Date of Award

5-2022

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biological Sciences

Committee Chair/Advisor

Lisa Bain

Committee Member

William Baldwin

Committee Member

Susan Chapman

Abstract

Synthetic phenolic antioxidants (SPAs) are a class of compounds used to increase the durability of polymers as well as to increase the shelf-life of food, cosmetics, and other personal care items. Of these SPAs is 2,4-di-tert-butylphenol (2,4-DBP). 2,4-DBP is primarily used in polyethylene crosspolymer pipes, which are now used as a replacement for the traditional copper pipes for household water distribution. However, 2,4-DBP has been found to leach from these pipes into the water, enabling a mode of exposure to humans. 2,4-DBP has been detected in human urine, serum, but more importantly, maternal serum, placenta, and cord blood. These findings lead to a question as to whether we should be concerned about the developmental effects of 2,4-DBP. Other common SPAs such as BHA, BHT, and AO2246 disrupt endocrine glands, the nervous system, and bone during embryonic development. As such, the goal of this study was to examine whether 2,4-DBP can disrupt multiple pathways of development. Human induced pluripotent stem (HiPS) cells were differentiated for up to 40 days along the myogenic or osteogenic pathway. Cells were collected at multiple stages to assess changes in mRNA expression of pathway-specific marker genes. Cells were also harvested for histochemistry and protein expression. RNA sequencing was additionally conducted to identify signaling pathways that were affected by exposure. The results indicate that 2,4-DBP exposure caused delays in osteogenic differentiation as indicated by misexpression of the gene markers MEOX1, PAX9, OPN, and RUNX2. RNA sequencing identified the canonical Wnt signaling pathway as a means by which osteogenic differentiation was impacted. Misexpression of the WNT3A protein and the CCDN1 gene further verify that osteogenesis was impacted. In conclusion, this study shows that 2,4-DBP impairs osteogenic differentiation. As this compound has not been previously investigated before, this work elucidates the potential developmental toxicity this new SPA may have on human health.

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