Intravenous Sodium Iodate Administration Induces Macula-Specific RPE Damage and Rod-Dominant Apoptosis in the Cynomolgus Monkey

Abstract

Purpose: Although sodium-iodate (SI)-induced retinal degeneration has been extensively studied in rodent models, its macular pathology and cone/rod vulnerability difference remains elusive. This study aims to characterize SI-induced macular pathology in cynomolgus monkeys.

Methods: Intravenous injections of SI were performed on four male cynomolgus monkeys including three young adults (Animal No. 1-3; five to six years old) and one juvenile (Animal No. 4; two years old) from a breeding colony. To optimize dosing, Animal No. 1 received 25 and 37.5 mg/kg SI; Animal No. 2 received a single SI dose (30 mg/kg) to confirm reproducibility. Animal No. 3 was used to examine subclinical effects at a lower dose (25 mg/kg). Animal No. 4 received increasing doses (30, 35, and 40 mg/kg). Retinal changes were evaluated using fundus photography, fluorescein angiography (FA), and optical coherence tomography (OCT). Histological analysis and transmission electron microscopy (TEM) were also performed.

Results: In Animal No. 1, prominent fluorescein leakage by FA and RPE elevation on OCT was observed in the macula after 37.5 mg/kg SI. Histology and TEM revealed that elevated RPE lesion was accompanied by significant RPE migration. Animal No. 2 exhibited similar retinal degeneration. Animal No. 3 exhibited no RPE barrier disruption but showed outer segment damage and RPE melanolipofuscin accumulation. Animal No. 4 showed minimal macular degeneration despite escalating doses. In the peripheral retina, rod apoptosis was evident, whereas macular cone cell death was limited even at high doses.

Conclusion: Systemic SI administration can induce macular degeneration with RPE barrier disruption in young-adult monkeys, supporting a macula- and cell-type-specific vulnerability.

Figure 1.

Fundus imaging and histopathology in a young adult cynomolgus monkey following intravenous injections of SI (Animal No. 1): Fundus photography (A, B, E, F), FA (C, D, G, H), and OCT (I–L) before and after intravenous administration of SI at a dose of 25 mg/kg on Days 0/7 and 37.5 mg/kg on Day 28. A whitish submacular lesion was observed in fundus photography from Day 37 to 58 (E and F). FA revealed fluorescein leakage and window defect (G and H). Decreased SW-FAF was observed in the macula (M). OCT detected an elevation of the RPE layer (I–L). Toluidine blue staining shows the histological features of the macula (N). The parafoveal region exhibited proliferation of migrating cells under the RPE (O), and some pigmented cells were also observed in the subretinal space (arrows in P). TEM revealed shortened, degenerated OS in the fovea (Q). Numerous migrating cells, both pigmented and non-pigmented, were observed between the elevated RPE and Bruch's membrane in the parafoveal region (R). BrM, Bruch's membrane; CC, choriocapillaris; ECM, extracellular matrix; IS, inner segment; OS, outer segments. Asterisk shows enucleation.

Figure 2.

Fundus imaging and histopathology in a young adult monkey after 30 mg/kg SI administration (Animal No. 2). Fundus photography (A–C), FA (D–F), SW-FAF (G and H), and OCT (I and J) before and after intravenous injections of 30 mg/kg SI on Day 0. Toluidine blue staining revealed foveal changes, including the RPE elevation and underlying migrating cells (K and L, see double arrowheads). TEM further showed OS degenerated and migrating cells locating between the RPE and Bruch's membrane in the fovea (see asterisk and double arrowheads in M). Cone photoreceptor morphology was relatively preserved (L and N). CC, choriocapillaris; IS, inner segment; OS, outer segments. Asterisk shows enucleation.

Figure 3.

Histopathology in a young adult monkey following intravenous injections of low-dose SI (Animal No. 3). Toluidine blue staining showed a preserved retinal structure in the fovea (A). TEM revealed that cone cell morphology in the fovea was kept intact (B). Vacuolation of OS were observed in the fovea (C). Melano-lipofuscin and vacuolations were observed in the RPE under the fovea (D and E). Asterisk shows enucleation.

Figure 4.

Histological findings in the peripheral retina from young adult monkeys (Animal No. 2 and No. 3): Cross-sections obtained from the peripheral retina of young adult monkeys (Animals No. 2 and No. 3) are shown. Apoptotic photoreceptor nuclei were frequently observed in the peripheral retina in Animal No. 3 following low-dose SI injections (25 mg/kg) (A and B). TEM demonstrated chromatin condensation and cellular shrinkage of rod photoreceptors (arrows in C), whereas OS structure was relatively preserved (D). Histological images of peripheral retinal sections from Animal No. 2 after a high dose (30 mg/kg) SI (E and F). Disruption of the external limiting membrane was observed, along with necrotic morphology of photoreceptors (arrows in G). OS damage was more severe compared to the low-dose group (H).

Figure 5.

Fundus imaging of a juvenile monkey after SI administration (Animal No. 4): Fundus photography (A–C), FA (E–G), SW-FAF (G and H), and OCT (I and J) before and after intravenous injections of 30, 35, and 40 mg/kg SI on Day 0, 14, and 28, respectively. Local pigmentary changes and the window defects were observed within the fovea (A–H). SW-FAF on Day 41 showed a decreased fundus autofluorescence compared to pretreatment conditions. Asterisk shows enucleation.