Thyroid Hormone Metabolism in the Non-Euthyroid Porcine Fetus
Creators: name: Ison, Erin Kay
Publisher: name: Purdue University Graduate School
Year: 2022
Subjects: Animal growth and development
Animal reproduction and breeding
Animal protection (incl. pests and pathogens)

description: Thyroid hormone is essential for regulating adult metabolism and proper fetal development. Under normal conditions, maternal and fetal thyroid hormones are subject to metabolism at the placenta and within fetal tissues through deiodination and sulfation to regulate fetal exposure to the bioactive hormone. Disruptions of the thyroid hormone system can result in non-thyroidal illness syndrome (NTIS), which is classified as the dysregulation of thyroid hormone homeostasis. The exact cause of the alterations in circulating thyroid hormone levels during NTIS is not well- known. In comparison, hypothyroidism results from the absence of thyroid hormone production and presents as low thyroid hormone levels. Porcine reproductive and respiratory syndrome virus (PRRSV) crosses the late gestation placenta and causes suppression of circulating maternal and fetal thyroid hormone. Chapter 2 investigates the potential role of thyroid hormone metabolism in this disruption. Pregnant gilts were challenged with PRRSV2 (n=22) or sham inoculated (n=5) at gestation day 85. Samples were collected on day 106, and viral load was assessed in fetal serum and thymus. From the entire fetal population, three distinct subsets of fetuses representing biological extremes were identified, including uninfected with no detectable viral load (UNIF), high viral load viable (HV-VIA), or high viral load with severe meconium staining (HV-MEC). In addition, control fetuses from sham inoculated gilts (CON) were used as a reference group. Samples of fetal liver, kidney, and the corresponding fetal placenta and maternal endometrium for n=10 fetuses per group were then used to evaluate gene expression. A total of 11 genes associated with thyroid hormone metabolism including deiodinases (DIO1,2,3), sulfotransferases (SULT1A3,1B1,1C2,1E1,2A1), sulfatase (STS), and solute carriers (SLC16A2,16A10) were quantified using absolute quantification qPCR. Evidence of fetal decompensation was observed within the high viral fetuses in the form of decreased DIO1 expression within the fetal liver and increased DIO3 expression in both components of the placenta. Circulating levels of T4 and inactive thyroid hormone metabolites, reverse-triiodothyronine (rT3) and two diiodothyronines (3,5-T2 and 3,3’-T2), were measured in fetal serum. While T4 was depressed, no change was observed in circulating rT3 levels, and neither T2 metabolite reached the lower detection limit. This may suggest that alterations in thyroid hormone metabolism generate a localized effect on hormone metabolites in the respective tissues. Alternatively, the low levels of available T3 and T4 limit the production of downstream metabolites to be found in serum. The cause-and-effect relationship between PRRSV infection, fetal thyroid disruption, and the effects on fetal thyroid hormone metabolism are unclear. Therefore, Chapter 3 developed a non-pathogenic model using methimazole (MMI) to induce hypothyroidism in the late gestation fetus and evaluate the impact on fetal development and thyroid hormone metabolism. Pregnant gilts were either treated with oral methimazole or equivalent sham from gestation day 85-106 (n=4/group), followed by classification of all fetuses as live, live but meconium stained, or dead. Fetuses exposed to MMI in-utero were notably hypothyroid with significantly suppressed serum T3 and T4 and histological evidence of goiter. Surprisingly, fetuses from MMI-treated dams were substantially larger but appeared to exhibit non-allometric growth with an increase in girth but not length. The liver, kidney, and the corresponding fetal placenta and maternal endometrium were collected from a subset of 16 fetuses per group to evaluate the relative expression of five genes associated with thyroid hormone metabolism, including three deiodinases and two solute carriers known to transport thyroid hormone. Compensatory transcription of DIO3 was observed in all tissues evaluated, suggesting increased vertical transfer of maternal thyroid hormone at the placenta and decreased breakdown of thyroid hormone within fetal organs. The evaluation of thyroid hormone metabolism within the fetus and within the placenta has allowed us to differentiate suppressed thyroid hormone levels of the pig fetus under pathogenic and non-pathogenic conditions. In the context of PRRSV infection, the observed decompensation of thyroid hormone metabolism would further exacerbate the hypothyroid state and is therefore consistent with NTIS. In contrast, fetuses with induced thyroid hormone suppression following maternal exposure to MMI showed compensatory thyroid hormone metabolism in the same tissues. This indicates true hypothyroidism and clearly demonstrates a fetal capacity to respond to such endocrine disruption.