Diminished Serum T4 Concentrations Induced by PTU or Brominated Flame Retardants (DE-71) are Necessary But Not Sufficient for a Congenital Malformation of the Brain

Louise Ramhøj, A. Kortenkamp, M. Scholze, Terje Svingen, Josef Köhrle, Marta Axelstad Petersen

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Abstract

Introduction
A number of environmental chemicals are capable of interfering with the bioavailability and the action of thyroid hormones (TH), which are essential for healthy brain development. In humans, even mild thyroxine (T4) insufficiency during pregnancy has been linked to lower child IQ, impaired language and motor development and increased risk of neurobehavioral disorders such as autism and schizophrenia. Our understanding of the consequences of TH insufficiency on the developing brain has been shaped by studies with the therapeutic antithyroid drug propylthiouracil (PTU). PTU administered to pregnant and lactating rats induces a wide range of brain malformations in their offspring attributed to low T4 during brain development. Here, we compare the effects of PTU and DE-71 (a commercial mixture of brominated diphenyl ethers) on TH and brain development.
Methods
PTU (0, 1 or 2.5 mg/kg/day) or DE-71 (20 or 40 mg/kg/day) was administered (p.o.) to Sprague-Dawley rat dams from gestation day (GD) 7 through to postnatal day (PD) 22. TH and TSH was measured in dams on GD 15, and male offspring were assessed for TH, TSH, heterotopia formation and cortical gene expression on PD 16.
Results/Discussion
Here, we show that offspring of PTU-exposed dams have congenital malformations of the brain in the form of periventricular heterotopia. They are irreversibly formed clusters of ectopic neurons in the corpus callosum, which are associated with low fetal and perinatal T4 levels. DE-71 induced serum T4 suppressions of a similar magnitude (~75% reduction), yet failed to produce heterotopia in offspring. Unlike PTU, exposure to DE-71 also did not affect expression of TH-regulated genes in the cortex.

Conclusions
Our results show that different mechanisms of perturbing the TH system causing same degree of T4 suppression can result in different outcomes on T3 and the hypothalamic-pituitary-thyroid axis as well as on bioindicators of TH-action in cortex and on an adverse outcome in the brain.
Original languageEnglish
Publication date2019
Number of pages2
Publication statusPublished - 2019
Event89th Annual Meeting of the American Thyroid Association - Chicago, United States
Duration: 30 Oct 20193 Nov 2019

Conference

Conference89th Annual Meeting of the American Thyroid Association
CountryUnited States
CityChicago
Period30/10/201903/11/2019

Cite this

Ramhøj, L., Kortenkamp, A., Scholze, M., Svingen, T., Köhrle, J., & Petersen, M. A. (2019). Diminished Serum T4 Concentrations Induced by PTU or Brominated Flame Retardants (DE-71) are Necessary But Not Sufficient for a Congenital Malformation of the Brain. Abstract from 89th Annual Meeting of the American Thyroid Association, Chicago, United States.
Ramhøj, Louise ; Kortenkamp, A. ; Scholze, M. ; Svingen, Terje ; Köhrle, Josef ; Petersen, Marta Axelstad. / Diminished Serum T4 Concentrations Induced by PTU or Brominated Flame Retardants (DE-71) are Necessary But Not Sufficient for a Congenital Malformation of the Brain. Abstract from 89th Annual Meeting of the American Thyroid Association, Chicago, United States.2 p.
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title = "Diminished Serum T4 Concentrations Induced by PTU or Brominated Flame Retardants (DE-71) are Necessary But Not Sufficient for a Congenital Malformation of the Brain",
abstract = "IntroductionA number of environmental chemicals are capable of interfering with the bioavailability and the action of thyroid hormones (TH), which are essential for healthy brain development. In humans, even mild thyroxine (T4) insufficiency during pregnancy has been linked to lower child IQ, impaired language and motor development and increased risk of neurobehavioral disorders such as autism and schizophrenia. Our understanding of the consequences of TH insufficiency on the developing brain has been shaped by studies with the therapeutic antithyroid drug propylthiouracil (PTU). PTU administered to pregnant and lactating rats induces a wide range of brain malformations in their offspring attributed to low T4 during brain development. Here, we compare the effects of PTU and DE-71 (a commercial mixture of brominated diphenyl ethers) on TH and brain development.MethodsPTU (0, 1 or 2.5 mg/kg/day) or DE-71 (20 or 40 mg/kg/day) was administered (p.o.) to Sprague-Dawley rat dams from gestation day (GD) 7 through to postnatal day (PD) 22. TH and TSH was measured in dams on GD 15, and male offspring were assessed for TH, TSH, heterotopia formation and cortical gene expression on PD 16.Results/DiscussionHere, we show that offspring of PTU-exposed dams have congenital malformations of the brain in the form of periventricular heterotopia. They are irreversibly formed clusters of ectopic neurons in the corpus callosum, which are associated with low fetal and perinatal T4 levels. DE-71 induced serum T4 suppressions of a similar magnitude (~75{\%} reduction), yet failed to produce heterotopia in offspring. Unlike PTU, exposure to DE-71 also did not affect expression of TH-regulated genes in the cortex.ConclusionsOur results show that different mechanisms of perturbing the TH system causing same degree of T4 suppression can result in different outcomes on T3 and the hypothalamic-pituitary-thyroid axis as well as on bioindicators of TH-action in cortex and on an adverse outcome in the brain.",
author = "Louise Ramh{\o}j and A. Kortenkamp and M. Scholze and Terje Svingen and Josef K{\"o}hrle and Petersen, {Marta Axelstad}",
year = "2019",
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note = "89th Annual Meeting of the American Thyroid Association ; Conference date: 30-10-2019 Through 03-11-2019",

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Ramhøj, L, Kortenkamp, A, Scholze, M, Svingen, T, Köhrle, J & Petersen, MA 2019, 'Diminished Serum T4 Concentrations Induced by PTU or Brominated Flame Retardants (DE-71) are Necessary But Not Sufficient for a Congenital Malformation of the Brain', 89th Annual Meeting of the American Thyroid Association, Chicago, United States, 30/10/2019 - 03/11/2019.

Diminished Serum T4 Concentrations Induced by PTU or Brominated Flame Retardants (DE-71) are Necessary But Not Sufficient for a Congenital Malformation of the Brain. / Ramhøj, Louise; Kortenkamp, A.; Scholze, M.; Svingen, Terje; Köhrle, Josef; Petersen, Marta Axelstad.

2019. Abstract from 89th Annual Meeting of the American Thyroid Association, Chicago, United States.

Research output: Contribution to conferenceConference abstract for conferenceResearchpeer-review

TY - ABST

T1 - Diminished Serum T4 Concentrations Induced by PTU or Brominated Flame Retardants (DE-71) are Necessary But Not Sufficient for a Congenital Malformation of the Brain

AU - Ramhøj, Louise

AU - Kortenkamp, A.

AU - Scholze, M.

AU - Svingen, Terje

AU - Köhrle, Josef

AU - Petersen, Marta Axelstad

PY - 2019

Y1 - 2019

N2 - IntroductionA number of environmental chemicals are capable of interfering with the bioavailability and the action of thyroid hormones (TH), which are essential for healthy brain development. In humans, even mild thyroxine (T4) insufficiency during pregnancy has been linked to lower child IQ, impaired language and motor development and increased risk of neurobehavioral disorders such as autism and schizophrenia. Our understanding of the consequences of TH insufficiency on the developing brain has been shaped by studies with the therapeutic antithyroid drug propylthiouracil (PTU). PTU administered to pregnant and lactating rats induces a wide range of brain malformations in their offspring attributed to low T4 during brain development. Here, we compare the effects of PTU and DE-71 (a commercial mixture of brominated diphenyl ethers) on TH and brain development.MethodsPTU (0, 1 or 2.5 mg/kg/day) or DE-71 (20 or 40 mg/kg/day) was administered (p.o.) to Sprague-Dawley rat dams from gestation day (GD) 7 through to postnatal day (PD) 22. TH and TSH was measured in dams on GD 15, and male offspring were assessed for TH, TSH, heterotopia formation and cortical gene expression on PD 16.Results/DiscussionHere, we show that offspring of PTU-exposed dams have congenital malformations of the brain in the form of periventricular heterotopia. They are irreversibly formed clusters of ectopic neurons in the corpus callosum, which are associated with low fetal and perinatal T4 levels. DE-71 induced serum T4 suppressions of a similar magnitude (~75% reduction), yet failed to produce heterotopia in offspring. Unlike PTU, exposure to DE-71 also did not affect expression of TH-regulated genes in the cortex.ConclusionsOur results show that different mechanisms of perturbing the TH system causing same degree of T4 suppression can result in different outcomes on T3 and the hypothalamic-pituitary-thyroid axis as well as on bioindicators of TH-action in cortex and on an adverse outcome in the brain.

AB - IntroductionA number of environmental chemicals are capable of interfering with the bioavailability and the action of thyroid hormones (TH), which are essential for healthy brain development. In humans, even mild thyroxine (T4) insufficiency during pregnancy has been linked to lower child IQ, impaired language and motor development and increased risk of neurobehavioral disorders such as autism and schizophrenia. Our understanding of the consequences of TH insufficiency on the developing brain has been shaped by studies with the therapeutic antithyroid drug propylthiouracil (PTU). PTU administered to pregnant and lactating rats induces a wide range of brain malformations in their offspring attributed to low T4 during brain development. Here, we compare the effects of PTU and DE-71 (a commercial mixture of brominated diphenyl ethers) on TH and brain development.MethodsPTU (0, 1 or 2.5 mg/kg/day) or DE-71 (20 or 40 mg/kg/day) was administered (p.o.) to Sprague-Dawley rat dams from gestation day (GD) 7 through to postnatal day (PD) 22. TH and TSH was measured in dams on GD 15, and male offspring were assessed for TH, TSH, heterotopia formation and cortical gene expression on PD 16.Results/DiscussionHere, we show that offspring of PTU-exposed dams have congenital malformations of the brain in the form of periventricular heterotopia. They are irreversibly formed clusters of ectopic neurons in the corpus callosum, which are associated with low fetal and perinatal T4 levels. DE-71 induced serum T4 suppressions of a similar magnitude (~75% reduction), yet failed to produce heterotopia in offspring. Unlike PTU, exposure to DE-71 also did not affect expression of TH-regulated genes in the cortex.ConclusionsOur results show that different mechanisms of perturbing the TH system causing same degree of T4 suppression can result in different outcomes on T3 and the hypothalamic-pituitary-thyroid axis as well as on bioindicators of TH-action in cortex and on an adverse outcome in the brain.

M3 - Conference abstract for conference

ER -

Ramhøj L, Kortenkamp A, Scholze M, Svingen T, Köhrle J, Petersen MA. Diminished Serum T4 Concentrations Induced by PTU or Brominated Flame Retardants (DE-71) are Necessary But Not Sufficient for a Congenital Malformation of the Brain. 2019. Abstract from 89th Annual Meeting of the American Thyroid Association, Chicago, United States.