Lecture 2: Environmental Impacts on Development PDF

🐣 Lecture 2: Environmental impacts on development LO: Explain the impact of ethanol on development with regard to the principles of teratology Ethanol as a teratogen FASD (Fetal alcohol spectrum disorde...

🐣 Lecture 2: Environmental impacts on development LO: Explain the impact of ethanol on development with regard to the principles of teratology Ethanol as a teratogen FASD (Fetal alcohol spectrum disorders) → a broad term that encompasses a range of effects that can occur in an individual whose mother consumed alcohol during pregnancy FAS - fetal alcohol syndrome ⇒ due to prenatal exposure to alcohol One of the most severe conditions under the umbrella of FASD Growth retardation Facial dysmorphologies Microcephaly (small head), maxillary hypoplasia (underdeveloped jaw), short nose, smooth philtrum CNS dysfunction Cognitive, motor, behavioural problems Lecture 2: Environmental impacts on development 1  Ethanol - principle 1: genetic susceptibility Alcohol dehydrogenase (ADH) → breaks down most ethanol in the body in the liver transforms ethanol into toxic compound acetaldehyde (a known carcinogen), which is further metabolise into acetate (less harmful) encoded by at least seven different genes five classes (I-V) of alcohol dehydrogenase hepatic form that is used primarily in humans is class 1 level of activity is dependent on: level of expression on allelic diversity Some people will metabolise ethanol better than others - ie. ADH can be differentially active in different people based on differences in the gene expression ⇒ eg. some mothers are with and without an ADH1B*3 allele Maternal ADH1B*3 allele provides some protection to the fetus from prenatal alcohol exposure Ethanol - principle 2: developmental stage PEA = prenatal exposure to alcohol Lecture 2: Environmental impacts on development 2  Diagram: PEA around the time of gastrulation and prechordal plate formation ⇒ more severe craniofacial defects PEA more later on, around the time of facial morphogenesis ⇒ more milder facial abnormalities Many facial features develop during the sixth through the ninth week of gestation In an experiment - the association with adverse birth outcomes was strongest in trimester 1 Can result in: short eye openings, thin border between the upper lip and facial skin, flat middle groove in the upper (ie. philtrum), undeveloped midface, wide distance between the right and left inner corners of the eyes, droopy eyelid (ie. ptosis). Ethanol - principle 3: mechanisms General concept: ethanol affects multiple different signalling pathways, leading to multiple different Lecture 2: Environmental impacts on development 3  Eg) PEA → inhibit Shh signalling → impact neural tube folding Eg) PEA → reduce BMP4 and WNT6 levels → reduce neural crest induction → severe cranofacial defects Ethanol - principle 4: access Ethanol crosses the blood brain barrier very easily to access the brain & also crosses the placenta easily to enter the fetal circulation Once ethanol enters the fetus, it will become metabolised in fetal tissues so it can spread right through all the cells of the embryo; combining with fatty acids to form fatty acid ethyl esters (FAEEs), which are then excreted by the fetus into newborn meconium (which is their first poop) Baby is not expose to ongoing ethanol unless the mother continues to consume it Lecture 2: Environmental impacts on development 4  Level of ethanol in fetus will change depending on the level of ethanol that’s in the mother & metabolism by mother liver and metabolise by the fetus itself is well Ethanol - principle 5 & 6 (end points & dose response) Fetal Alcohol Spectrum Disorders (FASD) is an umbrella term describing the range of effects that can occur in an individual The level of harm is dependent on the amount and frequency of alcohol use Diagram: High dose of ethanol/high amount of alcohol consumption, decreases over time ⇒ effects ranging from death or abortion or miscarriage TO stillbirth with severe birth defects TO severe craniofacial abnormalities TO FASD TO normal features with some cognitive deficits. Lecture 2: Environmental impacts on development 5  LO: Explain how endocrine disruptors can interfere with hormone signalling pathways Endocrine disruptors, such as DDT, are small molecules that interfere with hormone signalling pathways DDT is a pesticide that acts as an estrogenic compound, and its chief metabolic product DDE inhibits androgens Effect on wildlife - eg. thinning eggshell of bald eagles Banned in the US since 1972 and most of Europe Endocrine disruptors may not cause phenotype or birth defect, but interfere with physiological functioning, such as: Mimicing the effect of natural hormone (eg., estrogenic compound mimic natural estrogen). Lecture 2: Environmental impacts on development 6  Antagonise hormone - inhibit binding to a receptor, or block synthesis of a hormone. Affect synthesis, elimination or transportation of a hormone in the body. “Prime” the organism to be more sensitive to hormones later in life. Endocrine disruptors affect endocrine signalling pathways in a complex manner Multiple receptors for hormones with different effects Multiple signalling pathways Multiple effects on gene transcription Cross-talk between hormones LO: Describe how altered endocrine function can impact development Diethylstrilbestrol (DES), a synthetic estrogen (potent), was used as a drug to prevent miscarriage. In offspring of women treated with DES during pregnancy: Daughters had high rate of cell type changes in the reproductive tract, and some had clear cell adenocarcinoma Caused infertility, and other reproductive health issues DES can have significant effects on endocrine function & development by altering the expression of specific genes involved in developmental processes: 1) Wnt7a Inhibition Can disrupt the normal development of Mullerian ducts ⇒ leading to reproductive tract abnormalities, can result in conditions such as uterine malformations or infertility 2) Reduced Hox10 Expression Lecture 2: Environmental impacts on development 7  Wnt7a is necessary for the activation of specific signaling pathways that upregulate Hoxa10 expression in the developing reproductive tract ⇒ SO, Wnt7a inhibition reduce Hox10 expression Uterline development abnormality Decreased expression can result in impaired implantation ⇒ leading to infertility or increased risk of pregnancy complications LO: Discuss how small molecules and environmental factors can impact animal and human development and health. Phthalates as teratogenic agents Used as plasticizers (↑ flexbility, transparency, durability, and longevity for products) Lecture 2: Environmental impacts on development 8  enteric coatings of pharmaceutical pills and nutritional supplements, adhesives and glues, electronics, etc. Released into the environment there is no covalent bond between the phthalates and plasticsin which they are mixed leach and evaporate into food or the atmosphere Most common pthalate - DEHP Diet is believed to be the main source of DEHP and other phthalates in the general population Leaches into a liquid that comes in contact with the plastic; it extracts faster into nonpolar solvents (e.g. oils and fats in foods packed in PVC). Fatty foods such as milk, butter, and meats are a major source Manifestations Disrupts fetal testis testosterone biosynthesis Decreased gene expression and protein levels Decreased insulin-like factor 3 gene expression Cryptorchidism (absence of one or both testes from the scrotum) Reduced anogenital distance (feminization of perineum) Impact on food chain Teratogens and endocrine disruptors themselves don't directly increase pollution or release plastics into the environment, but the substances that often act as these disruptors can contribute to environmental pollution and plastic contamination Many endocrine disruptors, such as phthalates and bisphenol A (BPA), are used in the production of plastics. When plastic products degrade or are improperly disposed of, these chemicals can leach into the environment, contaminating soil, water, and air. Some of these compounds do not break down easily Lecture 2: Environmental impacts on development 9  Toxins, teratogens, endocrine disruptors can accumulate in certain tissues, and increase in concentration higher up the food chain. Impact on: polar bears, killer whales Impact of changing ecology on human health Bisphenol A (BPA) BPA leaches out of plastic BPA can bind to: several estrogen receptors, thyroid hormone receptors, androgen receptor, estrogen related receptor Effects of low doses of BPA in mouse: Male and female reproductive organs → abnormalities in sperm development, reduced testosterone lvs, disrupted ovarian function Metabolic tissues and organs Brain Sensitization to hormonal and carcinogen challenges Epidemiology studies in human suggests possible impact on fertility, metabolic syndrome, severity of asthma Diagram: In terms of dose effect Lecture 2: Environmental impacts on development 10  while teratogen may observed a linear rise in dose effect, ie. no dose = no effect, with the effects increasing as dosage increases, eventually leading to death for endocrine disruptors, there is a U/curve shaped relationship between dosage and effect, ie. low dosage = little effect, increasing dosage increases effects, reaching a peak, before further increasing dosage results in a decline in the effect. Transgeneration inheritance Endocrine disruptors can have transgenerational inheritance effects, meaning that the effects of exposure can be passed down to future generations, even if those generations were not directly exposed. Mechanism: Germ Cells Exposure: If an individual (F1 generation) is exposed to an endocrine disruptor during pregnancy, not only is the fetus (F2 generation) exposed, but so are the germ cells (future eggs or sperm) within that fetus, which will develop into the next generation (F3). If these germ cells are affected, the resulting offspring (F2 generation) could also carry the impact of the exposure. Transgenerational Effects: In some cases, the effects can persist even further, affecting the F4 generation and beyond. This happens if the endocrine disruptor causes epigenetic changes (like DNA methylation or histone modification) that are stable and heritable. Because these changes can be passed on through the germ line, observing the F4 generation is crucial to fully understand the potential long-term impact. Lecture 2: Environmental impacts on development 11  Transgenerational inheritance - mechanism? Exposure to endocrine disruptors can cause changes in DNA methylation, particularly in imprinted genes during critical developmental windows such as sex determination. These changes can be passed down through the germline, leading to altered gene expression and potential health effects in subsequent generations. DNA methylation is usually not heritable except at imprinted genes during sex determination, germ cells are re-methylated in a sex specific way Study by Mannikam et al. (2013): The study observed differential DNA methylation patterns in sperm of the F3 generation compared to the F1 generation, suggesting that the effects of early exposure can be transmitted through multiple generations, altering the epigenome. Scandinavian testicular cancer rates Increased rates in testicular cancer in Scandinavian countries is correlated with post-industrial revolution pollution from the UK Strong indicators of environmental causes Lecture 2: Environmental impacts on development 12