Hypothyroxinemia: Zoeller's response.

Soldin addresses an important issue that was not fully developed in my editorial (Zoeller 2003a), specifically, the description of thyroid status in experimental animals designed to model human conditions. There are two separate issues in this regard. The first is that the language describing thyroid status is well defined for humans but not for experimental animals. Clinical assays for the various hormones of the pituitary-thyroid axis are standardized (and calibrated) across clinical chemistry laboratories, and reference ranges have been published for various subgroups of the population (e.g., Adams et al. 1995; Singh et al. 2003; Wiersinga 2001). Therefore, terms such as "hypothyroxinemia" and "subclinical (or mild) hypothyroidism" have very specific definitions for humans. In contrast, experimental studies are internally controlled (i.e., using control groups), and there are no reference ranges or assays that are calibrated across research laboratories performing these assays. Therefore, caution is needed when applying terms such as "subclinical hypothyroidism" to experimental animals.

The second, and more important, issue is that the vast majority of research focused on identifying the role of thyroid hormone (TH) in brain development has modeled severe hypothyroidism (reviewed by Schwartz 1983). Perhaps for this reason, the "clinical" symptoms of severe hypothyroidism in animals, including reduction in litter size, body weight, and brain size, and a delay in developmental landmarks such as tooth eruption and eye opening, have come to be viewed as cardinal developmental effects of TH insufficiency. Therefore, by association, if these "clinical" signs are not observed, the implication is that there would be no other effects on brain development. In large part, the work by Lavado-Autric et al. (2003) was testing whether "subtle" (my term) hypothyroidism could affect brain development (Zoeller 2003b).

By "subtle," I meant that maternal thyroxine ([T.sub.4]) was reduced to a level below that of control animals but that overt effects on litter size, body weight, and other characteristics were not observed. Soldin is correct that the initial treatment of young adult female rats described by Lavado-Autric et al. (2003) was not subtle. Subgroups of these animals were treated for 10 days with a low iodine diet plus 1% potassium perchlorate in their drinking water. However, the animals were then taken off perchlorate treatment and placed on specifically designed diets for 3 months before being mated. Thus, the article by Lavado-Autric et al. is not about perchlorate treatment; it is about the sensitivity of the developing brain to TH insufficiency and the developmental timing of this vulnerability. The fact remains that there are no experimental studies designed to determine what might be considered a no effect level for maternal or neonatal TH insufficiency on brain development. However, this will be an important issue to clarify as we consider the significance of maternal hypothyroxinemia or the effects of thyroid toxicants on brain development.

The author declares he has no competing financial interests.

R. Thomas Zoeller

University of Massachusetts 

Amherst, Massachusetts

E-mail: [e-mail]

REFERENCES

Adams LM, Emery JR, Clark SJ, Carlton EI, Nelson JC. 1995. Reference ranges for newer thyroid function tests in premature infants. J Pediatr 126(1):122-127.

Lavado-Autric R, Auso E, Garcia-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P, et al. 2003. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 111(7):1073-1082.

Schwartz HL. 1983. Effect of thyroid hormone on growth and development. In: Molecular Basis of Thyroid Hormone Action (Oppenheimer JH, Samuels HH, eds). New York:Academic Press, 413-444.

Singh PK, Parvin CA, Gronowski AM. 2003. Establishment of reference intervals for markers of fetal thyroid status in amniotic fluid. J Clin Endocrinol Metab 88(9):4175-4179.

Wiersinga WM. 2001. Thyroid hormone replacement therapy. Horm Res 56(suppl 1):74-81.

Zoeller RT. 2003a. Thyroid toxicology and brain development: should we think differently? [Editorial]. Environ Health Perspect 111:A628.

Zoeller RT. 2003b. Transplacental thyroxine and fetal brain development. J Clin Invest 111(7):954-957.