Week 7&8 Flashcards
(27 cards)
General principles of Teratology
- Susceptibility depends on genotype of conceptus and its interaction with adverse environmental factors
- Susceptibility varies with developmental stage at exposure
- Agents act with specific mechanisms on developing cells & tissues to initiate pathogenesis (e.g. angiogenesis)
- Access to developing tissues depends on the nature of the agent
- Four manifestations are: death, malformation, growth retardation and functional deficit
- Frequency and degree of increases with dose (from ‘no effect’ to ‘totally lethal’ levels)
Stages pf development
Gametogenesis, fertilisation, Pre-implantation, Gastrulation, organogenesis, fetal period.
Classification of developmental
toxicity
Class 1: embryo lethality
– inducing embryo resorption or spontaneous abortion
Class 2: intrauterine growth retardation
– decrease in foetal body weight; low birth weight
Class 3: congenital malformation
– structural deformities (→ perinatal mortality)
Class 4: functional disorders
– defective postnatal abilities (→ prenatal mortality)
embryotoxicity
spontaneous abortion
fetotoxicity
decreased development
teratogenicity
malformations
DNA alterations and mutagenesis types
(a) chemical covalent reactions (DNA adducts)
- result in miss-pairing (base-pair substitution), base-loss and error-prone repair e.g. alkylating agents, nitrogen mustards
(b) intercalation resulting in frame shifts e.g. acridines, some cytotoxic antibiotics
(c) UV-induced chemical alterations
e.g. thymine dimers
DNA adducts
alkylation by genotoxins
How are chemical mutation caused?
1.DNA alterations and mutagenesis
2. DNA repair errors
3.Aneuploidy & polyploidy (errors in mitosis or meiosis)
DNA Repair Processes
- Base excision repair
- single base removal & repair (opposite strand as template) - Nucleotide excision repair
- removal of bulky adducts; involves 20 proteins removing up to 100 nucleotides; repair with opposite strand as template - Mismatch repair
- corrects mismatch base pair (bp) post replication - Recombinatorial repair
- repairs double strand DNA breaks &/or crosslinks
Carcinogenicity
2 year chronic testing.
3 different dose - high medium low
Measures - food/water consumption, body weight. Autopsy/histopathology and clinical chem at 0.5, 1, 1.5 and 2 years, type and incidence of tumors, other abnormalities
To be of concern, a chemical effect must be stat. greater than spont. tumour incidence
Cancer stages
Initiation, Transformation, promotion, progression.
normal cell, preneoplastic cell, neoplastic, benign neoplasm, malignant neoplasm
Initiation
- simple irreversible mutation in individual cells from a single sub-carcinogenic dose of carcinogen
Promotion
- depends on continued exposure; reversible if ceases
- no direct interaction with DNA; has a threshold dose (below which there is no effect)
- modifying factors - age, diet & hormonal influences
“Promoter” agent:
* causes expansion of initiated clones of cells. eg. saccharin
Progression
- irreversible; observable neoplasms
- cells show complex alterations in genetic structure, i.e.
- deletion, recombination or
irreversible changes in gene expression - instability of chromosomal constitution (“karyotype”) ->aneuploidy
“Progressor” agent: - converts initiated or promoted cell into a potentially malignant cell
Complete carcinogen
- induces cancer in normal cells
(combination initiator/promoter/progressor)
polymorphisms in human genes for important xenobiotic-metabolising enzymes
can cause genetic pre-disposition.
eg. Cytochrome P450 (CYP1A1, 2A6, 2D6, 2E1), Glutathione S-transferase (GSTM1 null phenotype), N-acetyl transferase (NAT2)
Oncogene & tumour suppressor gene mutations seen in many occupationally-induced tumours
IARC’s Overall Evaluations of
Carcinogenicity to Humans
Groups 1 (carcinogen), 2A, 2B (possible with animal data), 3 (insufficient evidence)
Carcinogen examples
benzene, mineral oils, alcohol, tobacco smoke
DNA-reactive (genotoxic) carcinogens
- Activation-independent organics
(alkylating agents, nitrogen mustards, epoxides) - Activation-dependent organics
(aliphatic halides; PAH; arylamines; nitrosamines; mycotoxins – aflatoxin AFB1; drugs – cyclophosphamide*) - Activation-independent inorganics
(Metals - Be, Cd, Cr as chromate, Ni;
metalloids - As; minerals - silica, asbestos)
Non-genotoxic (epigenetic) carcinogens
- Promoters: inhibits cell communication & contact inhibition
(liver enzyme inducer hepatocarcinogens - OC pesticides,
barbiturates, PCBs, PBBs, PCDDs - TCDD, saccharin) - Endocrine modifiers: for hormone-dependent tumours
(hormones – estrogen, DES, anti-androgens*; thyroid inhibitors; gastrin-elevating inducers of gastric
neuroendocrine tumours – omeprazole)
- Peroxisome proliferators: not in primates? (plasticiser phthalate esters, DEHP; hypolipidemic drugs – clofibrate, gemfibrozil)
Cytotoxics & immunosuppressives
carcinogen testing stages
Stage A: chemical structure
Stage B: short-term genotoxicity assays
Stage C: assays for non-genotoxic effects (in vitro & in vivo)
* Stage D: in vivo assays (genotoxicity, DNA binding, limited bioassays)
* Stage E: carcinogenicity bioassays (accelerated and long term bioassays)
Decision points
Decision Point 1: evaluation of findings of A & B
Decision Point 2: evaluation of findings of A to C
Decision Point 3: evaluation of findings of A to D
Decision Point 4: final evaluation of all findings and cancer hazard assessment
Animal Mechanisms NOT indicative of cancer hazard to humans
- rat kidney α2μ-globulin nephropathy –> kidney neoplasms
- rat stomach acid secretion suppression –> gastric neuroendocrine neoplasm
(gastrin-induced carcinoma of enterochromaffin-like cells) - rat urinary bladder neoplasias (crystallurias + lack of tight junctions)
- rodent liver peroxisome proliferator –> liver neoplasms
- rodent thyroid-pituitary disruption –> thyroid tumours
