Temporal impact of hypothyroidism on porcine fetal growth and skeletal development

In the fetal pig, circulating thyroid hormone and growth rate increase throughout gestation; however, the functional association between these coincident factors has not been established. We used a nonpathogenic model of induced fetal hypothyroidism, wherein pregnant gilts were treated with methimazole (MMI) for 21 days, starting on gestation days (GD) 34, 45, 55, or 65. The resulting fetal populations were deeply phenotyped, including body and organ weights, cranial and whole body morphometrics, radiography, and dual energy X-ray absorptiometry (DXA) of the fore- and hindlimbs. MMI increased absolute fetal thyroid weight by 74%, 581%, 551%, and 315% on GD 55, 66, 76, and 86, respectively, indicating successful MMI-induced fetal hypothyroidism at all time points. Crown rump length, girth, body weight, and the absolute weight of all fetal organs increased with GD, with no effects of hypothyroidism. However, MMI significantly reduced the length of the long bones in both fore- and hindlimbs by 11.1%-13.4% on GD 86, while bone area, as measured by DXA, decreased by 20%-21% for the same period. Collectively, these results indicate that overall fetal growth during mid to late gestation is not driven by thyroid hormones, but skeletal growth is negatively impacted by hypothyroidism in a temporally dependent manner.