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Late gestation fetal hypothyroidism alters cell cycle regulation across multiple organ systems
Alyssa A Smith1, Alexa Vesey1, Caden Helfrich1
1Department of Animal Sciences, Purdue University, West Lafayette, IN, 47906, USA.
Background:
Hypothyroidism is a common endocrine disruption observed in utero that adversely affects fetal growth and maturation leading to long-term impacts on health; however, the exact molecular mechanisms by which these deleterious effects occur are unknown. We hypothesize that fetal hypothyroidism during late gestation will disrupt cell cycle regulation in a tissue-specific manner. To evaluate this, eight pregnant gilts were dosed with either methimazole or an equivalent negative control during days 85-106 out of 114 days of gestation (n = 4/group). Following treatment, the gilts were humanely euthanized, and tissue samples of fetal heart, ileum, kidney, lung, liver, muscle, spleen, and thymus taken from two male and two female fetuses (n = 32) from each gilt.
Results:
The relative expression of three cell cycle promoters (CDK1, CDK2, and CDK4), and one cell cycle inhibitor (CDKN1A) was compared in each tissue to determine the effect of hypothyroidism on the developing fetus. All of the eight tissues examined experienced at least one significant up- or downregulation in the expression of the aforementioned genes as a result of treatment with methimazole. Substantial changes were observed in the liver and muscle, with the latter experiencing significant downregulations of CDK1, CDK2, and CDK4 as a result of treatment. In addition, all tissues were examined for changes in protein content, which further elucidated the impact of hypothyroidism on the fetal liver by the observation of a marked increase in protein content in the methimazole-treated group. Finally, the heart and liver were histologically examined for evidence of cellular hyperplasia and hypertrophy by measuring average nuclei density and size in each tissue, with the results showing a significant decrease in average nuclei size in the liver of hypothyroid fetuses.
Conclusions:
Collectively, these findings indicate the occurrence of organ-specific disruptions in cell cycle progression as a result of in utero hypothyroidism, which may explain the long term and widespread effects of hypothyroidism on fetal development.
Insights
In utero hypothyroidism disrupts fetal cell cycle regulation in specific organs, impacting growth and maturation. This study reveals tissue-specific gene expression changes and protein alterations, potentially explaining long-term health effects.
Area of Science:
- Endocrinology
- Developmental Biology
- Molecular Biology
Background:
- Hypothyroidism in utero affects fetal development and maturation, with unknown molecular mechanisms.
- This study investigates the impact of induced fetal hypothyroidism on cell cycle regulation.
Purpose of the Study:
- To determine the tissue-specific effects of late-gestation hypothyroidism on fetal cell cycle regulation.
- To identify molecular changes in gene and protein expression in response to induced hypothyroidism.
Main Methods:
- Pregnant gilts were administered methimazole or a control from days 85-106 of gestation.
- Fetal tissues (heart, ileum, kidney, lung, liver, muscle, spleen, thymus) were collected for gene expression, protein content, and histological analysis.
- Relative expression of cell cycle regulators (CDK1, CDK2, CDK4, CDKN1A) was quantified.
Main Results:
- Methimazole treatment caused significant up- or downregulation of cell cycle genes in all eight fetal tissues examined.
- Muscle tissue showed significant downregulation of CDK1, CDK2, and CDK4.
- Fetal liver exhibited increased protein content and decreased average nuclei size, indicating altered cellular structure.
Conclusions:
- In utero hypothyroidism induces organ-specific disruptions in fetal cell cycle progression.
- These findings provide molecular insights into the widespread, long-term health consequences of fetal hypothyroidism.
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