Dioxin Exposure Alters Molecular and Morphological Responses to Thyroid Hormone in Xenopus laevis Cultured Cells and Prometamorphic Tadpoles

Abstract

Amphibian metamorphosis is driven by thyroid hormone (TH). We used prometamorphic tadpoles and a cell line of the African clawed frog (Xenopus laevis) to examine immediate effects of dioxin exposure on TH. Gene expression patterns suggest cross-talk between the thyroid hormone receptor (TR) and aryl hydrocarbon receptor (AHR) signaling pathways. In XLK-WG cells, expression of Cytochrome P450 1A6 (cyp1A6), an AHR target, was induced 1000-fold by 100 nM TCDD (2, 3, 7, 8 tetrachlorodibenzo-p-dioxin). Kru ¨ppel-Like Factor 9 (klf9), the first gene induced in a cascade of TH responses tied to metamorphosis, was upregulated over 5-fold by 50 nM triiodothyronine (T3) and 2-fold by dioxin. Co-exposure to T3 and TCDD boosted both responses, further inducing cyp1A6 by 75% and klf9 about 60%. Additional canonical targets of each receptor, including trba and trbb (TR) and udpgt1a (AHR) responded similarly. Induction of TH targets by TCDD in XLK-WG cells predicts that exposure could speed metamorphosis. We tested this hypothesis in two remodeling events: tail resorption and hind limb growth. Resorption of ex vivo cultured tails was accelerated by 10 nM T3, while a modest increase in resorption by 100 nM TCDD lacked statistical significance. Hind limbs doubled in length over four days following 1 nM T3 treatment, but limb length was unaffected by 100 nM TCDD. TCDD co-exposure reduced the T3 effect by nearly 40%, despite TCDD induction of klf9 in whole tadpoles, alone or with T3. These results suggest that tissue-specific TCDD effects limit or reverse the increased metamorphosis rate predicted by klf9 induction.

Natural toxic impact and thyroid signalling interplay orchestrates riverine adaptive divergence of salmonid fish

“…As it was described in killifish dwelling in the dioxin‐polluted water bodies, the toxic resistance may be promoted via the aryl hydrocarbon receptor (AhR) pathway (Reid et al., 2018). Noteworthy that activity of AhR and its biotransformation protein factors responsible for binding of flavonoids and terpenoids (Denison & Nagy, 2003) depends upon the activity of thyroid hormone receptors which is determined by the T 3 content (Occhi et al., 2015; Taft et al., 2018; Vrzal et al., 2017). Therefore, intensification of the thyroid signalling activity seems an essential adaptation at sites within the coniferous forest zone.…”

Differences in responsiveness and sensitivity to exogenous disruptors of the thyroid gland in three anuran species

“…There is a constitutive expression of the deiodinase and high expression of TRα in hind limbs during premetamorphosis explaining the acceleration of limb development (Cai & Brown, ) as was observed in the three species studied. Tail resorption and hind limb growth has been used to quantify endocrine disruption although both events have a complex sensitivity/responsiveness to thyroid‐active substances (Taft, Colonnetta, Schafer, Plick, & Powell, ; Yaoita, ). Yaoita () described in Xenopus the mechanisms of differential expression of TRα mRNA at high and low levels of T4 in the hindlimbs and the tail of young tadpoles, respectively.…”

Unexpected metabolic disorders induced by endocrine disruptors in Xenopus tropicalis provide new lead for understanding amphibian decline

“…For the case of direct exposure to TCS, the observed developmental effects may be due to TCS's immediate impact on thyroid hormone levels (73), while BaP exposure may cause indirect effects through Ah-R cross talk with the thyroid hormone receptor (74). However, since F 1 animals were exposed to EDs only at the gamete stage, a similar explanation for the observed transgenerational impacts is less obvious.…”