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

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 environmentallyrelevant 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.

DNA oxidation induced by fetal exposure to BPA agonists impairs female meiosis

“…We also reveal that bisphenols effects are mediated by DNA oxidation. Numerous toxicological studies have linked prophase I alterations induced by pollutants, aneuploidy and folliculogenesis defect and, here, we demonstrated the central role of oxidative DNA damages in these ovarian reproductive failures (Cuenca et al, 2020;Gely-Pernot et al, 2017;Susiarjo et al, 2013) . This opens new research avenues considering DNA oxidation in the developing germline as the cause of adult reproductive defects.…”

“…Interestingly, common cellular (ie MLH1 and chiasmata distribution and MOF) and transcriptional meiotic signatures observed after bisphenols exposure and other pollutants such as phthalates in multiple organisms suggest a common mechanism of action of these molecules (Allard & Colaiácovo, 2010b;Cuenca et al, 2020;Gely-Pernot et al, 2017;Parodi et al, 2015;Shin et al, 2019;Susiarjo et al, 2007;Tu et al, 2019). In this study, we propose oxidative stress as an new player involved in bisphenol response that could impair the PGC differentiation.…”

“…This study highlights the central role of oxidative DNA damage in the meiotic response after bisphenol exposure. Numerous past studies proposed a role for estrogen signaling in the meiotic responses (ie delay of meiotic progression, alteration of crossover distribution and aneuploidy) due to the effect of molecules with a xenoestrogenic potential (Cuenca et al, 2020;Susiarjo et al, 2007;Tu et al, 2019). Our hypothesis is in agreement with an involvement of estrogen signaling during this process as DNA binding by the estrogen receptor drives the local production of oxidative DNA damages via LSD1, a Lysine-specific histone demethylase 1, activity in promoter and enhancer regions (Perillo et al, 2008).…”

Exposure to phthalates: germline dysfunction and aneuploidy

“…Analysis of the effects of DEHP exposure on the C . elegans germline revealed alterations in chromosome structure that might be linked to the altered germline‐specific gene expression of the arginine methyltransferase prmt‐5 , resulting in increased levels of DSB formation and crossover recombination and leading to genomic instability 42 . Therefore, studies in C .…”

A new experimental system to study meiotic recurrent non-allelic homologous recombination in budding yeast

“…These unknown factors might include enzymes involved in HR or coordination of chromosome pairing (Goldman and Lichten, 1996;Grushcow et al, 1999;Goldman and Lichten, 2000;Shinohara and Shinohara, 2013;Shinohara et al, 2019), as well as exposure to chemicals that may possibly perturb some of these key meiotic processes (Shin et al, 2019;Cuenca et al, 2020). Therefore, sensitive cell-based assay systems able to recapitulate the LCR-mediated meiotic NAHR process experimentally are needed in order to identify the genes and environmental factors that can modulate recurrent CNV formation (Lupski, 2015;Yauk et al, 2015;Conover and Argueso, 2016).…”