Dataset Information

Effects of in Utero Exposure to Dicyclohexyl Phthalate on Rat Fetal Leydig Cells.

ABSTRACT: Dicyclohexyl phthalate (DCHP) is one of the phthalate plasticizers. The objective of the present study was to investigate the effects of DCHP on fetal Leydig cell distribution and function as well as testis development. Female pregnant Sprague Dawley dams orally received vehicle (corn oil, control) or DCHP (10, 100, and 500 mg/kg/day) from gestational day (GD) 12 to GD 21. At GD 21.5, testicular testosterone production, fetal Leydig cell number and distribution, testicular gene and protein expression levels were examined. DCHP administration produced a dose-dependent increase of the incidence of multinucleated gonocytes at ≥ 100 mg/kg. DCHP dose-dependently increased abnormal fetal Leydig cell aggregation and decreased fetal Leydig cell size, cytoplasmic size, and nuclear size at ≥ 10 mg/kg. DCHP reduced the expression levels of steroidogenesis-related genes (including Star, Hsd3b1, and Hsd17b3) and testis-descent related gene Insl3 as well as protein levels of 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) and insulin-like 3 (INSL3) at ≥ 10 mg/kg. DCHP significantly inhibited testicular testosterone levels at ≥ 100 mg/kg. The results indicate that in utero exposure to DCHP affects the expression levels of fetal Leydig cell steroidogenic genes and results in the occurrence of multinucleated gonocytes and Leydig cell aggregation.

SUBMITTER: Li X

PROVIDER: S-EPMC4808909 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Effects of in Utero Exposure to Dicyclohexyl Phthalate on Rat Fetal Leydig Cells.

Li Xiaoheng X Chen Xiaomin X Hu Guoxin G Li Linxi L Su Huina H Wang Yiyan Y Chen Dongxin D Zhu Qiqi Q Li Chao C Li Junwei J Wang Mingcang M Lian Qingquan Q Ge Ren-Shan RS

International journal of environmental research and public health 20160223 3

Dicyclohexyl phthalate (DCHP) is one of the phthalate plasticizers. The objective of the present study was to investigate the effects of DCHP on fetal Leydig cell distribution and function as well as testis development. Female pregnant Sprague Dawley dams orally received vehicle (corn oil, control) or DCHP (10, 100, and 500 mg/kg/day) from gestational day (GD) 12 to GD 21. At GD 21.5, testicular testosterone production, fetal Leydig cell number and distribution, testicular gene and protein expre ...[more]

PMID: 26907321

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Project description:BackgroundExposure 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.ObjectiveWe 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.MethodsCell-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.ResultsDCHP 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.DiscussionAlthough 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. https://doi.org/10.1289/EHP9262.

Project description:Phthalates are widely used as plasticizers in the industry and are found in cosmetics, food and drink packaging, drugs, toys, households, medical devices, pesticides, personal care products, and paints. Phthalates exert endocrine disrupting and peroxisome proliferator effects in humans and wildlife associated with the pathogenesis of various diseases, including diabetes, obesity, infertility, cardiovascular diseases, metabolic syndrome, and cancer. Since phthalates are metabolized in the liver, which regulates the body's energy metabolism, long or short-term exposure to the phthalates is associated with impaired glucose, lipid, and oxidative stress metabolisms contributing to liver toxicity. However, the impact of in-utero exposure to DHP and DCHP on liver metabolism has not been studied previously. Thus, in this study, we evaluated serum biochemistry parameters, hematological markers, histopathological changes, and oxidative and pentose phosphate pathway (PPP) metabolisms in the liver following in-utero DHP and DCHP administration, respectively, in male and female rats. We found increased relative and absolute liver weights and impaired triglyceride, alanine transaminase (ALT), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) levels upon dicyclohexyl phthalate (DCHP) and di-n-hexyl phthalate (DHP). Histopathological changes, including congestion, sinusoidal dilatation, inflammatory cell infiltration, cells with a pyknotic nucleus, lysis of hepatocytes, and degeneration of hepatic parenchyma have been observed in the liver samples of DHP and DCHP dose groups. Moreover, increased glutathione s-transferase (GST), glucose 6-phosphate dehydrogenase (G6PD), and glutathione reductase (GR) activities have been found in the liver samples of DHP and DCHP-treated rats associated with impaired pentose phosphate pathway (PPP) and oxidative stress metabolism. First time in the literature, we showed that in-utero exposure to DHP and DCHP causes liver damage associated with impaired oxidative stress metabolism in male and female rats. Our data may guide researchers and governments to regulate and restrict phthalates in industrial products.

Dataset Information

Effects of in Utero Exposure to Dicyclohexyl Phthalate on Rat Fetal Leydig Cells.

Publications

Effects of in Utero Exposure to Dicyclohexyl Phthalate on Rat Fetal Leydig Cells.

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