Environmentally-relevant exposure to diethylhexyl phthalate (DEHP) alters regulation of double-strand break formation and crossover designation leading to germline dysfunction in Caenorhabditis elegans

Autoři: Luciann Cuenca aff001;  Nara Shin aff001;  Laura I. Lascarez-Lagunas aff001;  Marina Martinez-Garcia aff001;  Saravanapriah Nadarajan aff001;  Rajendiran Karthikraj aff002;  Kurunthachalam Kannan aff002;  Mónica P. Colaiácovo aff001
Působiště autorů: Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, United States of America aff001;  Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, New York, United States of America aff002;  Department of Pediatrics, New York University School of Medicine, New York City, New York, United States of America aff003
Vyšlo v časopise: Environmentally-relevant exposure to diethylhexyl phthalate (DEHP) alters regulation of double-strand break formation and crossover designation leading to germline dysfunction in Caenorhabditis elegans. PLoS Genet 16(1): e32767. doi:10.1371/journal.pgen.1008529
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008529


Exposure to diethylhexyl phthalate (DEHP), the most abundant plasticizer used in the production of polyvinyl-containing plastics, has been associated to adverse reproductive health outcomes in both males and females. While the effects of DEHP on reproductive health have been widely investigated, the molecular mechanisms by which exposure to environmentally-relevant levels of DEHP and its metabolites impact the female germline in the context of a multicellular organism have remained elusive. Using the Caenorhabditis elegans germline as a model for studying reprotoxicity, we show that exposure to environmentally-relevant levels of DEHP and its metabolites results in increased meiotic double-strand breaks (DSBs), altered DSB repair progression, activation of p53/CEP-1-dependent germ cell apoptosis, defects in chromosome remodeling at late prophase I, aberrant chromosome morphology in diakinesis oocytes, increased chromosome non-disjunction and defects during early embryogenesis. Exposure to DEHP results in a subset of nuclei held in a DSB permissive state in mid to late pachytene that exhibit defects in crossover (CO) designation/formation. In addition, these nuclei show reduced Polo-like kinase-1/2 (PLK-1/2)-dependent phosphorylation of SYP-4, a synaptonemal complex (SC) protein. Moreover, DEHP exposure leads to germline-specific change in the expression of prmt-5, which encodes for an arginine methyltransferase, and both increased SC length and altered CO designation levels on the X chromosome. Taken together, our data suggest a model by which impairment of a PLK-1/2-dependent negative feedback loop set in place to shut down meiotic DSBs, together with alterations in chromosome structure, contribute to the formation of an excess number of DSBs and altered CO designation levels, leading to genomic instability.

Klíčová slova:

Apoptosis – Caenorhabditis elegans – Germ cells – Gonads – Chromosome structure and function – Metabolites – Phthalates – X chromosomes


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