Di-(2-ethylhexyl) phthalate exacerbates abnormalities of testicular development in F1 males via inhibition the Wnt/β-catenin signaling pathway.

The theory of "Developmental Origins of Health and Disease (DOHaD)" espouses that environmental exposures to toxicants during critical developmental stages can affect health outcomes in adulthood. Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that can be transferred to developing organisms via the placenta and breast milk as an environmental endocrine disruptor. We herein implemented a cross-fostering model to decipher the contributions of prenatal vs. postnatal exposure to low or high dose DEHP (30 or 500 mg/kg-bw•d) on reproductive outcomes in male offspring and the underlying mechanism of action. Unexpectedly, we observed that postnatal DEHP exposure programmed weight gain in a dose-dependent manner, in-utero exposure to high dose DEHP appeared to constitute a significant factor in the weight loss of male offspring. Moreover, in the low dose group, offspring of control that were suckled by DEHP dams (CC-DE) generated a considerable number of adverse reproductive outcomes compared with the offspring of DEHP that were suckled by control dams (DE-CC), based on histopathologic alterations in the testis, blockage of sex hormone secretion, and transcriptional inhibition of steroid-hormone-related factors in the hypothalamic-pituitary-testicular (HPT) axis. However, DE-CC group affected reproductive dysfunction in male offspring more so than CC-DE in the high dose group. Mechanistically, DEHP contributed to the inhibition of steroidogenesis by perturbing the Wnt/β-catenin-signaling pathway. These studies confirm the sensitivity window in which future reproductive outcomes in offspring are influenced following developmental exposure to DEHP at two different dosages, and reveals a critical role for the Wnt/β-catenin signaling pathway in DEHP-induced male reproductive disorders. The study aims to reveal the contributions of the prenatal vs. postnatal DEHP exposure on the reproductive outcomes on male offspring and to elucidate DEHP's underlying mechanism of action in these paradigms. We found the postnatal "30-mg/kg DEHP" and intrauterine "500-mg/kg DEHP" environment contribution more to male offspring T biosynthesis decreased & reproductive impairment. Our finding highlights Wnt/β-catenin signaling by which DEHP-induced reproductive dysfunction in male offspring. [Display omitted] • Maternal exposure to DEHP impacts reproductive development in male mice offspring. • DEHP exposure in in-utero vs. postnatal periods on male fertility depends on dose. • DEHP disrupted sex hormone levels by interfering with the regulation of HPT axis. • DEHP/MEHP inhibited of the Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]