Triclosan Affects the Thyroid Axis of Amphibians

Dear Dr Lehman-McKeeman, In the article entitled “Triclosan and thyroid-mediated metamorphosis in Anurans: Differentiating growth effects from thyroid-driven metamorphosis in Xenopus laevis” (Fort et al., 2011), Fort and colleagues exposed premetamorphic Xenopus laevis tadpoles for 32 days through prometamorphosis to four different concentrations of triclosan (TCS). The authors state in the abstract that exposure of tadpoles to TCS increased larval growth based on whole body length, weight, and snout-vent length. They also state that “Endpoints measured to evaluate effects on thyroid-mediated metamorphosis including developmental stage, thyroid histology, TRβ expression, DI-2 and DI-3 expression, and thyroid gland T4 (thyroxine) and plasma T4 and T3 (triiodothyronine) levels were not affected by TCS exposure.” The discussion further states that “no adverse effects on thyroid histology were detected, and no changes in either thyroid gland T4 or serum T3 and T4 levels were found.” The statements regarding no effect of TCS on the thyroid axis misrepresent the data presented in the article. In fact, three thyroid endpoints measured by Fort et al. showed evidence of thyroid axis disruption. These include thyroid histology (thyroid gland hypertrophy and follicle cell height) and plasma T4 levels. The authors found a “TCS-concentration–related increase” in the occurrence of “minimal” thyroid gland hypertrophy and vascular congestion at day 32 (Table 3; Figures 1 and 2). As the TCS concentrations increased, so did the incidence of pathology such that at the highest TCS concentration, 8 of 10 animals showed thyroid gland hypertrophy and 6 of 10 showed increased vascular congestion (Table 3). Increased vascularity is consistent with larger gland size to accommodate gas, nutrient, and molecule exchange. Table 4 summarizes the thyroid histology measurements taken at the same time point. Follicle count and area, mean colloid area/animal, and mean colloid area/follicle were not significantly different from controls. However, thyroid gland area was significantly increased at three (0.3, 5.9, 29.6 μg/l) of the four TCS concentrations compared to controls. The 1.3 μg/l concentration had a p value of 0.053. Follicle cell height was significantly decreased compared with the control at the three higher concentrations tested (1.3, 5.9, and 29.6 μg/l). The OECD test guidelines include thyroid gland hypertrophy and follicular cell height as diagnostic of thyroid axis disruption (OECD, 2007; OECD, 2009). Therefore, the observations presented in the article show that thyroid histology is significantly affected by TCS exposure. Figure 3b presents the data obtained from measuring plasma T4 and T3 levels in stage-matched specimens. The stage matching indicated in this figure legend is not consistent with methods outlined in the “Test Method” section where animals were randomly selected (i.e., not stage matched) “for blood serum and thyroid gland tissue collection for T3 and T4 analysis” at day 32. Randomly selected animals could be anywhere between stages 58 and 62 (indicated in Table 2) which represent very different stages of development. Stage matching would have been the most appropriate way to analyze the data, so assuming this was done, the authors reported a significant change in plasma T4 levels at the 0.3 and 1.3 μg/l concentrations compared with controls (“Thyroid Hormone Analysis” section in the results; p = 0.012 and 0.004, respectively). Figure 3b recapitulates these measurements but is lacking the asterisks referred to in the figure legend to identify significant data. It is unclear whether the hormone levels measured were actually from serum or plasma since the two terms were used interchangeably throughout the article. The observation that T4 levels were significantly different in TCS-exposed animals compared with controls demonstrates that another aspect of the thyroid axis has been disrupted by TCS exposure. There is growing evidence that the thyroid axis is a target of disruption by TCS. How the disruption occurs is still not clear. However, contrary to the authors’ claims, they too provide further evidence of thyroid axis disruption by TCS.

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