2005 Fiscal Year Final Research Report Summary
ALTERED- RETINOID AND THYROXIN METABOLIC RESPONSE TO 2,3,7,8-TETRACHLORODIBENSO-p-DIOXIN
| Project/Area Number |
16510049
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Risk sciences of radiation/Chemicals
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| Research Institution | NATIONAL INSTITUTE FOR ENVIRONMENTAL STUDIES (NIES) |
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Principal Investigator |
NISHIMURA Noriko NATIONAL INSTITUTE FOR ENVIRONMENTAL STUDIES, ENDOCRINE DISRUPTORS & DIOXIN RESEARCH PROJECT, SENIOR RESEARCH FELLOW, 環境ホルモン・ダイオキシン研究プロジェクト, 主任研究員 (10097800)
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| Project Period (FY) |
2004 – 2005
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| Keywords | TCDD / RETINOIDS / THYROXIN / AHR-NULL MICE / TTR-NULL MICE / CROSS-FOSTERING |
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| Research Abstract |
To determine whether the disruption of thyroid hormone and retinoid homeostasis that occurs following exposure to 2,3,7,8-tetrachlodibenzo-p-dioxin (TCDD) can be mediated by the arylhydrocarbon receptor (AhR), pregnant AhR-heterozygous (AhR+/-) mice were administered a single oral dose of 10 μg/kg TCDD,at gestation dray 12.5. Serum and liver were collected on postnatal day 21 from vehicle-treated control or TCDD-treated AhR+/- and AhR-null (AhR-/-) mouse pups. While TCDD exposure resulted in a marked reduction of total thyroxin (TT4) and free T4 (FT4) levels in the serum from AhR+/- mice, TCDD had no effects on AhR-/- mice. Gene expressions of UDP-glucuronosyltransferase (UGT)1A6, cytochrome P450 (CYP) 1A1 and CYPIA2 in the liver were induced markedly by TCDD in AhR+/- but not in AhR-/- mice. Induction of OYP1A1 in response to TCDD was confirmed by immunohistochemical evidence in that CYP1A1 protein was conspicuously localized in the cytoplasm of hepatocytes in the centrilobular region
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. The levels of retinyl palmitate were greatly reduced in the liver of TCDD-exposed AhR+/- mice, but not in vehicle-treated AhR+/- mice. No effects of TCDD on retinoid levels in the liver were found in AhR-/- mice. We conclude that disruption of thyroid hormone and retinoid homeostasis is mediated entirely via AhR. Induction of UGT1A6 is thought to be responsible at least partly for the decreased serum thyroid hormone levels in TCDD-exposed mice.
We also studied to clarify whether lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is entirely responsible for the perturbation in thyroid hormone homeostasis during the neonatal period. Pregnant Holtzman rats were given a single oral dose of 1.0 μg TCDD/kg body weight on gestational day 15. Half of the litters were cross-fostered with the half of the dams treated with vehicle on postnatal day (PND) 1 to make four groups of rats, control (C/C), prenatal TCDD exposure only (T/C), postnatal TCDD exposure only (C/T), and both prenatal and postnatal TCDD exposure (T/T). On PND 21, the C/T and T/T groups, but not the T/C and C/C groups, showed a significant decrease in serum total thyroxin (TT4) and free thyroxin (FT4) concentrations in both sexes and a significant increase in serum thyroid-stimulating hormone (TSH) levels, particularly male pups. These two groups of male and female pups had significantly higher concentrations of TCDD in the liver, with marked induction of CYP1A1 mRNA And intense immunostaining of CYP1A1 in the liver. UGT1A6 and UGT1A7 mRNAs were induced in their livers, with marked immunostaining of UGT1A6. The transfer of TCDD from dams to the pups was confirmed by the detection of TCDD in mother's milk remaining in the stomachs of lactationally exposed pups on PND 1. The present results demonstrate that lactational, but not in utero, exposure to TCDD was responsible for the disruption of thyroid hormone homeostasis. Less
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Research Products
(12 results)
