Environmental contaminants and related systems that have implications for reproduction

NHANES III measured serum TSH, total serum T(4), antithyroperoxidase (TPOAb), and antithyroglobulin (TgAb) antibodies from a sample of 17,353 people aged > or =12 yr representing the geographic and ethnic distribution of the U.S. population. These data provide a reference for other studies of these analytes in the U.S. For the 16,533 people who did not report thyroid disease, goiter, or taking thyroid medications (disease-free population), we determined mean concentrations of TSH, T(4), TgAb, and TPOAb. A reference population of 13,344 people was selected from the disease-free population by excluding, in addition, those who were pregnant, taking androgens or estrogens, who had thyroid antibodies, or biochemical hypothyroidism or hyperthyroidism. The influence of demographics on TSH, T(4), and antibodies was examined. Hypothyroidism was found in 4.6% of the U.S. population (0.3% clinical and 4.3% subclinical) and hyperthyroidism in 1.3% (0.5% clinical and 0.7% subclinical). (Subclinical hypothyroidism is used in this paper to mean mild hypothyroidism, the term now preferred by the American Thyroid Association for the laboratory findings described.) For the disease-free population, mean serum TSH was 1.50 (95% confidence interval, 1.46-1.54) mIU/liter, was higher in females than males, and higher in white non-Hispanics (whites) [1.57 (1.52-1.62) mIU/liter] than black non-Hispanics (blacks) [1.18 (1.14-1.21) mIU/liter] (P < 0.001) or Mexican Americans [1.43 (1.40-1.46) mIU/liter] (P < 0.001). TgAb were positive in 10.4 +/- 0.5% and TPOAb, in 11.3 +/- 0.4%; positive antibodies were more prevalent in women than men, increased with age, and TPOAb were less prevalent in blacks (4.5 +/- 0.3%) than in whites (12.3 +/- 0.5%) (P < 0.001). TPOAb were significantly associated with hypo or hyperthyroidism, but TgAb were not. Using the reference population, geometric mean TSH was 1.40 +/- 0.02 mIU/liter and increased with age, and was significantly lower in blacks (1.18 +/- 0.02 mIU/liter) than whites (1.45 +/- 0.02 mIU/liter) (P < 0.001) and Mexican Americans (1.37 +/- 0.02 mIU/liter) (P < 0.001). Arithmetic mean total T(4) was 112.3 +/- 0.7 nmol/liter in the disease-free population and was consistently higher among Mexican Americans in all populations. In the reference population, mean total T(4) in Mexican Americans was (116.3 +/- 0.7 nmol/liter), significantly higher than whites (110.0 +/- 0.8 nmol/liter) or blacks (109.4 +/- 0.8 nmol/liter) (P < 0.0001). The difference persisted in all age groups. In summary, TSH and the prevalence of antithyroid antibodies are greater in females, increase with age, and are greater in whites and Mexican Americans than in blacks. TgAb alone in the absence of TPOAb is not significantly associated with thyroid disease. The lower prevalence of thyroid antibodies and lower TSH concentrations in blacks need more research to relate these findings to clinical status. A large proportion of the U.S. population unknowingly have laboratory evidence of thyroid disease, which supports the usefulness of screening for early detection.

Pregnant females are susceptible to intracellular pathogens and are biased towards humoral rather than cell-mediated immunity. Since TH1 cytokines compromise pregnancy and TH2 cytokines are produced at the maternal-fetal interface, we hypothesize that these TH2 cytokines inhibit TH1 responses, improving fetal survival but impairing responses against some pathogens.

While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.