Low-dose exposure to di-(2-ethylhexyl) phthalate (DEHP) increases susceptibility to testicular autoimmunity in mice

Hirai, Shuichi; Naito, Makoto; Kuramasu, Miyuki; Ogawa, Yoshiaki; Terayama, Hayato; Qu, Ning; Hatayama, Naoyuki; Hayashi, Shogo; Itoh, Masahiro

doi:10.1016/j.repbio.2015.06.004

Cited by 29 publications

(11 citation statements)

References 47 publications

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“…Madhubabu reported that oral exposure to allethrin had increasing lipid peroxidation and declining activities of catalase, glutathione peroxidase, glutathione‐S‐transferase and superoxide dismutase, consequently affecting fertility (Madhubabu and Yenugu, ). In the present study, SOD and GSH‐Px (ROS scavengers) were depleted and MDA was accumulated as a product of lipid peroxidation in GC‐2spd cells, consistent with previous findings that DEHP exposure induced spermatogenic disturbance mediated by oxidative stress (Hirai et al, ).…”

Section: Discussionsupporting

confidence: 93%

Di(2-ethylhexyl) phthalate induces apoptosis through mitochondrial pathway in GC-2spd cells

Dai

Zhang

et al. 2016

Environ. Toxicol.

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Di(2-ethylhexyl) phthalate (DEHP), a plasticizer of synthetic polymers, is a well-known endocrine disrupting chemical (EDC) and reproductive toxicant. Addressing the unclear mechanism of DEHP-induced reproductive dysfunction, this study used GC-2spd cells to investigate the molecular mechanism involved in the DEHP-induced toxicity in the male reproductive system. The results indicated that the apoptotic cell death was significantly induced by DEHP exposure over 100 μM. Furthermore, DEHP treatment could induce oxidative stress in GC-2spd cells involving in the decrease of superoxide dismutase (SOD) activity (200 μM) and glutathione peroxidase (GSH-Px) activity (50 and 100 μM). In addition, DEHP induction also caused the elevated ratios of Bax/Bcl-2, release of cytochrome c and decomposition of procaspase-3 and procaspase-9 in GC-2spd cells. Taken together, our work provided the evidence that DEHP exposure might induce apoptosis of GC-2spd cells via mitochondria pathway mediated by oxidative stress.

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Section: Discussionsupporting

confidence: 93%

Di(2-ethylhexyl) phthalate induces apoptosis through mitochondrial pathway in GC-2spd cells

Dai

Zhang

et al. 2016

Environ. Toxicol.

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“…In human macrophages, DEHP treatment increases the production of inflammatory cytokines, such as TNF-α, IL-1β, IL-8, and IL-6, which induces the inflammatory response during allergic reactions (Nishioka et al, 2012). DEHP promotes the development of immune responses and subsequent male infertility through increasing the expression of inflammatory mediators (Larsen et al, 2007; Hirai et al, 2015). Recent studies have reported that DEHP increased the production of inflammatory cytokines such as TNF-α and IL-1β in mice testes (Bahrami et al, 2018a,b).…”

Section: Discussionmentioning

confidence: 99%

Lactobacillus plantarum TW1-1 Alleviates Diethylhexylphthalate-Induced Testicular Damage in Mice by Modulating Gut Microbiota and Decreasing Inflammation

Tian

Feng

et al. 2019

Front. Cell. Infect. Microbiol.

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Diethylhexylphthalate (DEHP), acting as an endocrine disruptor, disturbed reproductive health. Here, we evaluated the effects of Lactobacillus plantarum TW1-1 ( L. plantarum TW1-1) on DEHP-induced testicular damage in adult male mice. Results showed that oral supplementation of L. plantarum TW1-1 significantly increased the serum testosterone concentration, enhanced the semen quality, and attenuated gonad development defects in DEHP-exposed mice. L. plantarum TW1-1 also alleviated DEHP-induced oxidative stress and inflammatory responses by decreasing the mRNA expression and serum protein concentration of different inflammatory factors [tumor necrosis factor-α, interleukin (IL)-1β and IL-6]. Furthermore, L. plantarum TW1-1 significantly reduced DEHP-induced intestinal hyper-permeability and the increase in the serum lipopolysaccharide level. Gut microbiota diversity analysis revealed that L. plantarum TW1-1 shifted the DEHP-disrupted gut microbiota to that of the control mice. At phylum level, L. plantarum TW1-1 reversed DEHP-induced Bacteroidetes increase and Firmicutes decrease, and restored Deferribacteres in DEHP-exposed mice. Spearman's correlation analysis showed that Bacteroidetes, Deferribacteres , and Firmicutes were associated with DEHP-induced testicular damage. In addition, the ratio of Firmicutes to Bacteroidetes (Firm/Bac ratio) significantly decreased from 0.28 (control group) to 0.13 (DEHP-exposed group), which was restored by L. plantarum TW1-1 treatment. Correlation analysis showed that the Firm/Bac ratio was negatively correlated with testicular damage and inflammation. These findings suggest that L. plantarum TW1-1 prevents DEHP-induced testicular damage via modulating gut microbiota and decreasing inflammation.

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“…Moreover, these adrenal data correlated with higher levels of C‐reactive protein and tumor necrosis factor in serum (Campioli et al ., ). Indeed, EDs appeared to alter the production of cytokines and other inflammatory mediators (Nielsen et al ., ; Kuo et al ., , ); they also increased testicular autoimmunity (Hirai et al ., ), and there is evidence showing that the effects of DEHP on asthma are mediated by DNA methylation (Wang et al ., ). Taken together, these data suggest that the immune locus affected by DNA methylation in the rat is a sensitive target of DEHP and raises the question of whether its human counterpart is also involved in the increase in immune‐related diseases.…”

Section: Is Dehp Affecting Long‐range Elements Controlling Gene Exprementioning

confidence: 99%

Prenatal phthalate exposure: epigenetic changes leading to lifelong impact on steroid formation

Martinez–Arguelles

Papadopoulos

2016

Andrology

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SUMMARYEndocrine disruptors (ED) are environmental pollutants that mimic endogenous hormonal signals. Exposure to EDs during fetal and early life is a public health concern because these are periods characterized by high cellular plasticity that influence the physiology and development of disease later in life. Phthalates are plasticizers used in the industry to manufacture polyvinyl chloride products and several consumer products. Di(2-ethylhexyl) phthalate (DEHP) is one of the most produced plasticizers; it is ubiquitously found contaminating the environment, and has been shown to be an ED. Human exposure to phthalates starts during fetal development and continues after birth through contact of the newborn with the environment and contaminated food sources. We used a rat model in which pregnant dams are gavaged with DEHP from gestational day 14 until birth to study the long-term effects of DEHP. This window of fetal exposure results in decreased circulating testosterone and aldosterone levels in adult male offspring and estradiol in the female. The observed steroid changes are likely of an epigenetic origin as DEHP is rapidly cleared after birth. Here, we review the long-term effects of fetal exposure to DEHP with a focus on the molecular and epigenetic changes, including DNA methylation, which may mediate long-term endocrine dysfunction.

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Low-dose exposure to di-(2-ethylhexyl) phthalate (DEHP) increases susceptibility to testicular autoimmunity in mice

Cited by 29 publications

References 47 publications

Di(2-ethylhexyl) phthalate induces apoptosis through mitochondrial pathway in GC-2spd cells

Di(2-ethylhexyl) phthalate induces apoptosis through mitochondrial pathway in GC-2spd cells

Lactobacillus plantarum TW1-1 Alleviates Diethylhexylphthalate-Induced Testicular Damage in Mice by Modulating Gut Microbiota and Decreasing Inflammation

Prenatal phthalate exposure: epigenetic changes leading to lifelong impact on steroid formation

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