The production of plastic products, which requires phthalate plasticizers, has resulted in the problems for human health, especially that of reproductive health. Phthalate exposure can induce reproductive disorders at various regulatory levels. The aim of this review was to compile the evidence concerning the association between phthalates and reproductive diseases, phthalates-induced reproductive disorders, and their possible endocrine and intracellular mechanisms. Phthalates may induce alterations in puberty, the development of testicular dysgenesis syndrome, cancer, and fertility disorders in both males and females. At the hormonal level, phthalates can modify the release of hypothalamic, pituitary, and peripheral hormones. At the intracellular level, phthalates can interfere with nuclear receptors, membrane receptors, intracellular signaling pathways, and modulate gene expression associated with reproduction. To understand and to treat the adverse effects of phthalates on human health, it is essential to expand the current knowledge concerning their mechanism of action in the organism.

https://www.mdpi.com/1660-4601/17/18/6811/pdf

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

Increased m6A RNA modification is related to the inhibition of the Nrf2-mediated antioxidant response in di-(2-ethylhexyl) phthalate-induced prepubertal testicular injury

Role of autophagy in di-2-ethylhexyl phthalate (DEHP)-induced apoptosis in mouse Leydig cells.

As a plasticizer, di(2-ethylhexyl) phthalate (DEHP) is the most usually used phthalate. Leydig cell is a male-specific cell, which plays a principal role in spermatogenesis and masculinization by the androgens of synthesis and secretion. Numerous researchers have indicated that DEHP can result in testicular toxicity by inducing oxidative stress. Lycopene (LYC) is a possible treatment option for male infertility due to its natural antioxidant properties. Our study was aimed to investigate whether LYC could rescue DEHP-induced Leydig cell damage. The mice were treated with DEHP (500 mg/kg BW/day or 1000 mg/kg BW/day) and/or LYC (5 mg/kg BW/day) for 28 days. We found that LYC attenuated DEHP-induced Leydig cell damage. Moreover, the protective role of LYC was verified by the histopathological and ultrastructural analysis of the Leydig cell. LYC suppressed oxidative stress that was induced by DEHP. In the Leydig cell, the expressions of the nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target genes were improved through LYC-mediated protection in DEHP-induced Leydig cell damage. Our findings indicated that LYC could increase the antioxidant capacity via mediating Nrf2 signaling pathway, thereby attenuating DEHP-induced Leydig cell damage.

Lycopene Prevents DEHP-Induced Leydig Cell Damage with the Nrf2 Antioxidant Signaling Pathway in Mice

Di(2-ethylhexyl) phthalate (DEHP), as a widespread environmental pollutant and an endocrine disruptor, can disturb the homeostasis of thyroid hormones (THs). In order to elucidate roles of the MAPK and PI3K/Akt pathways and hepatic enzymes in thyroid-disrupting effects of DEHP, Sprague-Dawley rats were dosed with DEHP by gavage for 30 consecutive days; Nthy-ori 3-1 cells were treated with DEHP with NAC, k-Ras siRNA or inhibitors (U0126 and wortmannin). Results showed that DEHP led to histopathologic changes in rat thyroid and liver, such as the decrease in thyroid follicular cavity diameter, hepatocyte edema. Triiodothyronine (T3), thyroxine (T4) and thyrotropin releasing hormone (TRH) were reduced. DEHP caused ROS production, oxidative stress and k-Ras upregulation, thereby activating the ERK and Akt pathways in vivo and in vitro. Moreover, TRH receptor (TRHr) level was elevated after the activation of the Akt pathway and was downregulated after the inhibition of the Akt pathway. However, TRHr was not modulated by the ERK pathway. Additionally, hepatic enzymes, including Ugt1a1, CYP2b1, Sult1e1, and Sult2b1, were significantly induced after DEHP exposure. Taken together, DEHP can perturb TH homeostasis and reduce TH levels. The activated Ras/Akt/TRHr pathway and induced hepatic enzymes play vital roles in thyroid-disrupting effects of DEHP.

/pdf/di2-ethylhexyl-phthalate-disrupts-thyroid-hormone-uk0fj0mesn.pdf

Li Wei

Papers

Di-(2-ethylhexyl) phthalate inhibits testosterone level through disturbed hypothalamic-pituitary-testis axis and ERK-mediated 5α-Reductase 2.