHaD) hypothesis - fetal life exposures may pre-dispose/programme to particular health trajectories in later life 2. Mechanisms of early life programming • Excessive glucocorticoid exposure alters fetal growth, development and metabolism (and causes epigenetic change) • Epigenetic changes – alterations to DNA methylation, histone protein modifications and/or non-coding RNA expression leads to altered/dysregulated gene expression, altering cell fate/function/behaviour • Organ development is influenced by environmental stimuli, and may impact health in adulthood • Some epigenetic changes are transmissible through the germ cells, meaning fetal exposure may have impacts for subsequent generationsTransition from prenatal to postnatal growth Postnatal Prenatal • Minor effect overall • Largely determines final adult height • Maternal size -> Birth size • SEX CHROMOSOMES have an effect Genetics • Maternal factors tend to override fetal • XY (Boys) taller than XX (Girls) genetic factors in determining prenatal growth Endocrine • Insulin and Insulin-like growth factors (IGFs) • After birth: Human growth factor (hGH) • IGF-2 – embryonic growth is the major hormone controlling growth • IGF-1 – later fetal and infant growth • Placental insufficiency most common cause • Adequate nutrition is essential for growth Nutrition of intrauterine growth restriction • e.g. Excessive food intake -> Obesity • Maternal diet -> Nutritional availability • e.g. Poor nutritional intake/Malabsorption -> Delayed-onset puberty or Reduced growth • Placental function is more influential in fetal • Factors influencing growth Environment growth than uterine capacity (Placenta carries • Socioeconomic status out PARs to create an environment for fetus that • Chronic disease prepares it for the environment outside) • Emotional status e.g. ACEPostnatal growth 4 recognised phases of growth: (1) Fetal: (3) Childhood: • Fastest period of growth (over life-course) • LONGER window of steady, slow growth (18 • Growth driven by HYPERPLASIA (increase in cell months to 12 years of age) number) • Good nutrition and health important • ENDOCRINE GROWTH regulation increasing 30% of eventual height 40% of eventual height (2) Infantile (period just after birth): (4) Pubertal: • Length increases by 50%, Head circumference by • Rising levels of sex hormones 30% (disproportionate head growth vs body) • Boost hGH production • Growth – largely NUTRITION DEPENDENT • Cause fusion of growth plates • Rapid but decelerating growth • TEMPORARY growth spurt (self-limiting) 15% of eventual height 15% of eventual heightTransition from prenatal to postnatal growthMini-puberty Gonadotrophin secretion HPG axis is transiently activated commences towards the end after birth (mini-puberty), after of the first trimester, peaks mid- release from restraint by placental pregnancy, then declines hormones Continues for around 6 months after birth before decliningRole of mini-puberty Role of mini-puberty is undetermined Elevated sex steroids in males during Role of minipuberty less clear in Elevated sex steroids in minipuberty mini-puberty seems to be important female infants. may also influence programming of for normal gonadal development. body composition and linear (testicular tissue and penile • Estradiol levels fluctuate growth. through first few months after development) birth • High testosterone levels in • Follicular development occurs boys during minipuberty, may in the ovary partly explain the higher • Important for patterning and growth velocity observed in development of mammary boys compared to girls. tissue?What triggers puberty? • Control of puberty onset -> Unclear, but influenced by metabolic status Release of Act on GnRH neurons - promote Regulate release of pulsatile GnRN release (involved neurokinin Kisspeptin peptides in puberty onset) KNDy neurons *Mutations in KISS1R delays onset of puberty GnRh pulses increase in frequency and amplitude towards puberty Intermittent GnRh pulsesDevelopmental milestones during puberty Compliance with this sequence is known as consonance.Developmental domains There are 4 Developmental domains Fine motor skills Gross motor skills (crawling, walking) (manipulation of small objects e.g. holding a pencil) Speech, Language and Hearing skills Social behaviour and play skills (talking in simple phrases, then (e.g. playing peek-a-boo) sentences)Developmental domains – gross motor skillsDevelopmental domains – fine motor skillsDevelopmental domains – language skillsDevelopmental domains – social/behavioural skillsDevelopmental domains Developmental milestones by median ageDevelopmental domains Postnatal growth? • Drivers of growth are different before and after birth • Growth through infancy is divided into four distinct phases Hormonal changes and puberty • HPG axis is activated in utero • A transient minipuberty occurs for the first six months after birth, characterized by high levels of reproductive hormones • The trigger for puberty is unclear, puberty onset likely involves kisspeptin regulation of GnRH pulses Developmental domains • There are four distinct developmental domains • Gross motor, fine motor • Language, speech and hearing and social behavioural and play • Divergence from the milestones of these may indicate issues with developmental delayFundamentals of a good screening test Disease that the test is screening for: • Should be able to be identified early/before critical point • Treatable • Prevent/Reduce morbidity/mortality The test should also be: • Acceptable/Easy to administer • Cost-effective • Reproducible and accurate resultsDevelopmental delay GLOBAL vs SPECIFIC Developmental delay Global developmental delay: significant delay in reaching two or more developmental milestones Specific developmental disorder: refers to delays in developmental domains in the absence of sensory deficits, subnormal intelligence or poor educational conditionsGlobal developmental delay Causes of GOBAL Developmental delay: Causes of MOTOR SKILL Developmental delay: • Chromosomal abnormalities e.g. Down’s syndrome, Fragile X • As an aspect of global developmental delay • Cerebral palsy • Metabolic • Congenital dislocation of the hip e.g. hypothyroidism, inborn errors of metabolism • Antenatal and perinatal factors • Muscular dystrophies Infections, drugs, toxins, anoxia, trauma, folate deficiency Neural tube defects • Social deprivation • Environmental-social issues • Chronic illness Causes of LANGUAGE SKILL Developmental delay: Quantifying developmental delay: • Hearing loss • Schedule of growing skills (0-5y) • Autism spectrum disorders • Griffiths developmental scale (0-6y) • Lack of stimulation • Bayley Scales of Infant Development (1m-42m) • Impaired comprehension of language – e.g. • Denver developmental screening tests (0-6y) developmental dysphasia • Impaired speech production – e.g. stammer, dysarthriaThank you!QR Code - feedback