Synthetic phenolic antioxidant propyl gallate induces male infertility through disruption of calcium homeostasis and mitochondrial function

• Published in: Environmental pollution (1987) 2019-05, Vol.248, p.845-856
• Main Authors: Ham, Jiyeon, Lim, Whasun, Park, Sunwoo, Bae, Hyocheol, You, Seungkwon, Song, Gwonhwa
• Format: Article
• Language: English
• Subjects: Apoptosis; Calcium; Infertility; Mitochondria; Propyl gallate
• ISSN: 0269-7491; 1873-6424
• DOI: 10.1016/j.envpol.2019.02.087

Propyl gallate (propyl 3,4,5-trihydroxybenzoate, PG) is a phenolic antioxidant that has been used for oil-containing foods to prevent acidification. Owing to its antioxidant properties, PG has been applied to various fields and active research is currently underway to prove PG as an anticancer agent. However, there are still concerns about PG as a possible reproductive toxicant. Therefore, we determined whether PG induced male infertility. Our results indicated that PG induced testicular dysfunction in both Leydig and Sertoli cells via suppression of cell viability and steroidogenesis. These normal testis functions were destroyed by PG-induced mitochondrial dysfunction and calcium homeostasis dysregulation. In addition, PG disrupted the expression of several genes associated with the testis function and induced endoplasmic reticulum stress. Furthermore, we verified PG-induced mRNA expression changes in steroidogenesis enzymes and hormone receptors in vitro and in vivo. From the results of the qPCR analysis, we further confirmed the PG-mediated reduction in the mRNA expression of genes related to testis functions by in situ hybridization. Finally, we demonstrated that PG induced testicular toxicity via the disruption of mitochondrial or ER function and the inhibition of testicular development-related genes in mice. Schematic hypothesis of the model of propyl gallate (PG)-induced testicular toxicity. Propyl gallate induced an antiproliferative effect on mouse Leydig and Sertoli cells via mitochondrial dysfunction and calcium dysregulation. Propyl gallate regulates MAPK and PI3K/Akt signaling transduction, dependent on cell type (Leydig or Sertoli cells). Additionally, PG dysregulated the function of the testes based on the perturbation of the mRNA expression of various hormone receptors. [Display omitted] •Propyl gallate induces cell cycle arrest of mouse testicular cells via cyclin suppression.•Propyl gallate dysregulates steroidogenesis necessary for testicular cells.•Propyl gallate inhibits the normal growth and survival of testicular cells.•Propyl gallate may lead to the failure of spermatogenesis and male infertility.