Environmental Exposure and Disease

Multiple choice

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Short Answer Model Answers

SA1 (4 marks): UV-B radiation from sunlight is absorbed by adjacent thymine bases on the same DNA strand in melanocytes. The absorbed energy forms a covalent cyclobutane ring between the two thymines, a thymine dimer (cyclobutane pyrimidine dimer, CPD) [1]. The dimer distorts the DNA double helix, preventing normal base pairing and blocking DNA polymerase during replication [1]. If not repaired by nucleotide excision repair (NER) before the cell divides, DNA polymerase stalls or inserts incorrect bases, typically producing CC→TT signature mutations [1]. In melanocytes, if these mutations occur in the BRAF proto-oncogene (commonly V600E, activating the MAPK/ERK pathway) or the CDKN2A tumour suppressor (encoding p16), the cell can divide uncontrollably → melanoma [1].

SA2 (5 marks): Lung cancer mechanism: tobacco smoke contains >70 carcinogens (e.g. benzopyrene) absorbed across the bronchial epithelium and metabolically activated to electrophiles that covalently bond to DNA bases forming DNA adducts → errors during replication → mutations in proto-oncogenes (KRAS) and tumour suppressors (TP53) → with continued smoking, multiple mutations accumulate in the same cell line over 20–30 years → uncontrolled cell division → lung cancer [2]. COPD/emphysema mechanism: tobacco smoke irritants trigger chronic airway inflammation → continuous recruitment of macrophages and neutrophils → release of elastase, which degrades elastin in alveolar walls → progressive destruction of alveolar walls (↓gas exchange surface area, loss of elastic recoil) → air trapping = emphysema; goblet cell hyperplasia produces excess mucus → chronic bronchitis [2]. Key difference: lung cancer involves mutagenic DNA damage disrupting cell cycle regulation (uncontrolled division, requiring decades of accumulated mutations), whereas COPD involves inflammatory tissue destruction (proteolytic degradation of lung architecture) that can begin within years without DNA mutation in proto-oncogenes [1].

SA3 (6 marks): Definition and distinction: epigenetics refers to heritable changes in gene expression that do not alter the DNA nucleotide sequence; in contrast, a genetic mutation changes the actual sequence. An epigenetic change leaves the sequence intact but modifies whether the gene is accessible for transcription; epigenetic changes can sometimes be reversed, most mutations cannot [1]. DNA methylation mechanism: the addition of a methyl group (–CH₃) to cytosine at CpG sites by DNA methyltransferases; when a gene's promoter contains many methylated CpG sites, methyl-binding proteins compact the chromatin and prevent transcription factors from binding → the gene is silenced despite an intact sequence [2]. Environmental exposure example: tobacco smoke can cause hypermethylation of the CDKN2A promoter (encoding p16) in bronchial cells → p16 not produced → CDK4/6 uninhibited → Rb hyperphosphorylated → E2F released → cells proceed through S phase without the G1 checkpoint, the same functional outcome as a loss-of-function mutation, achieved without changing the sequence [2]. Significance: this shows environmental exposures can produce the same functional outcomes as genetic mutations through a different, potentially reversible mechanism, and explains why individuals with identical DNA sequences can have different cancer susceptibility based on exposure history, a molecular basis for gene-environment interaction underlying multifactorial disease [1].