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. 2016 Aug 24;7(1):36.
doi: 10.1186/s13293-016-0089-3. eCollection 2016.

Sex-specific Phenotypes of Hyperthyroidism and Hypothyroidism in Mice

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Free PMC article

Sex-specific Phenotypes of Hyperthyroidism and Hypothyroidism in Mice

Helena Rakov et al. Biol Sex Differ. .
Free PMC article

Abstract

Background: Thyroid dysfunction is more common in the female population, however, the impact of sex on disease characteristics has rarely been addressed. Using a murine model, we asked whether sex has an influence on phenotypes, thyroid hormone status, and thyroid hormone tissue response in hyper- and hypothyroidism.

Methods: Hypo- and hyperthyroidism were induced in 5-month-old female and male wildtype C57BL/6N mice, by LoI/MMI/ClO4 (-) or T4 i.p. treatment over 7 weeks, and control animals underwent sham treatment (N = 8 animals/sex/treatment). Animals were investigated for impact of sex on body weight, food and water intake, body temperature, heart rate, behaviour (locomotor activity, motor coordination, and strength), liver function, serum thyroid hormone status, and cellular TH effects on gene expression in brown adipose tissue, heart, and liver.

Results: Male and female mice showed significant differences in behavioural, functional, metabolic, biochemical, and molecular traits of hyper- and hypothyroidism. Hyperthyroidism resulted in increased locomotor activity in female mice but decreased muscle strength and motor coordination preferably in male animals. Hypothyroidism led to increased water intake in male but not female mice and significantly higher serum cholesterol in male mice. Natural sex differences in body temperature, body weight gain, food and water intake were preserved under hyperthyroid conditions. In contrast, natural sex differences in heart rate disappeared with TH excess and deprivation. The variations of hyper- or hypothyroid traits of male and female mice were not explained by classical T3/T4 serum state. TH serum concentrations were significantly increased in female mice under hyperthyroidism, but no sex differences were found under eu- or hypothyroid conditions. Interestingly, analysis of expression of TH target genes and TH transporters revealed little sex dependency in heart, while sex differences in target genes were present in liver and brown adipose tissue in line with altered functional and metabolic traits of hyper- and hypothyroidism.

Conclusions: These data demonstrate that the phenotypes of hypo- and hyperthyroidism differ between male and female mice and indicate that sex is an important modifier of phenotypic manifestations.

Keywords: Hyperthyroidism; Hypothyroidism; Mice; Sex difference; Sex steroid hormone; Thyroid hormone action; Thyroid hormone transport.

Figures

Fig. 1
Fig. 1
Study design for phenotypic characterization of hyper- and hypothyroidism in female and male mice. Two weeks were used to study the euthyroid control state of male and female mice (run-in period), followed by 3 weeks induction period without experiments other than monitoring body weight and food and water intake. After the induction period, male and female mice were analyzed under hyper- and hypothyroid conditions over a period of 4 weeks and compared to sham-treated controls
Fig. 2
Fig. 2
Body weight change, food and water intake in euthyroid, T4 or LoI/MMI/ClO4 treated mice. Time course of the average body weight (BW) of male and female mice over an experimental period of 9 weeks under a control, b T4, and c LoI/MMI/ClO4 treatment. Average food intake was related to BW during experiment in d euthyroid, e hyperthyroid, and f hypothyroid conditions in mice of both sexes. After run-in period mice were placed on low-iodine diet for the induction of hypothyroidism, or on control iodine diet by the same supplier to adapt the nutritional intake (euthyroid and hyperthyroid groups). Arrows indicate the start of treatment. Time course of average water intake was monitored over the experimental period of 9 weeks under g control, h TH excess, and i TH deprivation of male and female mice. Data are presented as mean ± SD, N = 8 animals/sex/treatment/time point; two-way ANOVA followed by the Bonferroni post hoc analysis applied for time and sex effects, *p < 0.05, **p < 0.01, ***p < 0.001 above graph represent multiple-testing results
Fig. 3
Fig. 3
Influence of sex and change of TH serum concentrations on body temperature and heart rate. a Body temperature was assessed by rectal temperature measurements and b non-invasive ECG was performed on conscious mice of both sexes under euthyroid, hyperthyroid, and hypothyroid conditions. Data are presented as mean ± SD, N = 8 animals/sex/treatment; two-way ANOVA followed by the Bonferroni post hoc analysis applied for treatment and sex effects, *p < 0.05, **p < 0.01, ***p < 0.001 above bars represent multiple-testing results
Fig. 4
Fig. 4
Behavioural assessment of male and female mice under T4 excess or deprivation. The chimney test was used to a examine muscle strength, tonus, and coordination of movements in male and female mice under euthyroid, hyperthyroid, or hypothyroid conditions. The open field was used to investigate activity and exploratory behaviour. b Total distance travelled was measured to assess activity, and c frequency of rearings was determined to assess exploratory behaviour. The rotarod test was used for an overall assessment of coordination and motor function in male and female mice before the start of treatment (training period) and under sham (d), T4 (e), or LoI/MMI/ClO4 (f) treatment. Data are presented as mean ± SD, N = 8 animals/sex/treatment; two-way ANOVA followed by the Bonferroni post hoc analysis applied for sex and treatment effects of ac and unpaired Student’s t test for sex effect of df, *p < 0.05, **p < 0.01, ***p < 0.001 represent multiple-testing or t test results
Fig. 5
Fig. 5
Serum TH status in euthyroid controls, T4 or LoI/MMI/ClO4 treated male and female mice. a Total thyroxine (TT4), b free thyroxine (fT4), and c free triiodothyronine (fT3) concentrations were determined in sera by ELISA after 7 weeks of treatment. d Total cholesterol and e triglyceride serum concentrations were determined by ELISA at the end of experiment in sera of euthyroid, hyperthyroid, and hypothyroid mice of both sexes. Data are presented as mean ± SD, N = 8 animals/sex/treatment for TH concentrations, N = 4/sex/treatment animals for total cholesterol and triglyceride concentrations; two-way ANOVA followed by the Bonferroni post hoc analysis applied for sex and treatment effects, *p < 0.05, **p < 0.01, ***p < 0.001 above bars represent multiple-testing results
Fig. 6
Fig. 6
TH effects in brown adipose tissue (BAT), heart, and liver of male and female mice. Fold changes of representative TH-responsive genes were measured by quantitative RT-PCR in a BAT, d heart, and g liver tissue of hyperthyroid or hypothyroid mice of both sexes and normalized to tissue samples of euthyroid control mice. For BAT Dio2, Ucp1, and PGC1α expression; for heart Dio2, Myh6, and Hcn4 expression; and for liver Dio1, Tbg, and Me1 expression were quantified. Additionally, mRNA expression of TH transporter genes were analyzed in b BAT, e heart, and h liver. For BAT: Mct8, Mct10, Oatp3a1, Lat2, for heart: Mct8, Ntcp, Lat1, Lat2, and for liver: Mct8, Mct10, Lat1, Lat2. Furthermore, euthyroid sex comparison was analyzed in c BAT, f heart, and i liver of all genes, and gene expression in female tissues was normalized to male samples. Data are presented as mean ± SD, N = 5–7 animals/sex/treatment; unpaired Student’s t test, *p < 0.05, **p < 0.01, ***p < 0.001 represent t test results

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References

    1. Vanderpump MPJ. The epidemiology of thyroid disease. Br Med Bull. 2011;99:39–51. doi: 10.1093/bmb/ldr030. - DOI - PubMed
    1. Clayton JA, Collins FS. NIH to balance sex in cell and animals studies. Nature. 2014;509:282–283. doi: 10.1038/509282a. - DOI - PMC - PubMed
    1. Hammes SR. Sex matters in preclinical research. Mol Endocrinol. 2014;28:1209–1210. doi: 10.1210/me.2014-1209. - DOI - PMC - PubMed
    1. Bianco AC, Anderson G, Forrest D, Galton VA, Gereben B, Kim BW, et al. American thyroid association guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid. 2014;24:88–168. doi: 10.1089/thy.2013.0109. - DOI - PMC - PubMed
    1. Engels K, Rakov H, Zwanziger D, Moeller LC, Homuth G, Koehrle J, et al. Differences in mouse hepatic thyroid hormone transporter expression with age and hyperthyroidism. Eur Thyroid J. 2015;4(Suppl 1):81–6. doi: 10.1159/000381020. - DOI - PMC - PubMed

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