Transfer of Thyroxine from the Mother to the Rat Fetus Near Term: Effects on Brain 3,5,3'-Triiodothyronine Deficiency*

Escobar, Gabriella Morreale de; Obregón, Marı́a Jesús; Oña, Carmen Ruiz de; Rey, Francisco Escobar del

doi:10.1210/endo-122-4-1521

Cited by 85 publications

(7 citation statements)

References 52 publications

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“…There were no apparent MMI treatment-related effects on the offspring's body weights over the 3–4 PND. As expected [4], [26], the INTACT pups on the tap water recorded normal size and growth during development, while defects due to the MMI treatment in CH rats were evident by a reduction in body weight (Supplementary File S3; panel A) and tail length (Supplementary File S3; panel B) from the second week of life. Upon weaning on PND30, biochemical hypothyroidism was shown, and significantly low circulating T3 (pg/ml) (9.93±0.66 vs. 7.80±0.83; P = 0.0008) and elevated TSH (ng/ml) (2.73±2.04 vs .…”

Section: Resultssupporting

confidence: 73%

“…Within 24 h after birth, excess pups were removed so that 8 pups were kept per dam. The indirect MMI exposure method (i.e., through maternal milk) utilized in this experiment has been extensively employed to induce a transitory congenital-neonatal hypothyroidism (CH) for the determination of short- and long-term physiological effects [4], [26], [29], [30]. Briefly, 0.02% MMI was administered in the drinking water for pregnant rats from GD12 until weaning at post-natal day (PND) 30, which is when pups were mature enough to support their own nutritional needs.…”

Section: Methodsmentioning

confidence: 99%

“…Administration of the antithyroid drug methimazole (MMI) to pregnant rats before the onset of fetal thyroid function is known to abolish both the maternal and fetal thyroid function [26]. In this context, exposure to MMI during the fetal-neonatal period of life is an attractive model to study the influence of CH on the adult pattern of genes that are under the control of the THs during rat development [4].…”

Section: Introductionmentioning

confidence: 99%

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Influence of Neonatal Hypothyroidism on Hepatic Gene Expression and Lipid Metabolism in Adulthood

Santana-Farré¹,

Mirecki-Garrido²,

Bocos

et al. 2012

PLoS ONE

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Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood.

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Section: Resultssupporting

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of Neonatal Hypothyroidism on Hepatic Gene Expression and Lipid Metabolism in Adulthood

Santana-Farré¹,

Mirecki-Garrido²,

Bocos

et al. 2012

PLoS ONE

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“…Inhibi tion of TRH-induced TSH release can be expected to become increasingly sensitive to Tj concentrations as gestational age ad vances [26], Thirdly, the decrease in the fetal TSH/ FT4 ratio also suggests that the thyroid gland becomes progressively more responsive to TSH during the second half of pregnancy [5,9], The placenta is freely permeable to thy rotropin-releasing hormone, IgG, and drugs used to treat thyroid disease, such as pro pylthiouracil, methimazole, iodine and pro pranolol [27], Placental transfer of thyroid hormones has been demonstrated in animal experiments [29]. Previous data from hu man neonatal cord blood have suggested that small amounts of T3 cross the placenta when maternal concentrations are high, whereas at physiologic concentrations pla cental transfer is limited [4], Recently, it has been demonstrated in a rat model that physiologic doses of T3 are substantially transferred into the fetal compartment [18,30]. Interestingly, we have observed a sig nificant correlation between maternal TT3 and fetal TT4 and T3 levels.…”

Section: Discussionmentioning

confidence: 99%

Thyroid Function in Fetus and Mother during the Second Half of Normal Pregnancy

Radunovic

Nastic²,

Mandelbrot³

et al. 1991

Neonatology

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Thyroid hormones, thyroxine-binding globulin (TBG) and thryrotropin (TSH) concentrations were measured in 46 paired fetal and maternal blood samples collected between 17 and 36 weeks of gestation. The samples were selected retrospectively from fetuses that had undergone cordocentesis for prenatal diagnosis, had been found to be unaffected and confirmed healthy at birth. In maternal serum, total thyroxine (TT₄) and triiodothyronine (TT₃) concentrations were high, but free thyroxine (FT₄) and free triiodothyronine (FT₃) were within normal adult ranges; reverse T₃ (RT₃) increased and TSH levels decreased towards term. Fetal TT₄, FT₄, TT₃, FT₃, TBG and TSH levels significantly increased whereas RT₃ sharply decreased with gestational age. The ratio of fetal TSH/FT₄ significantly decreased, suggesting that the set point for negative feedback of pituitary TSH secretion is changing while the sensitivity of the thyroid gland to TSH increases throughout gestation. There was no significant correlation between the maternal and fetal TBG, TSH, TT₄ and FT₄, whereas maternal TT₃ was positively correlated with fetal TT₄, FT₄, TT₃ and FT₃. Normal reference values for maternal and fetal iodothyronines, TBG and TSH throughout the second half of gestation provide insight into fetal thyroid development and may be useful for prenatal diagnosis.

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“…Because fetal thyroid functions in rats begin at approximately GD 17 (Gilbert and Zoeller, 2010), the MMI administration started on GD 15. MMI is able to pass through the placenta and reach the fetuses during gestation (Marchant et al, 1977;De Escobar et al, 1988;Sack et al, 1995), and it is excreted into breast milk and taken by pups on PNDs (Johansen et al, 1982;Cooper, 1984). The date of birth was designated PND 0.…”

Section: Subjectmentioning

confidence: 99%

Acoustic alterations of ultrasonic vocalization in rat pups induced by perinatal hypothyroidism

Wada

2017

NeuroToxicology

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Perinatal hypothyroidism causes serious damage to auditory functions that are essential for vocalization development. In rat pups, perinatal hypothyroidism potentially affects the development of ultrasonic vocalization (USV) as a result of hearing deficits. This study examined the effect of perinatal hypothyroidism on the development of USVs in rat pups. Twelve pregnant rats were divided into three groups and treated with the anti-thyroid drug methimazole (MMI) via drinking water, from gestational day 15 to postnatal day (PND) 21. The MMI concentration (w/v) was 0% (control group), 0.01% (low-dose group), or 0.015% (high-dose group). After birth, the pups were individually separated from the dam and littermates on PNDs 5, 10, 15, and 20, and their USVs were recorded for 5min. On PNDs 5 and 10, compared with the control group, the low- and high-dose groups exhibited reductions of both frequency-modulated and downward USVs. On PND 15, however, the low- and high-dose groups displayed increases in number, duration, and amplitude of USVs compared with those in the control group. Lower body weights were observed for the low- and high-dose groups than for the control group. Total thyroxine concentrations in plasma were dose-dependently reduced. The onset of auditory functions appeared on PNDs 11-14. Thus, the rat pups were unable to hear externally produced USVs before PND 11. USVs emitted on PNDs 5 and 10 might have been spontaneous and independent of the pups' own or littermate-emitted USVs. The developmental retardation of vocalization-related organs or muscles might underlie the acoustic alterations of USVs on PNDs 5 and 10. The greater number, duration, and amplitude of USVs on PND 15, after which the hearing onset occurred, suggested that the elevation of auditory thresholds occurred as a result of hearing deficits in the low- and high-dose groups. Perinatal hypothyroidism appears to have caused acoustic alterations in the USV development.

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Transfer of Thyroxine from the Mother to the Rat Fetus Near Term: Effects on Brain 3,5,3'-Triiodothyronine Deficiency*

Cited by 85 publications

References 52 publications

Influence of Neonatal Hypothyroidism on Hepatic Gene Expression and Lipid Metabolism in Adulthood

Influence of Neonatal Hypothyroidism on Hepatic Gene Expression and Lipid Metabolism in Adulthood

Thyroid Function in Fetus and Mother during the Second Half of Normal Pregnancy

Acoustic alterations of ultrasonic vocalization in rat pups induced by perinatal hypothyroidism

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