Compensatory mechanisms in response to induced hypothyroidism in the late gestation pig fetus

Abstract

To understand the effect of fetal thyroid gland disruption on development in swine, we evaluated thyroid hormone levels, growth and developmental characteristics, and gene expression associated with thyroid hormone metabolism in late gestation fetuses exposed to methimazole (MMI). Pregnant gilts were given either oral MMI or equivalent sham from gestation day 85–106 (n = 4/group), followed by intensive phenotyping of all fetuses (n = 120). Samples of liver (LVR), kidney (KID), fetal placenta (PLC) and the corresponding maternal endometrium (END) were collected from a subset of fetuses (n = 32). Fetuses exposed to MMI in utero were confirmed hypothyroid, with a significant increase in thyroid gland size, goitrous thyroid histology, and dramatically suppressed thyroid hormone in serum. In the dams, no differences in temporal measurements of average daily gain, thyroid hormone, or rectal temperatures relative to controls suggest that MMI had little effect on maternal physiology. However, fetuses from MMI treated gilts exhibited significant increases in body mass, girth, and vital organ weights, but no differences in crown-rump length or bone measurements suggest non-allometric growth. The PLC and END showed a compensatory decrease in expression of inactivating deiodinase (DIO3). Similar compensatory gene expression was observed in fetal KID and LVR with a downregulation of all deiodinases (DIO1, DIO2, DIO3). Minor alterations in the expression of thyroid hormone transporters (SLC16A2 and SLC16A10) were observed in PLC, KID and LVR. Collectively, MMI crosses the fetal placenta of the late gestation pig, resulting in congenital hypothyroidism, alterations in fetal growth, and compensatory responses within the maternal fetal interface.

Impact of methimazole‐induced hypothyroidism on postnatal swine

“…These histological changes in thyroid structure were consistent with pathological signs of goiter seen in rats exposed to MMI (Tsujio et al, 2007) as well as in hypothyroid human patients (Mizukami et al, 1993). Interestingly, the thyroid histology following MMI treatment differed from recent observation in fetal swine which showed a loss of eosinophilic colloid and collapse of thyroid follicle shape, but an undisturbed epithelial structure (Ison et al, 2023). We hypothesize this apparent difference in porcine thyroid response to MMI results from reduced pituitary capacity for TSH production during development of the HPT axis in the prenatal swine.…”

“…Hypothyroidism has been noted to impact the expression of genes associated with deiodinases in rats, specifically through increased activation (DIO2) and decreased deactivation (DIO3) of thyroid hormone (Gereben et al., 2008 ; Silva & Matthews, 1984 ). Previous work in the fetal swine demonstrated altered hepatic deiodinase gene expression (DIO1, DIO2, DIO3) in response to severe MMI induced hypothyroidism (Ison et al., 2023 ). In contrast the present study found no significant change in hepatic deiodinase expression in response to mild systemic hypothyroidism.…”

“…The serum levels of total T4 and T3 were measured utilizing a commercially available Total T4 ELISA (Cat# 07M275A) and Total T3 Chemiluminescence Immunoassay (Cat# 07M175A) (MP Biomedicals, Solon, OH, USA). The assay procedures were followed as instructed from the manufacturer and followed as previously demonstrated in swine (Ison et al., 2023 ). In summary, 25 μL and 50 μL of serum were analyzed in duplicate for T4 and T3 respectively.…”

The role of the thyroid in polycystic ovary syndrome

“…Significant hypothyroidism accompanied by elevated TRH led to hyperprolactinemia, interruption of pulsatile LH secretion, decreased SHBG synthesis, interruption of peripheral estrogen metabolism, and increased ovarian androgen production ( 125 ). In a study of female pigs, hypothyroidism led to increased gonadotropin receptor sensitivity in the ovaries, which ultimately promoted ovarian hypertrophy and the formation of multiple ovarian cysts ( 126 ). Moreover, hypothyroidism may lead to severe and irregular menstrual bleeding, spotting during the menstrual cycle, insufficient endometrial thickness, ovulation disorders, and eventually endometrial hyperplasia disorders ( 127 , 128 ).…”

Late gestation fetal hypothyroidism alters cell cycle regulation across multiple organ systems

“…These effects are consistent with the long-term implications of fetal hypothyroidism in humans, with observed clinical symptoms such as mental retardation [ 10 ], delayed bone development [ 11 ], and poor growth [ 12 ]. As swine are a commonly used biomedical model [ 13 ], the current study utilizes a porcine model of congenital hypothyroidism in which MMI, which we have previously shown to cross the porcine placenta and induce severe fetal hypothyroidism [ 14 ], is used to examine the molecular impact of late gestation hypothyroidism on the developing fetus.…”