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What are persistent organophosphates (POPs), what are their sources and why are they a concern for humans as well as other animal species? Give two examples of POPs and explain how humans come into contact with them. Be sure that your answer clearly indicates that you understand the concept of biomagnification.
- POPS: Persistant Organic Pollutants = organic compounds that are toxic. They are harmful to HUMANS and ENVIR.
- Concern for humans: 1. having effects on human systems such as NERVOUS, Endocrine, Reproductive & Immune. Stored in Adipose tissue
- 2. degrade VERY SLOWLY, and travel long distances
- 3. Subject to BIOMAGNIFICATION as the food chain moves up. For example, if we eat multiple fish that have been exposed to various POPs, we develop a MAGNIFICATION of POPs from the buildup of each fish we eat. From here, the farther up the food chain the more POPs
- 2 examples of POPs: PCDD/Fs and PCBs
- PCDD/Fs: produced from MEDICAL WASTE, Industrial-related processes and garbage combustion
- PCBs: produced for Plastics, Industrial APPLIANCES
- FOOD sources are most common now, since more regulations limit POPs in developed nation
What is the arylhydrocarbon receptor (AhR) and how does it function in the cell?
- AhR: Ligand receptor TRANSCRIPTION Factor in cell
- Fxn: affects xenobiotic metabolism
- Mechanism to function:
- 1. TCDD binds with AhR in Cytosol, followed by binding of Molecular chaperone complex AND Importins…then transfer to Nucleus.
- 2. AhR HeteroDIMERIZES with ARNT and acts as transcription factor that Binds to XENObiotic response elements
- 3. Genes regulating Xenobiotic metabolism TRANSCRIBED, then Heterodimer released and dissoc.
- 4. Exportins bind to AhR and translocation back to cytosol occurs where proteasomes degrade AhR
What are the metabolic/physiological processes that AhR can affect?
- Involved in xenobiotic metabolism: detoxification of man-made substances
- Circadian rhythm
- Organ development
What are hMADS? What was the source of these cells? How were they induced to differentiate? What cell type(s) did they differentiate into and how was differentiation confirmed?
- hMADS: human MULTIPOTENT Adipose-derived STEM cells that differentiate as adipocytes (white adipo, brown adipo, osteobasts or myoblasts)
- Source of cells: Adult WHITE adipose tissue, Isolated AFTER LIPOSUCTION
- To induce differentiation: these adipocytes utilized Insulin and T3 hormone
- To Confirm differentiation: Leptin and Adiponectin secretion were present (marker of human adipocytes)
Based on the qRT-PCR results in the hMADS cells, what affect did the POPs have on genes involved in the inflammatory pathway with regards to obesity? The up- and down-regulation of ten genes in particular were analyzed in this study- describe the function of four of these genes and state whether they were up-regulated or down-regulated.
- TCDD and PCB-126 (POPs analyzed): Gnerally Up-regulated in INFLAMMATORY pathway with regards to obesity
- PCB-153: Generally Down-regulated with regards to obesity in INFLAMMATORY pathway
- 1.IL1ra: Encodes for protein that acts as ANTAGONIST to IL1A and IL1B,
- UPREG of all 3 (TCDD, PCB-126 and PCB-153)
- 2. IL6: encodes for cytokine that fxns in INFLAMMATION and MATURATION of B cells,
- DOWNREG with PCB-153
- 3. IL8: Encodes for Inflammatory response cytokine mediator involved with CHEMOATTRACTION,
- UPREG TCDD and PCB-126
- 4. MCP1: Encodes for Cytokine involved in INFLAMMATION,
- UPREG with TCDD and PCB-126, DOWNREG with PCB-153
What’s the significance of the KO mice and what similar control was done in the hMADS cells? Briefly explain the mechanism by which POPs interact with the Aryl hydrocarbon receptor (AhR) pathway.
- KO mice have the genes for AhR knocked out, showing the importance of AhR related to TCDD treatment to mice.
- Effects were seen with treatment to increase IL10 expression (anti-inflammatory) vs in KO there was NO Transcriptional Increase
- Mech to POP with AhR pathway:
- 1. TCDD binds with AhR in cytosol, then molecular chaperone complex and importins bind to AhR, then translocation to nucleus
- 2. AhR heteroDIMERIZES with ARNT to form TRANSCRIPTION Factor, which binds to XRE (xenobiotic response elements) sequence in gene promoter.
- 3. Genes regulating xenobiotic metabolism are TRANSCRIBED, then HeteroDIMER released from DNA and dissoc
- 4. Exportins bind to AhR and translocation back to cytosol where degradation by Proteasomes
Discuss the overall significant findings of the research study focusing on which POPs had significant effects versus those that did not. Identify which cell type(s) the POPs had the greatest impact on.
- Overall significance: TCDD (dioxin) and PCB-126 (dioxin-like) had SIGNIFICANT effects on obesity-related inflammation vs PCB-153 (non-dioxin like POP), which had NO effect
- POPs had a much greater impact on the undifferentiated precursor hMADS when compared to the differentiated human adult adipocytes