Analysis of the Molecular Mechanisms Underpinning Germline Dysfunction Stemming from Exposure to Environmental Chemicals in C. elegans
Cuenca-Rivera, Luciann L.
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CitationCuenca-Rivera, Luciann L. 2020. Analysis of the Molecular Mechanisms Underpinning Germline Dysfunction Stemming from Exposure to Environmental Chemicals in C. elegans. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractMeiosis is a tightly regulated process by which the genetic material of diploid organisms is halved giving rise to haploid gametes (i.e. eggs or sperm). Errors during meiosis can lead to improper chromosome segregation with a myriad of negative reproductive health consequences. Mounting evidence from mammalian studies has linked environmental chemical exposures to reproductive health impairments. However, although classical toxicology studies in mammalian systems have been informative about the impact of environmental chemicals on human reproductive health, knowledge about the molecular mechanisms by which environmentally-relevant doses of these chemicals impact meiosis remains elusive. Here we investigated the mechanisms by which two ubiquitously present chemicals: diethylhexyl phthalate (DEHP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), impair meiotic prophase I and reproductive capacity using the nematode Caenorhabditis elegans as a model. DEHP is a plasticizer widely used in the manufacturing of polyvinylchloride-containing plastics. TCDD is a by-product of industrial processes well-known for its use as a defoliant herbicide during the Vietnam War era. Our studies show that exposure to either DEHP or TCDD alters meiotic progression and impairs double-strand break repair (DSBR) in the germlines of adult hermaphrodites. Defects in late meiotic prophase I lead to aberrant chromosome morphogenesis and impaired chromosome remodeling in diakinesis oocytes. Moreover, we found evidence of elevated DSB formation persisting through late pachytene that may stem from impaired DSB negative feedback loop regulation as evidenced by DSB-1-positive nuclei extending into mid and late pachytene, and a reduction in both COSA-1/CNTD1-marked CO designation sites and Polo-like kinase 1/2 (PLK-1/2)-dependent phosphorylation of SYP-4 at those substages. Finally, exposure to either chemical alters the germline-specific expression of subsets of genes involved in DSB repair and DNA damage response as well as chromosome structure as observed by synaptonemal complex lengthening along the X chromosome. We propose that these exposures alter chromosome structure and gene expression leading to elevated DSB formation and impaired DSB repair, thereby impairing maintenance of genomic integrity and accurate chromosome segregation. Taken together, these studies provide new mechanistic insight on the impact that environmentally-relevant exposures to DEHP and TCDD exert on meiosis in the context of a metazoan.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365517
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