Dicyclohexyl phthalate blocks Leydig cell regeneration in adult rat testis

Lv, Yao; Fang, Yinghui; Chen, Panpan; Duan, Yue; Huang, Tongliang; Ma, Leikai; Xie, Lubin; Chen, Xianwu; Chen, Xiaofang; Gao, Jimin; Ge, Ren‐Shan

doi:10.1016/j.tox.2018.10.020

Cited by 38 publications

(52 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another study also detected DCHP in >88% of cord blood samples in a cohort of pregnant women, with a mean concentration of ∼ 125 lg=L (Huang et al 2014). Despite these findings in a human population, there were very few studies examining the in vivo effects of DCHP exposure in rodent models and previous studies that also used relatively high doses of DCHP (e.g., 10-2,500 mg=kg) BW per day (Ahbab et al 2017;Lake et al 1982;Li et al 2016;Lv et al 2019). Although the dose used in our study still seems to be high, it is important to note that many plastic-associated EDCs (e.g., BPA, BPB, DEHP, TBC) have been identified by us and others as potent PXR agonists (Helsley and Zhou 2017;Sui et al 2012Sui et al , 2014Sui et al , 2015Zhou 2016).…”

Section: Discussionmentioning

confidence: 99%

“…DCHP has been previously used to treat rodents at relatively high doses, from 10 to 2,500 mg=kg BW per day (Ahbab et al 2017;Lake et al 1982;Li et al 2016;Lv et al 2019). In the present study, we treated the mice with 10 mg=kg BW per day DCHP for 7 d. Our selected doses were significantly lower than concentrations experimentally used in previous studies.…”

Section: Animalsmentioning

confidence: 99%

See 1 more Smart Citation

Effects of Dicyclohexyl Phthalate Exposure on PXR Activation and Lipid Homeostasis in Mice

Sui

Meng

Chen

et al. 2021

Environ Health Perspect

View full text Add to dashboard Cite

BACKGROUND: Exposure to plastic-associated endocrine disrupting chemicals (EDCs) has been associated with an increased risk of cardiovascular disease (CVD) in humans. However, the underlying mechanisms for this association are unclear. Many EDCs have been shown to function as ligands of the nuclear receptor pregnane X receptor (PXR), which functions as xenobiotic sensor but also has pro-atherogenic effects in vivo. OBJECTIVE: We sought to investigate the contribution of PXR to the adverse effects dicyclohexyl phthalate (DCHP), a widely used phthalate plasticizer, on lipid homeostasis and CVD risk factors. METHODS: Cell-based assays, primary organoid cultures, and PXR conditional knockout and PXR-humanized mouse models were used to investigate the impact of DCHP exposure on PXR activation and lipid homeostasis in vitro and in vivo. Targeted lipidomics were performed to measure circulating ceramides, novel predictors for CVD. RESULTS: DCHP was identified as a potent PXR-selective agonist that led to higher plasma cholesterol levels in wild-type mice. DCHP was then demonstrated to activate intestinal PXR to elicit hyperlipidemia by using tissue-specific PXR-deficient mice. Interestingly, DCHP exposure also led to higher circulating ceramides in a PXR-dependent manner. DCHP-mediated PXR activation stimulated the expression of intestinal genes mediating lipogenesis and ceramide synthesis. Given that PXR exhibits considerable species-specific differences in receptor pharmacology, PXR-humanized mice were also used to replicate these findings. DISCUSSION: Although the adverse health effects of several well-known phthalates have attracted considerable attention, little is known about the potential impact of DCHP on human health. Our studies demonstrate that DCHP activated PXR to induce hypercholesterolemia and ceramide production in mice. These results indicate a potentially important role of PXR in contributing to the deleterious effects of plastic-associated EDCs on cardiovascular health in humans. Testing PXR activation should be considered for risk assessment of phthalates and other EDCs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Effects of Dicyclohexyl Phthalate Exposure on PXR Activation and Lipid Homeostasis in Mice

Sui

Meng

Chen

et al. 2021

Environ Health Perspect

View full text Add to dashboard Cite

show abstract

“…Serum T concentrations from pooled samples were determined using the Immulite2000 Total T Kit (Sinopharm, Hangzhou, China) in Department of Clinical Chemistry of our hospital as previously described 20 . The lowest detectable level of T was 0.1 ng/ml.…”

Section: Methodsmentioning

confidence: 99%

“…rotein sample preparation and Western blotting were carried out as previously described. 20 In brief, one male pup testis from each litter was randomly selected, and homogenized in ice-cold protein lysis buffer, and the protein concentration was determined by BCA protein assay kit (Takara, Otsu, Japan). An aliquot of protein solution (30 μg)…”

Section: Western Blottingmentioning

confidence: 99%

Perfluorotridecanoic acid inhibits fetal Leydig cell differentiation after in utero exposure in rats via increasing oxidative stress and autophagy

Zou

Yan

et al. 2021

Environmental Toxicology

View full text Add to dashboard Cite

Perfluorotridecanoic acid (PFTrDA) is a long-chain perfluoroalkyl substance, and its effect on the differentiation of fetal Leydig cells remains unclear. The objective of this study is to explore the effect of in utero PFTrDA exposure on the differentiation of fetal Leydig cells and investigate its underlying mechanisms. Pregnant Sprague-Dawley female rats were daily administered by gavage of PFTrDA at doses of 0, 1, 5, and 10 mg/kg from gestational day 14 to 21. PFTrDA had no effect on the body weight of dams, but significantly reduced the body weight and anogenital distance of male pups at birth at a dose of 10 mg/kg. PFTrDA significantly decreased serum testosterone levels as low as 1 mg/kg. PFTrDA did not affect fetal Leydig cell number, but promoted abnormal aggregation of fetal Leydig cells at doses of 5 and 10 mg/kg. PFTrDA down-regulated the expression of Insl3, Lhcgr, Scarb1, Star, Hsd3b1, Cyp17a1, Nr5a1, and Dhh as well as their proteins. PFTrDA lowered the levels of antioxidants (SOD1, CAT, and GPX1), induced autophagy as shown by increased levels of LC3II and beclin1, and reduced the phosphorylation of mTOR. In conclusion, PFTrDA inhibits the differentiation of fetal Leydig cells in male pups after in utero exposure mainly through increasing oxidative stress and inducing autophagy.

show abstract

“…qPCR was carried out using SYBR GREEN as an indicator using Bio-Rad real time PCR system. The standard curve method was adopted as previously described (Lv et al, 2019). The Ct values were recorded after a series of diluted standards of mouse liver cDNAs, and the linear equation of Ct values vs. logarithm [dilution of standards] was generated, and the concentration of the target mRNA was calculated according to their Ct value.…”

Section: Quantitative Real-time Polymerase Chain Reactionmentioning

confidence: 99%

5-Bis-(2,6-difluoro-benzylidene) Cyclopentanone Acts as a Selective 11β-Hydroxysteroid Dehydrogenase one Inhibitor to Treat Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

Guan

Wang

et al. 2021

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Background: 11β-Hydroxysteroid dehydrogenase one is responsible for activating inert glucocorticoid cortisone into biologically active cortisol in humans and may be a novel target for the treatment of nonalcoholic fatty liver disease.Methods: A series of benzylidene cyclopentanone derivatives were synthesized, and the selective inhibitory effects on rat, mouse and human 11β-hydroxysteroid dehydrogenase one and two were screened. The most potent compound [5-bis-(2,6-difluoro-benzylidene)-cyclopentanone] (WZS08), was used to treat nonalcoholic fatty liver disease in mice fed a high-fat-diet for 100 days.Results: WZS08 was the most potent inhibitor of rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, with half maximum inhibitory concentrations of 378.0, 244.1, and 621.1 nM, respectively, and it did not affect 11β-hydroxysteroid dehydrogenase two at 100 μM. When mice were fed WZS08 (1, 2, and 4 mg/kg) for 100 days, WZS08 significantly lowered the serum insulin levels and insulin index at 4 mg/kg. WZS08 significantly reduced the levels of serum triglycerides, cholesterol, low-density lipoprotein, and hepatic fat ratio at low concentration of 1 mg/kg. It down-regulated Plin2 expression and up-regulated Fabp4 expression at low concentration of 1 mg/kg. It significantly improved the morphology of the non-alcoholic fatty liver.Conclusion: WZS08 selectively inhibits rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, and can treat non-alcoholic fatty liver disease in a mouse model.

show abstract

Dicyclohexyl phthalate blocks Leydig cell regeneration in adult rat testis

Cited by 38 publications

References 41 publications

Effects of Dicyclohexyl Phthalate Exposure on PXR Activation and Lipid Homeostasis in Mice

Effects of Dicyclohexyl Phthalate Exposure on PXR Activation and Lipid Homeostasis in Mice

Perfluorotridecanoic acid inhibits fetal Leydig cell differentiation after in utero exposure in rats via increasing oxidative stress and autophagy

5-Bis-(2,6-difluoro-benzylidene) Cyclopentanone Acts as a Selective 11β-Hydroxysteroid Dehydrogenase one Inhibitor to Treat Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

Contact Info

Product

Resources

About