Triclosan Affects Thyroid Hormone-Dependent Metamorphosis in Anurans

Our original work on Rana catesbeiana (bullfrog) tadpoles exposed to triclosan (TCS) during induction of precocious metamorphosis that was presented in Veldhoen et al. (2006) suggested that frog tadpoles exposed to the antibacterial agent exhibit changes through prometamorphosis. In a recent study, Fort et al. (2010) exposed premetamorphic Xenopus laevis tadpoles to triclosan for 21 days into prometamorphosis. This work, published in Toxological Sciences (Fort et al., 2010), stated that environmentally relevant TCS concentrations do not alter the normal course of thyroid-mediated metamorphosis in this standard anuran model. Herein, we describe the apparent discrepancy between these two studies, and on examination of the data presented in the study of Fort et al. (2010), we do not come to the same conclusion that triclosan had no effects on metamorphosis. Fort et al. (2010) stated that “larval developmental stage at exposure day 21 was not significantly different from controls based on observed parameters.” A major indicator of exposure effect is progression through the developmental stages as defined by Nieuwkoop and Faber (NF; Nieuwkoop and Faber, 1994). The relevant stages in the study are between NF stages 54 and 66; the range of stages attained by NF stage 51 tadpoles after 21 days of exposure. Even though these are numerical stages, they are categorical, defined by distinctive morphological characteristics. The number of tadpoles that were at these stages was reported in Table 3 of the study of Fort et al. (2010), and chi-square analysis was performed. The authors stated that “Overall, the frequency of each developmental stage in each of the treatment concentrations following 21 days of exposure to TCS was not significantly different from each other (chi-square, p = 0.319).” It was not clear how the analysis was done, but using the same data as presented in Table 3 in the study of Fort et al. (2010) in a 9 × 5 contingency table with NF 54–56, 63–64, and 65–66 stages grouped and all other stage categories kept separate gave a chi-square = 48.7, p = 0.029, degrees of freedom = 32. In addition, a pairwise 7 × 2 contingency table comparison of the control with each of the TCS treatments individually gave the results shown in Table 1. Chi-square analysis of NF developmental stage frequency attained by Xenopus laevis tadpoles at day 21 of TCS exposure. The frequency data was presented originally in Table 3 of Fort et al. (2010) Note. The NF 54–56 and 57 groups were not considered for this analysis because these groups contained values of zero. Chi-square analysis of NF developmental stage frequency attained by Xenopus laevis tadpoles at day 21 of TCS exposure. The frequency data was presented originally in Table 3 of Fort et al. (2010) Note. The NF 54–56 and 57 groups were not considered for this analysis because these groups contained values of zero. Therefore, the data presented by Fort et al. (2010) do indeed show that TCS at the three lower exposure concentrations had an effect on the postembryonic development of X. laevis tadpoles. This is consistent with our observations with the bullfrog (Veldhoen et al., 2006.). Moreover, the authors observed that tails from stage-matched NF 60 tadpoles showed significantly elevated thyroid hormone receptor β (TRβ) transcript levels in the two middle concentrations examined. The 1.5-fold increase observed relative to the control animals was interpreted as “likely not biologically significant,” and the authors point to a lack of concentration dependence of the TCS exposure on altered transcript abundance. Putting this information in context, TRβ transcript levels increase in the tadpole tail by approximately sevenfold between NF stages 54 and 60 (Wagner and Helbing, 2005). This implies that instead of the usual approximately sevenfold increase apparent in untreated animals, TCS-exposed Xenopus tadpoles showed a ∼10-fold increase. Such an increase in abundance of the TRβ transcript is highly suggestive of an accelerated metamorphosis program, and thus, the study of Fort et al. (2010) again supports the observation of a biological effect upon tadpole development following exposure to TCS. The changes in TRβ transcript levels noted by the authors are reminiscent of an “inverted U” response curve characteristic of an endocrine disruptor exposure event (Welshons et al., 2003). The lack of a concentration-dependent response at the time point examined referred to in the study abstract does not necessarily imply a lack of biological response. In summary, the overall conclusion and title of the study of Fort et al. (2010) does not properly reflect the data presented. Rather, the fact that the authors did not observe a change in thyroxine levels or thyroid histology, but did record changes in molecular and developmental endpoints, is useful in determining the mode of action of TCS on amphibian metamorphosis.

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