Fort DJ et al. (2023), Influence of systemic copper toxicity on early ...

XB-ART-59320

J Appl Toxicol 2023 Mar 01;433:431-445. doi: 10.1002/jat.4393.

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Influence of systemic copper toxicity on early development and metamorphosis in Xenopus laevis.

Fort DJ , Todhunter KJ , Wolf JC , Long K , Poland CA , McGrath M , Baken S , Mackie C .

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The primary objective of the present study was to examine the influence of early systemic toxicity resulting from copper (Cu) exposure on metamorphic processes in Xenopus laevis. A 28-day exposure study with copper, initiated at developmental stage 10, was performed using test concentrations of 3.0, 9.0, 27.2, 82.5, and 250 μg Cu/L. The primary endpoints included mortality, developmental stage, embryo-larval malformation, behavioral effects, hindlimb length (HLL), growth (snout-vent length [SVL] and wet body weight), and histopathology. The 28-day LC50 value with 95% confidence intervals was 61.2 (51.4-72.9) μg Cu/L with 250 μg Cu/L resulting in complete lethality. Developmental arrest in the 82.5 and delay in the 27.2 μg Cu/L treatments was observed as early as study day 10 continuing throughout the remainder of exposure. SVL-normalized HLL, body weight, and SVL in the 27.2 and 82.5 μg Cu/L treatments were significantly decreased relative to control. At 82.5 μg Cu/L, and thyroid gland size was markedly reduced when compared with controls consistent with the stage of developmental and growth arrest. Concentration-dependent findings in the intestine, liver, gills, eyes, and pharyngeal mucosa were consistent with non-endocrine systemic toxicity. These were prevalent in the 9.0 and 27.2 μg Cu/L treatment groups but were minimally evident or absent in the 82.5 μg/L group, which was attributed to developmental arrest. In conclusion, developmental delay in larvae exposed to 27.2 and 82.5 μg Cu/L was the result of systemic toxicity occurring in early development prior hypothalomo-pituitary-thyroid axis (HPT)-driven metamorphosis and was not indicative of endocrine disruption.

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Species referenced: Xenopus laevis
GO keywords: response to toxic substance [+]

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	FIGURE 1 Effects of 28-day Cu exposure initiated at Nieuwkoop and Faber stage 10 on survival in X. laevis. The 28-day LC50 with 95% confidence interval provided in text box.
	Effects of 28-day Cu exposure on development and growth in X. laevis. From top to bottom: 0.00 (control), 3.0, 9.0, 27.2, and 82.5 μg Cu/L

	FIGURE 4 Effect of 28-day Cu exposure on hindlimb length (mm). Data points represent mean ± SEM. Gray coloration represents significant decreasing trend (Jonckheere–Terpstra test, p = 0.0034).
	FIGURE 5 Effect of 28-day Cu exposure on SVL-normalized hindlimb length. Data points represent mean ± SEM. Gray coloration represents significant decreasing trend (Jonckheere–Terpstra test, p = 0.0034).
	FIGURE 6 Effect of 28-day Cu exposure on SVL. Data points represent mean ± SEM. Gray coloration represents significant decreasing trend (Jonckheere–Terpstra test, p = 0.0162).
	FIGURE 7 Effect of 28-day Cu exposure on wet body weight. Data points represent mean ± SEM. Gray coloration represents significant decreasing trend (Jonckheere–Terpstra test, p = 0.0092).
	FIGURE 8 (A) Thyroid from a control tadpole. (B) Thyroid from a tadpole exposed to 9.0 μg Cu/L. (C) Thyroid from a tadpole exposed to 27.2 mg Cu/L. (D) Left and right thyroids from a tadpole exposed to 82.5 μg Cu/L. (E) Eye from a control tadpole (a = anterior chamber, c = cornea, l = lens, p = posterior chamber, r = retina). (F) Eye from a tadpole exposed to 27.2 μg Cu/L. A–D, bar = 25 mm. E–F, bar = 100 mm.
	FIGURE 9 (A) Gill from a control tadpole. (B) Gill from a tadpole exposed to 27.2 mg Cu/L. (C) Liver from a control tadpole. (D) Liver from a tadpole exposed to 27.2 μg Cu/L. (E) Small (s) and large (l) intestines from a control tadpole. (F) Small (s) and large (l) intestines from a tadpole exposed to 27.2 μg Cu/L. A–D, bar = 25 mm. E–F, bar = 50 mm.