Sex, Genetics, and the Control of Thyroxine and Thyrotropin in Mice

Abstract

Previously, we studied the genetic basis for variability in total thyroxine (TT4) as part of investigating induced Graves' hyperthyroidism in panels of genetically diverse recombinant inbred (RI) mice. Because Graves' disease occurs predominantly in women, we used female mice. A limitation of this approach is that thyrotropin (TSH) is undetectable by some assays in most female mice. Variation in levels of serum TSH, TT4, and free thyroxine (FT4) was measured in males from three related RI families (CXB, BXH, and AXBXA) followed by quantitative genetic analysis and mapping of these traits. In general, TSH levels were higher in males than females. FT4 levels were also higher in males than in females, but TT4 sex differences were absent or inconsistent. Chromosomal linkage was only observed for TSH in BXH males and for FT4 in AXBXA males. Different chromosomes were linked to TT4 in males of the three RI sets. The most striking finding came from genetic linkages in males versus our previous data for females. TT4 was linked to the same chromosomal loci in CXB males and females. In contrast, TT4, FT4, and TSH were linked to different "sex-specific chromosomes" in AXBXA and BXH families. In three RI mouse families, TSH and FT4 were significantly higher in males than females. Linkage analysis revealed chromosomal overlap for TT4 in males and females for one RI set but striking sex differences for TT4, FT4, and TSH linkage in two RI sets. Our findings provide a cautionary note: genetic linkage analysis of thyroid hormones traits in mice should be studied separately in males and females.