Maternal exposure to dioxin reduces hypothalamic but not pituitary metabolome in fetal rats: a possible mechanism for a fetus-specific reduction in steroidogenesis

Matsumoto, Yuki; Ishida, Tatsuro; Takeda, Tomoki; Koga, Takayuki; Fujii, Megumi; Ishii, Yuji; Fujimura, Yoshinori; Miura, Daisuke; Wariishi, Hiroyuki; Yamada, Hideyuki

doi:10.2131/jts.35.365

Cited by 20 publications

(21 citation statements)

References 31 publications

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“…19,31) In brief, total RNA was extracted from the liver and intestine using an RNeasy Mini Kit (QIAGEN GmbH, Hilden, Germany). The RNA (250 ng) obtained was treated with genomic DNA (gDNA) Eraser for digestion of contaminating gDNA, and reverse-transcribed to its cDNA, using a PrimeScript 32) The amount of target mRNA was normalized by β-actin mRNA, and is shown as a ratio to the control.…”

Section: Methodsmentioning

confidence: 99%

“…Regarding the reproductive and developmental disorders produced by dioxin, our previous studies have revealed that treating pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener of dioxins, markedly alters the metabolomic pattern including the components of the tricarboxylic acid cycle in the hypothalamus of male fetuses. 19,20) In view of the background mentioned above, the initial objective of the present study was to identify the components, the levels of which are changed in a dioxin-specific fashion, in the urine and feces of pubertal rats. It has long been known that TCDD and related substances reduce food consumption in animals 21,22) and this may be at least one of the reasons why dioxins produce wasting syndrome exemplified as body weight loss.…”

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confidence: 99%

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Dioxin-Produced Alteration in the Profiles of Fecal and Urinary Metabolomes: A Change in Bile Acids and Its Relevance to Toxicity

Kakizuka

Takeda

Komiya

et al. 2015

Biological & Pharmaceutical Bulletin

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This study investigated dioxin-induced changes in metabolomes in pubertal rat excrement. The administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or restricting dietary intake (pair-fed group) markedly altered the metabolomic profile including lipids, hormones, and vitamins in the urine and feces. TCDD caused an increase in the fecal chenodeoxycholic acid and taurocholic acid content and in urinary adrenaline and 17β-estradiol, while the urinary melatonin level was reduced by TCDD. These changes were not observed in the pair-fed group. In accordance with the elevated level of fecal bile acids, TCDD reduced the intestinal expression of the apical sodium-dependent bile salt transporter, which plays a role in resorbing bile acids from the bile duct. In addition, CYP7A1, a rate-limiting enzyme for bile acid biosynthesis, was attenuated by TCDD treatment, although TCDD induced hepatic CYP8B1, an enzyme essential for cholic acid synthesis. Supplying cholic acid or chenodeoxycholic acid to TCDD-exposed rats tended to restore the TCDD-produced reduction in serum triglycerides, whereas no similar trend was observed in wasting syndrome and lipid accumulation in the liver. These results suggest that: 1) TCDD alters the circulating levels of bile acids and hormones via a mechanism distinct from an attenuation in dietary intake, although the majority of TCDDinduced changes in nutrient contents in the excrement is due to a reduction in food intake; and 2) TCDD facilitates the excretion of bile acids and disrupts their biosynthesis, resulting in the disturbance of lipid homeostasis.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Dioxin-Produced Alteration in the Profiles of Fecal and Urinary Metabolomes: A Change in Bile Acids and Its Relevance to Toxicity

Kakizuka

Takeda

Komiya

et al. 2015

Biological & Pharmaceutical Bulletin

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“…RT-PCR-The expression of mRNAs was quantified by realtime RT-PCR according to the method described previously (21). In brief, total RNA was extracted from the testis, pituitary, and hypothalamus using an RNeasy Mini Kit (Qiagen GmbH, Hilden, Germany).…”

Section: Materials-tcddmentioning

confidence: 99%

“…Our recent study has suggested that TCDD suppresses GnRH-mediated PKC and PKA and/or their downstream mechanisms in cultivated fetal pituitary to attenuate gonadotropin synthesis (20). In addition, TCDD reduces a number of fetal hypothalamic constituents, including neurotransmitters regulating GnRH secretion (21). Therefore, it would be reasonable to consider that gonadotropin production in the fetal pituitary is damaged by a combination of the TCDD effects on the pituitary and its regulatory organ, the hypothalamus, although many more studies are needed for a fuller understanding.…”

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confidence: 99%

“…More basically, the following question remains unanswered: what is the mechanism underlying a ␤-subunit-and fetal age-specific reduction by TCDD in LH/FSH expression? Regarding the fetal age-specific nature, the details of its onset and termination should also be clarified, although we observed in a previous work that an LH␤ reduction by TCDD disappeared 1 week after birth (21).…”

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Dioxin Silences Gonadotropin Expression in Perinatal Pups by Inducing Histone Deacetylases

Takeda

Fujii

Taura

et al. 2012

Journal of Biological Chemistry

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Background: Dioxin attenuates the fetal production of luteinizing hormone (LH) to imprint impaired sexual behavior. Results: Fetal exposure to dioxin induces histone deacetylases to attenuate the acetylation status of histones twisted around the LH␤ gene. Conclusion: Histone deacetylation in the pituitary contributes to the dioxin-induced damage to fetal/infant steroidogenesis. Significance: This study provides a new insight into the mechanism underlying sexual immaturity caused by dioxin.

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Dioxin-induced fetal growth retardation: the role of a preceding attenuation in the circulating level of glucocorticoid

et al. 2014

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Exposure of pregnant rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at a low dose causes developmental disorders such as growth retardation and sexual immaturity in their pups. Our previous studies have demonstrated that TCDD attenuates the expression of pituitary luteinizing hormone in fetuses, resulting in the impairment of sexual behavior after they reach maturity. In this study, we focused on growth disturbance and investigated whether TCDD affects the expression of growth hormone (GH), another pituitary hormone which is essential for normal development in perinatal pups. The result showed that maternal exposure to TCDD (1 µg/kg) at gestational day (GD) 15 reduced the fetal expression of GH from the onset at GD18. In accordance with this, TCDD attenuated the pup weight during the perinatal period. We then examined the effect of TCDD on the serum concentration of corticosterone, which plays a key role in the proliferation of GH-producing cells, and found that TCDD reduces the circulating level of corticosterone in the mothers at GD18 and the male fetuses at GD19. The reduction in fetuses seems to be due to increased inactivation rather than reduced synthesis, because TCDD induces the fetal expression of hepatic enzymes participating in the metabolism of glucocorticoids without changing the expression of steroidogenic proteins in the pituitary-adrenal axis. Supplying corticosterone to TCDD-exposed mothers restored or tended to restore a TCDD-induced reduction in pup weight as well as the levels of pituitary GH mRNA and serum GH. These results suggest that TCDD lowers GH expression and growth retardation owing, at least partially, to a reduction in the circulating level of glucocorticoid in pregnant mothers and their fetuses.

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Maternal exposure to dioxin reduces hypothalamic but not pituitary metabolome in fetal rats: a possible mechanism for a fetus-specific reduction in steroidogenesis

Cited by 20 publications

References 31 publications

Dioxin-Produced Alteration in the Profiles of Fecal and Urinary Metabolomes: A Change in Bile Acids and Its Relevance to Toxicity

Dioxin-Produced Alteration in the Profiles of Fecal and Urinary Metabolomes: A Change in Bile Acids and Its Relevance to Toxicity

Dioxin Silences Gonadotropin Expression in Perinatal Pups by Inducing Histone Deacetylases

Dioxin-induced fetal growth retardation: the role of a preceding attenuation in the circulating level of glucocorticoid

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