Total gadolinium tissue deposition and skin structural findings following the administration of structurally different gadolinium chelates in healthy and ovariectomized female rats

Abstract

Objective: To assess the retention of gadolinium (Gd) in skin, liver, and bone following gadodiamide or gadoteric acid administration.

Methods: Gd was measured in skin, liver and femur bone in female rats 10 weeks after administration of 17.5 mmol Gd/kg over 5 days of Gd agents. Rat skin microscopy, energy filtering transmission electron microscopy and elemental analysis were performed, and repeated after receiving the same dosage of gadodiamide in rats with osteoporosis induced with bilateral ovariectomy (OVX). The OVX was performed 60 days after the last injection of gadodiamide and animals sacrificed 3 weeks later.

Results: Gd concentration was 180-fold higher in the skin, 25-fold higher in the femur, and 30-fold higher in the liver in rats received gadodiamide than rats received gadoteric acid. The retention of Gd in the skin with gadodiamide was associated with an increase in dermal cellularity, and Gd encrustation of collagen fibers and deposition inside the fibroblasts and other cells. No differences in Gd concentration in liver, skin, and femur were observed between rats receiving gadodiamide with or without OVX.

Conclusions: Gd tissue retention with gadodiamide was higher than gadoteric acid. Tissues Gd deposition did not alter following gadodiamide administration to ovariectomized rats.

Keywords: Gadolinium (Gd); bone deposition; osteoporosis; skin; ultrastructural.

Figure 1

Phase one study. Total gadolinium concentration (nmol/g, by ICP-MS measurement) observed in liver (A), skin (B) and bone (C) samples of rats receiving saline (control), gadodiamide or gadoteric acid. Significant higher concentration was noted in the liver, skin, and bone (femur) of the rats following gadodiamide administration than following gadoteric acid administration. ***, P<0.001 vs. other groups. Gd, gadolinium.

Figure 2

Phase 1 study. HE histology (original magnification, ×200). (A) Saline-treated rats showed normal collagen fibril density; (B) gadoteric acid and (C) gadodiamide induced spindle cell and stellate cell hyperplasia, and resulted in denser collagen fibril. The gadodiamide-treated rats show thicker epidermis layer and more abundant and denser collagen fibril than the gadoteric acid treated rats.

Figure 3

Phase 1 study. HE histology (original magnification, ×200) shows thickness of epidermis layer in saline treated rat (A), gadoterate meglumine treated rat (B), gadodiamide treated rat (C). Gadodiamide treated rats have the thickest epidermis layer, followed by the gadoterate meglumine treated rats. Saline treated rats show normal epidermis layer thickness.

Figure 4

Phase 1 study. EM reveals alterations of collagen fibres and lysosomal Gd deposition in the gadodiamide treated rats. (A) Collagen fibre diameter variation in a collagen bundle without abnormalities in the fibre profile. Note one fibre with Gd³⁺ incrustations (circle represents the area analysed by the EELS elemental analysis); (B) example of a collagen bundle with typical distribution of some collagen fibres surrounded by “halo” formation, overview; (C) detail showing the extend of the “halo” phenomenon including three collagen fibres and one with a dark Gd³⁺ deposition; (D) longitudinal section of a collagen fibre with dark Gd incrustation displaying a fuzzy filamentous texture; (E) corresponding recorded EELS spectrum from the area encircled in image D confirming Gd³⁺ content in the analyzed deposition (red = recorded sample spectrum; green = Gd reference spectrum); (F) example of multiple lysosomal Gd³⁺ rich inclusions with granular texture in perifollicular smooth muscle cells. Gd, gadolinium; EELS, electron energy loss spectroscopy.

Figure 5

Phase 2 study. Total Gd³⁺ concentration (nmol/g, ICP-MS measurement) in liver (A), skin (B); and bone (C) samples of rats receiving gadodiamide with or without OVX and of control rats. OVX, ovariectomy; Gd, gadolinium.

Figure 6

Phase 2 study. HE histology (original magnification, × 200) shows normal collagen fibril density under the epidermis layer in (A), obtained from saline-treated rats underwent OVX. Both in gadodiamide only (B) and in gadodiamide + OVX -treated rats (C), -treated rats, spindle cell and stellate cell hyperplasia were found, resulting in denser collagen fibril. OVX, ovariectomy.

Figure 7

Phase 2 study. HE histology (original magnification, ×200) shows the thickness of epidermis layer in a saline treated rat underwent OVX (A), a gadodiamide treated only rat (B), and a gadodiamide + OVX treated rat (C). Saline treated rat underwent OVX show normal epidermis layer thickness, while gadodiamide treated only rat and gadodiamide + OVX treated rat have similarly thickened epidermis layer. OVX, ovariectomy.

Figure 8

Phase 2 study. EM findings in gadodiamide treated rat and gadodiamide + OVX rat. EM shows Gd³⁺ deposits associated mainly with dermal collagen and elastic fibres, and some fibroblasts. (A) High power magnification displays the filamentous texture of the collagen fibre Gd³⁺ incrustation in a gadodiamide + ovariectomy treated rat; (B) example of an elastic fibre with dark Gd³⁺-rich deposition in a gadodiamide only treated animal; (C) multiple dark lysosomal granular Gd³⁺ deposits in fibroblasts of a gadodiamide + ovariectomised rat; (D) elemental mapping by the ESI method (red = Gd³⁺, green = Fe^2+/3+) revealed the spatial Fe^2+/3+ and Gd³⁺ colocalization in the lysosome of fat associated cells; (E,F) documentation of corresponding recorded positive Fe and Gd EELS spectra of the lysosomal inclusion mapped in image D. Gd, gadolinium; EELS, electron energy loss spectroscopy.