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Effect of DEHP exposure on mouse ovaries. (A) Control and DEHP-treatment group of 20 dpp mouse ovarian morphology. (B-C) Control and DEHP-treatment groups of 20 dpp mouse ovarian HE histochemical sections. (D) The percentages of small antral follicles in the control and DEHP-treatment groups. (E) The percentages of large antral follicles in the control and DEHP-treatment groups. Compared to the control group the percentage of each group was presented as mean ± SD. All experiments were repeated at least three times independently. (* P < 0.05; ** P < 0.01).
Source publication
Di (2-ethylhexyl) phthalate (DEHP) is a widely used plastic additive. As an environmental endocrine disruptor, it has been shown to be harmful to the mammalian reproductive system. Previous studies indicated that DEHP inhibited the development of mouse ovarian follicles. However, the mechanisms by which DEHP affects ovarian antral follicle developm...
Citations
... For example, MA-10 Leydig cells treated with MEHP displayed a dose dependent increase of ROS that was linked to a decrease of cAMP and progesterone production [214]. Evidence also shows how both MEHP and DEHP exposure inhibited mouse ovarian antral follicle cell growth through activation of the oxidative stress signaling pathway [215,216]. In humans, concentrations of the marker for oxidative stress, 8-OHdG, and phthalate metabolites (monoethyl phthalate [MEP], MBP, MBzP, MEHP, MEHHP) were positively correlated in the follicular fluid of women pursuing in vitro fertilization, proposing an impact of phthalates on female reproductive health [217]. ...
Phthalates' pervasive presence in everyday life poses concern as they have been revealed to induce perturbing health defects. Utilized as a plasticizer, phthalates are riddled throughout many common consumer products including personal care products, food packaging, home furnishings, and medical supplies. Phthalates permeate into the environment by leaching out of these products which can subsequently be taken up by the human body. It is previously established that a connection exists between phthalate exposure and cardiovascular disease (CVD) development; however, the specific mitochondrial link in this scenario has not yet been described. Prior studies have indicated that one possible mechanism for how phthalates exert their effects is through mitochondrial dysfunction. By disturbing mitochondrial structure, function, and signaling, phthalates can contribute to the development of the foremost cause of death worldwide, CVD. This review will examine the potential link among phthalates and their effects on the mitochondria, permissive of CVD development.
... At the cellular level, administration of DBP and DEHP during culture led to altered steroidogenesis and granulosa cells arrest in G0/G1 phases of the cell cycle with higher apoptosis [78,87]. A possible underlying molecular mechanism could be the increased expression of FSH receptor (FSHR), triggered by xenoestrogen actions [90]. ...
... fetal ovary, impairing female fertility in adulthood [92]. In adulthood, exposure to phthalates leads to antral follicle apoptosis and impaired follicle growth [67,70,73,74,76,89,90]. In addition to apoptosis, xenoestrogens also lead to an imbalance of ovarian follicle classes with more mature follicles at the expense of the primordial follicle pool [77]. ...
... DEHP-induced damage of ovary function and abnormal reproductive capacity is extensively associated with oxidative stress in ovarian granulosa cells, owing to the increased expression of oxidative-related genes, suppression of the expression of antioxidant genes , and downregulation of antioxidant enzymes (Li et al. 2016). Oxidative stress is caused by an imbalance between the generation and removal of reactive oxygen species (ROS), leading to DNA damage and the oxidative modification of proteins (Tirichen et al. 2021). ...
... As shown in Figure 1B, ROS levels significantly increased at 1 lM DEHP exposure (p < 0.05). This indicated that 1 lM DEHP could induce oxidative stress and impair cell viability in ovarian granulosa cells, as described in previous studies (Li et al. 2016;Tripathi et al. 2019). Ultimately, we selected 1 lM DEHP for subsequent experiments. ...
Context
di-(2-Ethylhexyl) phthalate (DEHP) has potential reproductive toxicity. Bu-Shen-Tian-Jing formulations (BSTJFs) are beneficial for female reproductive capacity. However, BSTJF2 has much lower cytotoxicity than BSTJF1.
Objective
To investigate the effects of BSTJFs on ovarian granulosa cells exposed to DEHP and determine the potential molecular mechanisms.
Methods and materials
Human granulosa-like tumor cell line (KGN) cells were divided into control, DEHP, BSTJF1 and BSTJF2 groups. The DEHP group were given 1 μM DEHP for 24 h. They were then given BSTJF1 at 200 μg/mL or BSTJF2 at 100 μg/mL for 24 h. The control group was treated with the same concentration of DMSO (0.1%). Oxidative stress and mitochondrial function were measured. The mRNA and protein expression levels of HDAC3 and HSP90AA were determined. Integrative network pharmacology analysis of BSTJF2 was also performed.
Results
DEHP (1 μM) significantly suppressed the proliferation of KGN cells by 17%, significantly increased ROS levels by 28% and MDA levels by 47%, significantly decreased MMP levels by 22% and mtDNA copy by 30%. DEHP significantly increased protein expression of HDAC3 by 21%and HSP90AA by 64%. All these changes were significantly reversed by BSTJFs. Integrative network pharmacology analysis revealed HSP90AA was a key target (degree = 8). Both RGFP966 and BSTJF2 significantly reversed the increased expression of HDAC3 and HSP90AA, attenuated oxidative stress, and mitochondrial damage which were induced by DEHP.
Conclusion
BSTJFs might have therapeutic potential on oxidative stress and mitochondrial damage through the HDAC3/HSP90AA pathway which encourages further clinical trials.
... grina, also referred to as trim3, is an anti-apoptotic protein present in cell membranes and has been implicated in the regulation of cell survival and apoptosis, as opposed to the regulation of Ca 2+ concentration and neurotransmitter release [79]. Studies on grina-mediated apoptosis in various organisms such as mice, humans, and zebrafish have been conducted [79,80]. grina has been found to play a crucial role in regulating apoptosis during neuronal development and endoplasmic reticulum (ER) stress [81]. ...
As a quintessential marine teleost, Paralichthys olivaceus demonstrates vulnerability to a range of pathogens. Long-term infection with Edwardsiella tarda significantly inhibits fish growth and even induces death. Gills, blood, and kidneys, pivotal components of the immune system in teleosts, elicit vital regulatory roles in immune response processes including immune cell differentiation, diseased cell clearance, and other immunity-related mechanisms. This study entailed infecting P. olivaceus with E. tarda for 48 h and examining transcriptome data from the three components at 0, 8, and 48 h post-infection employing weighted gene co-expression network analysis (WGCNA) and protein–protein interaction (PPI) network analysis. Network analyses revealed a series of immune response processes after infection and identified multiple key modules and key, core, and hub genes including xpo1, src, tlr13, stat1, and mefv. By innovatively amalgamating WGCNA and PPI network methodologies, our investigation facilitated an in-depth examination of immune response mechanisms within three significant P. olivaceus components post-E. tarda infection. Our results provided valuable genetic resources for understanding immunity in P. olivaceus immune-related components and assisted us in further exploring the molecular mechanisms of E. tarda infection in teleosts.
... Occupational DEHP exposure may lead to oxidative distress and DNA damage [19]. DEHP and its metabolites can break down DNA in the liver [48], ovary [49], oocytes [28], Leydig cells [50], and placental trophoblasts cells [51] through reactive oxygen species (ROS). We also observed DNA damage in the placenta of mouse and HTR-8 cells. ...
Di (2-ethyl-hexyl) phthalate (DEHP) is a wildly used plasticizer. Maternal exposure to DEHP during pregnancy blocks the placental cell cycle at the G2/M phase by reducing the efficiency of the DNA repair pathways and affects the health of offsprings. However, the mechanism by which DEHP inhibits the repair of DNA damage remains unclear. In this study, we demonstrated that DEHP inhibits DNA damage repair by reducing the activity of the DNA repair factor recruitment molecule PARP1. NAD⁺ and ATP are two substrates necessary for PARP1 activity. DEHP abated NAD⁺ in the nucleus by reducing the level of NAD⁺ synthase NMNAT1 and elevated NAD⁺ in the mitochondrial by promoting synthesis. Furthermore, DEHP destroyed the mitochondrial respiratory chain, affected the structure and quantity of mitochondria, and decreased ATP production. Therefore, DEHP inhibits PARP1 activity by reducing the amount of NAD⁺ and ATP, which hinders the DNA damage repair pathways. The supplement of NAD⁺ precursor NAM can partially rescue the DNA and mitochondria damage. It provides a new idea for the prevention of health problems of offsprings caused by DEHP injury to the placenta.
... It is likely that individual phthalates in the mixture, particularly DEHP, contributed to the toxicity of the mixture. In one study, Li et al. evaluated the prepuberal effects of intraperitoneal exposure to DEHP (0, 20, and 40 µg/kg at 5 dpp, 10 dpp, and 15 dpp) on antral follicle growth [39]. Phthalate-exposed ovaries collected at 20 dpp had a smaller volume compared to controls. ...
... In addition, DEHP exposure resulted in a decreased percentage of large antral follicles, upregulation of apoptosis-related genes, and inhibition of cell-proliferation-related genes compared to controls. DEHP exposure also resulted in reactive oxygen species accumulation and decreased expression of antioxidant enzymes, suggesting that DEHP exposure induces oxidative stress and apoptosis, impacting ovarian follicle growth during the prepuberal stage in mice [39]. In another study, the effects of DEHP were evaluated in lactating mice. ...
The female reproductive system is dependent upon the health of the ovaries. The ovaries are responsible for regulating reproduction and endocrine function. Throughout a female’s reproductive lifespan, the ovaries undergo continual structural changes that are crucial for the maturation of ovarian follicles and the production of sex steroid hormones. Phthalates are known to target the ovaries at critical time points and to disrupt normal reproductive function. The US population is constantly exposed to measurable levels of phthalates. Phthalates can also pass placental barriers and affect the developing offspring. Phthalates are frequently prevalent as mixtures; however, most previous studies have focused on the effects of single phthalates on the ovary and female reproduction. Thus, the effects of exposure to phthalate mixtures on ovarian function and the female reproductive system remain unclear. Following a brief introduction to the ovary and its major roles, this review covers what is currently known about the effects of phthalate mixtures on the ovary, focusing primarily on their effects on folliculogenesis and steroidogenesis. Furthermore, this review focuses on the effects of phthalate mixtures on female reproductive outcomes. Finally, this review emphasizes the need for future research on the effects of environmentally relevant phthalate mixtures on the ovary and female reproduction.
... A significant increase in abnormal metaphase II spindles that may result in aneuploidy was observed in mature oocytes . Further, DEHP was found to inhibit the antral follicle enlargement process in pre-pubertal mice exposed to 20 or 40 μg/kg DEHP at PND 5, 10 and 15 (Li et al., 2016a). This inhibition was linked to disturbed oxidative status and increased follicle somatic cell apoptosis caused by DEHP exposure. ...
Over the past century, evidence has emerged that endocrine disrupting chemicals (EDCs) have an impact on reproductive health. An increased frequency of reproductive disorders has been observed worldwide in both wildlife and humans that is correlated with accidental exposures to EDCs and their increased production. Epidemiological and experimental studies have highlighted the consequences of early exposures and the existence of key windows of sensitivity during development. Such early in life exposures can have an immediate impact on gonadal and reproductive tract development, as well as on long-term reproductive health in both males and females. Traditionally, EDCs were thought to exert their effects by modifying the endocrine pathways controlling reproduction. Advances in knowledge of the mechanisms regulating sex determination, differentiation and gonadal development in fish and rodents have led to a better understanding of the molecular mechanisms underlying the effects of early exposure to EDCs on reproduction. In this manuscript, we review the key Contents lists available at ScienceDirect
... DEHP induced the differential gene expression of Hsp90ab1, Rhoa, Grina and Xdh which may play an important role in this process. (30) TBT-Tributyltin chloride (TBT) is endocrine disruptor chemical. With the oral administration in rats it increases testosterone levels and induces irregular estrous cycle. ...
... DEHP induced the differential gene expression of Hsp90ab1, Rhoa, Grina and Xdh which may play an important role in this process. (30) TBT-Tributyltin chloride (TBT) is endocrine disruptor chemical. With the oral administration in rats it increases testosterone levels and induces irregular estrous cycle. ...
... These compounds impact folliculogenesis, ovulation and steroidogenesis, and may induce a long-lasting effect on reproductive, but also on non-reproductive health as these processes are important for the cardiovascular, skeletal and brain health. In vitro studies provided evidence, partially confirmed in animal models (114,115), suggesting a possible disruptive effect of environmental pollutants on the antral stage. However, the impact on human folliculogenesis is still poorly known and could be elucidated by long-term epidemiological observations on large datasets. ...
An increasing number of pollutants with endocrine disrupting potential are accumulating in the environment, increasing the exposure risk for humans. Several of them are known or suspected to interfere with endocrine signals, impairing reproductive functions. Follicle-stimulating hormone (FSH) is a glycoprotein playing an essential role in supporting antral follicle maturation and may be a target of disrupting chemicals (EDs) likely impacting female fertility. EDs may interfere with FSH-mediated signals at different levels, since they may modulate the mRNA or protein levels of both the hormone and its receptor (FSHR), perturb the functioning of partner membrane molecules, modify intracellular signal transduction pathways and gene expression. In vitro studies and animal models provided results helpful to understand ED modes of action and suggest that they could effectively play a role as molecules interfering with the female reproductive system. However, most of these data are potentially subjected to experimental limitations and need to be confirmed by long-term observations in human.
