Abstract
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.
Highlights
Errors in achieving accurate chromosome segregation during meiosis can result in the formation of either eggs or sperm carrying an incorrect number of chromosomes and has been implicated in 4% of still births, 50% of clinically-recognized miscarriages, congenital birth defects and infertility observed in humans [1,2,3,4]
Diethylhexyl phthalate (DEHP), a commonly used plasticizer found in personal care and household products, has emerged as an endocrine disruptor that exerts reprotoxicity in mammals
We propose that DEHP exposure induces an excess number of double-strand breaks (DSBs) by interfering with mechanisms set in place to turn off DSBs once CO designation is accomplished and by altering chromosome structure resulting in increased chromatin accessibility to the DSB machinery
Summary
Errors in achieving accurate chromosome segregation during meiosis can result in the formation of either eggs or sperm carrying an incorrect number of chromosomes (aneuploidy) and has been implicated in 4% of still births, 50% of clinically-recognized miscarriages, congenital birth defects and infertility observed in humans [1,2,3,4]. Thousands of man-made chemicals, including endocrine disrupting chemicals (EDCs) such as phthalates, are highly prevalent in the environment and their impact on meiosis is not fully understood. DEHP is present in a variety of consumer products including: clothing, personal care products, children’s toys, food packaging, vinyl flooring, carpets, wires, medical devices and construction materials [8]. The ubiquity of DEHP extends to non-PVC materials such as makeup, adhesives, fillers, pills and printing inks [9]. Exposure to DEHP can occur via inhalation, ingestion and dermal absorption as it is detected in the air, water and soil, respectively [10, 11]. The widespread use of DEHP underscores the importance of understanding how it impacts meiosis and thereby reproductive health
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