Dioxin Silences Gonadotropin Expression in Perinatal Pups by Inducing Histone Deacetylases

Takeda, Tomoki; Fujii, Megumi; Taura, Junki; Ishii, Yuji; Yamada, Hideyuki

doi:10.1074/jbc.m111.335158

Cited by 29 publications

(5 citation statements)

References 40 publications

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“…This observation would agree with a possibility that LA competes with a TCDD-induced reduction in the pituitary expression of gonadotropins by recovering the contents of hypothalamic neurotransmitters. On the other hand, we have recently reported that TCDD reduces the fetal expression of LH via a reduction in the acetylation of histone twisted around LH gene promoter [52]. Regarding this finding, another recent study has demonstrated that the status of histone acetylation in the brain is affected by energy status [53].…”

Section: Discussionmentioning

confidence: 92%

Restoration of Dioxin-Induced Damage to Fetal Steroidogenesis and Gonadotropin Formation by Maternal Co-Treatment with α-Lipoic Acid

Koga

Ishida²,

Takeda³

et al. 2012

PLoS ONE

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an endocrine disruptor, causes reproductive and developmental toxic effects in pups following maternal exposure in a number of animal models. Our previous studies have demonstrated that TCDD imprints sexual immaturity by suppressing the expression of fetal pituitary gonadotropins, the regulators of gonadal steroidogenesis. In the present study, we discovered that all TCDD-produced damage to fetal production of pituitary gonadotropins as well as testicular steroidogenesis can be repaired by co-treating pregnant rats with α-lipoic acid (LA), an obligate co-factor for intermediary metabolism including energy production. While LA also acts as an anti-oxidant, other anti-oxidants; i.e., ascorbic acid, butylated hydroxyanisole and edaravone, failed to exhibit any beneficial effects. Neither wasting syndrome nor CYP1A1 induction in the fetal brain caused through the activation of aryl hydrocarbon receptor (AhR) could be attenuated by LA. These lines of evidence suggest that oxidative stress makes only a minor contribution to the TCDD-induced disorder of fetal steroidogenesis, and LA has a restorative effect by targeting on mechanism(s) other than AhR activation. Following a metabolomic analysis, it was found that TCDD caused a more marked change in the hypothalamus, a pituitary regulator, than in the pituitary itself. Although the components of the tricarboxylic acid cycle and the ATP content of the fetal hypothalamus were significantly changed by TCDD, all these changes were again rectified by exogenous LA. We also provided evidence that the fetal hypothalamic content of endogenous LA is significantly reduced following maternal exposure to TCDD. Thus, the data obtained strongly suggest that TCDD reduces the expression of fetal pituitary gonadotropins to imprint sexual immaturity or disturb development by suppressing the level of LA, one of the key players serving energy production.

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Section: Discussionmentioning

confidence: 92%

Restoration of Dioxin-Induced Damage to Fetal Steroidogenesis and Gonadotropin Formation by Maternal Co-Treatment with α-Lipoic Acid

Koga

Ishida²,

Takeda³

et al. 2012

PLoS ONE

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“…Recent studies in mammals (Wu et al , 2004; Okino et al , 2006; McClure et al , 2011; Singh et al , 2011; Manikkam et al , 2012a; Manikkam et al , 2012b; Takeda et al , 2012; Somm et al , 2013; Takeda et al , 2014) and zebrafish (Olsvik, et al, 2014) have demonstrated that exposure to TCDD alters DNA methylation patterns not only in the exposed generation, but also in subsequent generations. However, the mechanism of action by which toxicants affect DNA methylation is unknown.…”

Section: Discussionmentioning

confidence: 99%

Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters DNA methyltransferase (dnmt) expression in zebrafish (Danio rerio)

Aluru

Kuo

Helfrich

et al. 2015

Toxicology and Applied Pharmacology

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DNA methylation is one of the most important epigenetic modifications involved in the regulation of gene expression. The DNA methylation reaction is catalyzed by DNA methyltransferases (DNMTs). Recent studies have demonstrated that toxicants can affect normal development by altering DNA methylation patterns, but the mechanisms of action are poorly understood. Hence, we tested the hypothesis that developmental exposure to TCDD affects dnmt gene expression patterns. Zebrafish embryos were exposed to 5 nM TCDD for one hour from 4 to 5 hours post-fertilization (hpf) and sampled at 12, 24, 48, 72 and 96 hpf to determine dnmt gene expression and DNA methylation patterns. We performed a detailed analysis of zebrafish dnmt gene expression during development and in adult tissues. Our results demonstrate that dnmt3b genes are highly expressed in early stages of development, and dnmt3a genes are more abundant in later stages. TCDD exposure upregulated dnmt1 and dnmt3b2 expression, whereas dnmt3a1, 3b1, and 3b4 are downregulated following exposure. We did not observe any TCDD-induced differences in global methylation or hydroxymethylation levels, but promoter methylation of aryl hydrocarbon receptor (AHR) target genes was altered. In TCDD-exposed embryos, AHR repressor a (ahrra) and c-fos promoters were differentially methylated. To characterize the TCDD effects on DNMTs, we cloned the dnmt promoters with xenobiotic response elements and conducted AHR transactivation assays using a luciferase reporter system. Our results suggest that ahr2 can regulate dnmt3a1, dnmt3a2 and dnmt3b2 expression. Overall, we demonstrate that developmental exposure to TCDD alters dnmt expression and DNA methylation patterns.

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“…The teratogenicity of this drug was likely due to its ability to inhibit histone deacetylases, thereby altering the chromatin conformation and regulating gene transcription ( 27 ). In addition, the increased deacetylation of histones was important in the TCDD-induced reduction in luteinizing hormone β in the fetal pituitary ( 28 ). It has been determined that the acetylation of H3 and H4 was markedly increased at the CYP1B1 promoter in the MCF-7 human breast cancer cell line following dioxin treatment, which is dependent on p300 ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Histone acetylation is involved in TCDD-induced cleft palate formation in fetal mice

Yuan

Qiu

et al. 2016

Molecular Medicine Reports

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The aim of the present was to evaluate the effects of DNA methylation and histone acetylation on 2,3,7,8-tetrachlo-rodibenzo-p-dioxin (TCDD)-induced cleft palate in fetal mice. Pregnant mice (n=10) were randomly divided into two groups: i) TCDD group, mice were treated with 28 µg/kg TCDD on gestation day (GD) 10 by oral gavage; ii) control group, mice were treated with an equal volume of corn oil. On GD 16.5, the fetal mice were evaluated for the presence of a cleft palate. An additional 36 pregnant mice were divided into the control and TCDD groups, and palate samples were collected on GD 13.5, GD 14.5 and GD 15.5, respectively. Transforming growth factor-β3 (TGF-β3) mRNA expression, TGF-β3 promoter methylation, histone acetyltransferase (HAT) activity and histone H3 (H3) acetylation in the palates were evaluated in the two groups. The incidence of a cleft palate in the TCDD group was 93.55%, and no cases of cleft palate were identified in the control group. On GD 13.5 and GD 14.5, TGF-β3 mRNA expression, HAT activity and acetylated H3 levels were significantly increased in the TCDD group compared with the control. Methylated bands were not observed in the TCDD or control groups. In conclusion, at the critical period of palate fusion (GD 13.5–14.5), TCDD significantly increased TGF-β3 gene expression, HAT activity and H3 acetylation. Therefore, histone acetylation may be involved in TCDD-induced cleft palate formation in fetal mice.

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Dioxin Silences Gonadotropin Expression in Perinatal Pups by Inducing Histone Deacetylases

Cited by 29 publications

References 40 publications

Restoration of Dioxin-Induced Damage to Fetal Steroidogenesis and Gonadotropin Formation by Maternal Co-Treatment with α-Lipoic Acid

Restoration of Dioxin-Induced Damage to Fetal Steroidogenesis and Gonadotropin Formation by Maternal Co-Treatment with α-Lipoic Acid

Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters DNA methyltransferase (dnmt) expression in zebrafish (Danio rerio)

Histone acetylation is involved in TCDD-induced cleft palate formation in fetal mice

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