Plasticizer Bis(2-ethylhexyl) Phthalate Causes Meiosis Defects and Decreases Fertilization Ability of Mouse Oocytes in Vivo

Abstract

Bis­(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer in polyvinyl chloride (PVC) plastics. Humans and animals are widely and continuously exposed to DEHP, especially with respect to diet, which is associated with reproductive diseases. Nevertheless, the effects and underlying mechanisms of DEHP exposure on oocytes in vivo remain ambiguous. In this study, we found that oral administration of DEHP (40 μg/kg body weight per day for 14 days) markedly reduced the maturation and fertilization of oocytes in vivo. In addition, DEHP caused oxidative stress, increased reactive oxygen species generation, promoted early apoptosis, and resulted in DNA damage in mouse oocytes. Moreover, DEHP exposure caused mitochondrial damage, reduced ATP content, down-regulated actin expression, and disturbed the spindle assembly and chromosome alignment in mouse oocytes. Furthermore, DEHP exposure remarkably impaired the localization and protein level of Juno, the sperm receptor on the membrane of oocytes. The levels of DNA methylation, H3K9me3, and H3K9ac were also altered in the DEHP-exposed mouse oocytes. Thus, our results indicated that DEHP exposure reduced the maturation and fertilization capabilities of mouse oocytes by affecting cytoskeletal dynamics, oxidative stress, early apoptosis, meiotic spindle morphology, mitochondria, ATP content, Juno expression, DNA damage, and epigenetic modifications in mouse oocytes.

Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

“…Data showed that DEHP induced the altered development of the primordial germ cells, germ cell survival, meiotic progression and increased follicle atresia [ 128 ]. In addition, DEHP disturbed the maturation and activation of oocytes before fertilization via meiotic maturation inhibition and oxidative stress [ 129 ]. Exposure to DEHP at 25 mg/m 3 by inhalation [ 130 ] and prenatal exposure to a mixture of DEP, DEHP, DnBP, DiNP, DiBP, and BBzP at 20, 200 and 500 mg/kg [ 131 ] impaired the estral cycle, particularly ovulation and estradiol synthesis in rats and mice, as well [ 130 , 131 ].…”

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

“…While DEHP-induced congression failure has not been previously described, several studies suggest that congression failure may stem from perturbations to spindle machinery components such as microtubules, actin filaments and the dynein and kinesin motor proteins or to problems with the interactions between kinetochores and the spindle. DEHP was recently shown to disrupt meiotic spindle assembly and chromosome alignment by reducing cytoskeletal actin expression in mice [70,71]. In depletion studies of human kinesins, involved in the regulation of the attachment of spindle MTs to kinetochores, abnormal congression and chromosome misalignment was observed [71].…”

“…Alternatively, the induction of a greater number of DSBs may be attributed to the interaction of DEHP or its metabolites with the peroxisome proliferatoractivated receptors (PPARs), a nuclear family of receptors that function as transcription factors that activate genes involved in steroidogenesis and antioxidative stress [75,76]. Given that stimulation of PPAR by DEHP or its metabolites activates an oxidative stress response, leading to DNA fragmentation and increased apoptosis of either sperm or oocytes in multiple organisms, we cannot discard the possibility that an excess number of DNA lesions may result from oxidative stress damage mediated by the interaction between DEHP and the C. elegans PPAR homolog NHR-49 [34,70,77,78]. Several studies have shown that elevated exposure to DEHP in humans was associated with 8-hydroxy-deoxyguanosine, a biomarker of oxidative damage to DNA [79][80][81].…”

Effect of environmental contamination on female and male gametes – A lesson from bovines

“…Alterations in mitochondrial distribution were associated with increased ROS levels and decreased mitochondrial membrane potential (ΔΨm) ( Figure 1 C,C': Kalo and Roth, 2015 ). In mice, oral treatment with DEHP (40 μg/kg BW) increased ROS levels in the oocytes, along with disruption of mitochondrial function and reduction in ATP levels ( Lu et al., 2019 ). In equine, an increase in ROS and ATP levels was recorded in oocytes that were exposed to 12 µM DEHP ( Ambruosi et al., 2011 ).…”