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An Overview on the Toxic Morphological Changes in the Retinal Pigment Epithelium after Systemic Compound Administration

¹ ALTANA Pharma AG, Institute of Preclinical Drug Safety, Hamburg 22885, Germany
² University of Tuebingen, Section of Experimental Vitreoretinal Surgery, Tuebingen 72074, Germany

Correspondence: Address correspondence to: Lars Mecklenburg, Veterinary Pathologist ALTANA Pharma AG, Institute of Preclinical Drug Safety, Haidkrugsweg 1, 22885 Barsbuettel, Germany; e-mail:lars.mecklenburg{at}altanapharma.com

	Abstract

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Many medications that are administered systemically for nonocular conditions may evoke ocular toxicological complications. Therefore, the eye is routinely investigated histopathologically in preclinical in vivo toxicity studies. The retinal pigment epithelium is a likely target for systemically administered compounds, since the underlying choroid is highly vascularized. The specialized pigment epithelium has numerous functions that all maintain the integrity and function of photoreceptors. Consequently, toxic effects on the pigment epithelium will eventually affect the neural retina. The potential of pigment epithelial cells to respond to toxic injury is limited, but a standardized terminology to describe its morphological changes does not exist in the scientific literature. Detailed morphologic analysis, however, might allow early detection of retinotoxicity and may provide evidence on the underlying pathomechanism. We here review toxic effects on the pigment epithelium focusing in particular on the morphology of toxic cell injury. Morphological changes comprise hypertrophy, intracytoplasmic accumulation of cellular components, loss of cell polarity, degeneration, metaplasia, and formation of subretinal membranes. Some of these changes are reversible whereas others are permanent, leading to impaired function of the pigment epithelium and eventually to photoreceptor loss and retinal atrophy.

Key Words: Retina • RPE • eye • subretinal • ocular toxicity

Abbreviations: ARMD, age-related macular degeneration • GES, guanidinoethyl sulfonate • PCNA, proliferating cell nuclear antigen • POS, photoreceptor outer segments • RCS, Royal College of Surgeons • RPE, retinal pigment epithelium

	Introduction

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The blood-retinal barrier prevents many systemically administered drugs from entering the eye via the circulatory system. Yet many medications that are administered systemically for nonocular conditions may still gain access to the eye and evoke ocular toxicological complications (Zinn and Greenseid, 1975; Koneru et al., 1986; Scroggs and Klintworth, 1994). The mechanisms by which these toxins exert their harmful effects on the eye are varied and in most cases remain poorly understood (Meier-Ruge, 1973; Scroggs and Klintworth, 1994). In man, ocular toxicity associated with systemic drug therapy can result in retinal degeneration (Moorthy and Valluri, 1999), although it most frequently comprises visual disturbances including decreased visual acuity, impaired color perception, visual field defects, scotomata, night blindness, visual perseveration beyond the physiological afterimage (palinopsia), and an illusory movement of the physical environment (oscillopsia) (Scroggs and Klintworth, 1994). Sildenafil, for example, inhibits phosphodiesterase-5 activity, and is associated with transient visual symptoms, typically blue tinge to vision, photophobia light, and blurry vision (Marmor and Kessler, 1999; Laties and Sharlip, 2006).

To detect the potential for retinal toxicity, the eye is routinely investigated clinically and histopathologically in pre-clinical toxicity studies conducted in rodent and nonrodent species (Heywood and Gopinath, 1990; Kuiper et al., 1997; Whiteley and Peiffer, 2002). Non-inflammatory degenerative changes in the retina are generally described as retinal atrophy (Greaves and Faccini, 1984; Whiteley and Peiffer, 2002). Whereas the end stage of retinal degeneration is morphologically uniform, early stages may exhibit distinct morphological abnormalities that may provide evidence for the underlying pathomechanism. This is particularly true for the retinal pigment epithelium (RPE). To our knowledge, there is no harmonized nomenclature in terms of morphological abnormalities in the RPE, making it difficult to compare different studies with each other.

Moreover, morphological abnormalities in RPE cells cannot be assessed in terms of their functional relevance, since little is known about their pathogenesis, their involvement in disease process, and ultimately in regeneration. A more precise evaluation of RPE pathology might therefore allow a better understanding in terms of pathogenesis and relevance for human risk assessment. Finally, a precise knowledge of RPE pathology may allow earlier recognition of substance-related effects, since retinal atrophy is a late stage disease process whereby photoreceptor cells are lost. We here provide a detailed description of the various forms of drug-induced RPE pathology, providing the reader with an accurate terminology to describe morphological lesions in the RPE.

	Embryology, Anatomy, and Function of the Pigment Epithelium

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The RPE derives embryologically from the same neural anlage as the neural retina, but is differentiated into a secretory epithelium (Marmorstein et al., 1998). It is a monolayer of cuboidal cells that is closely associated with the rod and cone photoreceptors, separating them from the capillary bed of the choroid (Bok, 1993). The developing RPE cells slowly increase in number throughout fetal development; after birth however, they only increase in size to cover the increased surface area. Mitoses are not seen after birth, and under normal circumstances, the RPE does not undergo cell division (Rizzolo, 1997).

Each RPE cell is differentiated into an apical portion facing the photoreceptors, and a basal portion that is situated on Bruch’s membrane (Bok, 1993). The apical side has numerous long microvilli, whereas the basal side shows large infoldings (Figure 1). Apical and basal membranes of RPE cells are distinct with respect to receptoral and ion channel properties (Mamorstein, 2001). In differentiated RPE cells, the electrogenic sodium-potassium pump (Na/K-ATPase) is primarily expressed on the apical membrane (Rizzolo, 1990; Ruiz et al., 1996), whereas the chloride-bicarbonate exchange transporter is located at the basolateral membrane (Lin and Miller, 1994). RPE cells are usually characterized by melanin-containing organelles, i.e., melanosomes (Boulton, 1998; Schraermeyer and Heimann, 1999). Mature melanosomes are located at the apical cell surface, often within microvilli (Figure 1).

View larger version (226K): [in this window] [in a new window]   Figure 1 Normal morphology of a retinal pigment epithelial cell (RPE) and its association with the choriocapillaris (CH) and the photoreceptor outer segments (POS). Note Bruch’s membrane (B), melanosomes (M), lysosomes (L), apical microvilli (V), and cell nucleus (N). Healthy adult Cynomolgus macaque. Eye fixed in glutaraldehyde and embedded in epon. Ultrathin section photographed by transmission electron microscopy. Original magnification: 5,040x.

With regard to their functions and their capacity, RPE cells are virtually unique among all epithelia of the body. They have no photoreceptive or neural function, but are necessary for the support and viability of the photoreceptors (Bok, 1993; Marmor, 1998).

The RPE serves various functions that are based on its physical and biochemical properties (Table 1). Beside absorption of stray light, adhesion between neural retina and choroid, and secretion of various growth factors, the most important functions are (i) synthesis and maintenance of the interphotoreceptor matrix, (ii) photoreceptor membrane turnover, and (iii) retinoid metabolism (Bok, 1993). These functions are briefly discussed next (for review see Strauss, 2005).

These metabolites (such as glucose, nutrients, and retinol) are required by photoreceptors and are transported to the apical surface by special intracellular carrier proteins. The described differences between the apical and basolateral membranes allow net movement of Na⁺, K⁺, HCO^–₃, and water from the subretinal space into the choroid, and net movement of Cl^– from the choroid into the subretinal space (reviewed in Strauss, 2005). Carbonic anhydrase regulates the intracellular HCO^–₃ concentration and thus determines the intracellular pH (Wolfensberger, 1999). Transport of ions is not only required for the long-term maintenance of the interphotoreceptor matrix, but also facilitates spatial buffering of fast occurring changes in the ion composition of the subretinal space, induced by light-absorption (Steinberg, 1985).

Photoreceptor Membrane Turnover
To prevent large fluctuations in rod length, old discs are lost from the tips of the outer segment by phagocytic activity of the RPE (Bosch et al., 1993; Bok, 1993). Recognition signals that subserve outer segment shedding and phagocytosis are still obscure (Bok, 1988), but involve _V β₅-integrin (Finnemann et al., 1997), macrophage scavenger receptor CD36 (Finnemann and Silverstein, 2001), and the receptor tyrosine kinase c-mer (D’Cruz et al., 2000). Packets of discs are engulfed and transported as phagosomes to cytoplasmic sites where they fuse with lysosomal granules and are degraded within a few hours (Feeney-Burns et al., 1988). Some of these breakdown products may be recycled, while others are voided into the choriocapillaris via Bruch’s membrane. Any undigested residual bodies remain as lipofuscin, which is a pigment that accumulates in various postmitotic cells exposed to high oxidative stress, such as neurons and myocytes. In the RPE therefore, lipofuscin presumably derives from peroxidation of polyunsaturated fatty acids originating from the photoreceptor outer discs. It is not extruded from the cell but slowly accumulates and finally occupies a considerable part of the cell volume in elderly individuals (Schraermeyer and Heimann, 1999) (Figure 5a).

View larger version (411K): [in this window] [in a new window]   Figure 5 Lipofuscin deposition in RPE cells (arrows). POS = photoreceptor outer segments, CH = choroid. (a) 50-year-old man with age-related lipufuscin accumulation. Autofluorescence. (b) 4-year-old Cynomolgus macaque treated with an unspecified mild retinotoxic agent for 4 weeks. Autofluorescence. Eyes fixed in formalin and embedded in paraffin.

	Spontaneous Pathology of the Pigment Epithelium

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Photoreceptors, particularly the rods, are lost during aging. However, the ratio of photoreceptors to RPE cells remains largely the same, suggesting a parallel loss of these closely apposed cells (Gao and Hollyfield, 1992). Due to this close relationship, morphological or clinical distinction between RPE and photoreceptor dysfunction is often impossible. A number of spontaneous diseases in mammals are associated with RPE pathology that comprises the following morphological features.

Hypertrophy (i.e., increased cell size, due to an increase in intracellular structural components) of the RPE can occur for no apparent reason and without any clinical impact. Congenital hypertrophy of the RPE is a common finding in man with familial adenomatous polyposis of the intestine (Lloyd et al., 1990; McKay, 1993) or neuroepithelial tumors in the central nervous system (Munden et al., 1991). In all species, hypertrophy of the RPE is commonly associated with detachment of the neural retina, or with trauma leading to photoreceptor loss. This RPE pathology is clinically known as "pseudoretinitis pigmentosa" (Lee, 2002). Injured RPE cells exhibit retraction of pigment granules from the cell apices and become rounded (Fite et al., 1985). Although it is believed that RPE cells are postmitotic and cannot be replaced, trauma and detachment are well known to result in hyperplasia (i.e., an increase in cell number) (Kalnins et al., 1995; Lee, 2002; Men et al., 2003). RPE cells can proliferate, but they may also migrate into the subretinal space or undergo metaplasia to fibroblasts or osteoblasts (Lee, 2002; Toyran et al., 2005).

As a consequence of fibroblastic metaplasia, the pigment epithelium may form a multilayered accumulation of RPE cells, known as epiretinal or subretinal membranes (Grierson et al., 1994). Dedifferentiation of RPE cells and metaplasia, also known as epithelial-mesenchymal transition, involves TGF-β/Smad-signaling (Saika et al., 2004), as well as expression of bone morphogenetic proteins and growth differentiation factor (Toyran et al., 2005). RPE metaplasia and proliferation may complicate rhegmatogenous retinal detachment and may lead to proliferative vitreoretinopathy, a serious complication of retinal detachment in man (Kirchhof and Sorgente, 1989).

Morphologic changes in the RPE (such as those described above) are frequently involved in hereditary retinopathies in man and animals. In man, this diverse group of clinical entities with progressive degeneration of rods and cones and a secondary involvement of the RPE is referred to as "retinitis pigmentosa" (Lee, 2002). Similar diseases known as "progressive retinal atrophy" or "photoreceptor dysplasia" exist in animals such as dogs, cats, monkeys and rodents (Aguirre et al., 1998). As in man, the RPE only shows changes in advanced stages of the disease process. A classic example of an inherited retinal dysplasia is the "Royal College of Surgeons" (RCS) rat. These animals carry a spontaneous mutation in the Mertk gene that encodes for the receptor tyrosine kinase c-mer, which is crucial for phagocytosis of shed outer segments (Vollrath et al., 2001). Consequently, RPE cells of RCS rats are unable to phagocytize outer segment membranes and lack phagosomes, leading to photoreceptor loss and retinal dystrophy (Herron et al., 1969; Strauss et al., 1998).

Another characteristic morphologic finding in RPE cells is the accumulation of normal or abnormal cellular components. Those components may be mucopolysaccharides or glycoproteins, such as in inherited storage diseases, or lipofuscin. The latter occurs in hereditary and acquired diseases of various species, such as retinal pigment epithelial dystrophy in dogs (Aguirre et al., 1998), and is a normal feature of aging, particularly in primates (Dorey et al., 1989).

Age-related macular degeneration (ARMD) is an important RPE-related cause of visual deterioration in aging man (Garner et al., 1994). Although oxidative stress is thought to play an important role in the pathogenesis of AMRD, its development is still poorly understood. RPE cells either degenerate, or they are hypertrophic and hyperplastic, often with loss of melanin and intracellular accumulation of lipofuscin (Garner et al., 1994). Necrotic RPE cells, with massive lipofuscin content, are discharged into the subretinal space, and gaps within the RPE layer may result. Cells that are shed into the subretinal space may retain RPE characteristics, such as tight junctions with the overlaying cells, stubby microvilli, and abundant smooth endoplasmic reticulum, which distinguish them from macrophages (Ishikawa et al., 1983).

One characteristic of ARMD is the formation of deposits between the RPE cell basal membrane and the inner collagenous layer of Bruch’s membrane. These deposits are known either as basal linear deposits, "soft drusen" or "hard drusen" (colloid bodies), depending on their size (Garner et al., 1994; Hageman and Mullins, 1999; Russell et al., 2000). They are composed of numerous extracellular matrix components, such as vitronectin, apolipoprotein E, complement proteins and amyloid proteins (Mullins et al., 1997; Hageman et al., 1999; Mullins et al., 2000; Anderson et al., 2004) and likely result from cellular remnants and debris derived from degenerated RPE cells. This may induce local inflammation and finally lead to choroidal neovascularization (Anderson et al., 2002). In addition to RPE cell pathology, inner and outer segments of photoreceptors are gradually lost, and the outer nuclear layer is eventually replaced by glial cells (Garner et al., 1994).

Drusen-like bodies and a macular pigmentary anomaly may occur spontaneously in the eye of Rhesus and Cynomolgus macaques (Fine and Kwapien, 1978; El-Mofty et al., 1980, Feeney-Burns et al., 1981; Stafford et al., 1984; Ulshafer et al., 1987; Engel et al., 1988). The incidence is reported to be between 6% and 84%, clearly increasing with age (Fine and Kwapien, 1978). Beside the typical drusen, vacuolated and lipid-laden RPE cells ("lipoidal degeneration") are found, which can be detected by indirect ophthalmoscopy as yellowish-white irregular dots of variable size.

	Toxic Effects on the Pigment Epithelium

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Toxic compounds affecting the retina can be subdivided into those primarily affecting the photoreceptors or ganglion cells and those affecting the pigment epithelium (Heywood, 1982; Heywood and Gopinath, 1990). However, since the RPE is closely associated with the photoreceptors, damage to the rods and cones will also affect RPE cells (and vice versa), and determination of the primary target cell may be impossible. In addition, not all functional impairments of the RPE will result in significant morphological alterations, suggesting that sophisticated electrophysiological methods need to be applied in order to detect very early stages of toxicity.

Although ocular structure and function are similar between mammalian species, differences in ocular anatomy should be taken into account when choosing an animal species for pre-clinical toxicity testing. For example, vascularization—and hence blood flow—differs significantly between mammalian species (Buttery et al., 1990). Moreover, the retinal organization into macula and fovea is restricted to primates (Provis, 2001). In fact, there are large topographical differences in RPE pathology throughout the ocular fundus, both in spontaneous and in toxic diseases (Aguirre et al., 1998).

Another complication of preclinical toxicity testing in animals is the fact that dogs, but not primates, rodents or swine, have a tapetum lucidum, a focally extensive specialized structure within the choroid that improves night vision. Some xenobiotics induce toxicity of tapetal cells that secondarily affects the RPE (Heywood and Gopinath, 1990; Dillberger et al., 1996; Aguirre et al., 1998), and further challenges risk assessment for humans. Finally, the anatomy of Bruch’s membrane varies between species, being poorly defined in the dog (Aguirre et al., 1998).

Pigmentation of the eye may also affect the outcome of toxicity testing, since many compounds show significant affinity to melanin and therefore accumulate in the pigmented compartments of the eye, particularly the RPE (Leblanc et al., 1998). Binding to melanin, however, is not predictive of ocular toxicity. In fact, some drugs, such as vigabatrin (Butler et al., 1987) are detoxified by melanin binding, whereas others may accumulate in the eye and exert intrinsic toxicity (Eves et al., 1999; Dayhaw-Barker, 2002). Drugs that bind to melanosomes can alter their ion composition (particularly the concentration of calcium) and their morphology, resulting in the expulsion from RPE cells (Schraermeyer, unpublished data).

There is a large variety of different coumpounds that affect the retina after systemic administration, associated with particular morphological alterations of the pigment epithelium (Grant and Schuman, 1993). Shown below is a list of compounds compiled from data that is publically available, that specifically have shown morphological RPE toxicity in in vivo animal studies.

Aluminium
Intraperitoneal application of aluminium chloride to rats causes retinal toxicity, which is characterized by a thinnig of the RPE and loss of POS (Lu et al., 2002).

Aminophenoxyalkanes
Aminophenoxyalkanes have schistosomicidal activity, and upon systemic administration, retinal toxicity has been demonstrated in several animal species, including rat, rabbit, cat, dog, and monkey (Collins et al., 1967). The mechanism of toxicity has not been clarified, but appears to focus on the pigment epithelium (Glocklin and Potts, 1962; Orzalesi et al., 1967b; Lee and Valentine, 1991). Retinal toxicity is dose-related in rats and independent of pigmentation (Lee and Valentine, 1990, 1991). Twelve hours after a single oral administration of 25 mg/kg 1,4,-bis(4-aminophenoxy)-2-phenylbenzene to rats, RPE cells show necrosis with swelling of mitochondria and endoplasmic reticulum, nuclear pyknosis or karyorrhexis, and disintegration of cytoplasmic organelles. Cell death rapidly progresses and becomes associated with disruption of POS.

Intact RPE cells accumulate disrupted lamellar discs and myelin bodies. By four days, both necrotic and regenerated immature RPE cells are found. Immature RPE cells are characterized by a large vesicular nucleus, prominent nucleoli, scant cytoplasmic organelles with few melanosomes, and a lack of long apical microvilli. By seven days, the RPE shows marked hyperplasia, forming up to seven cell layers between Bruch’s membrane and a partially detached and folded neural retina with excessive outer segment disruption. After another seven days, RPE hyperplasia has regressed to a single cell layer. Few pigmented cells are found in the subretinal space, and outer segments start to regenerate. 57 days after treatment, the retina has regained normal morphology. If a higher dose is administered, RPE and POS changes are more severe and photoreceptors are permanently lost, resulting in irreversible retinal atrophy (Lee and Valentine, 1991).

Cationic Amphophilic Drugs (Tricyclic Antidepressants)
Amiodarone, chloroamitriptyline, chlorphentermine, clomipramine, imipramine, iprindole, various aminoglycosides, and other cationic amphophilic compounds interfere with the enzymatic degradation of phospholipids. Consequently, their systemic administration results in accumulation of phospholipids in various retinal cells, including the pigment epithelium (retinal lipidosis), which is reminiscent of glycosaminoglycan storage observed in some inherited mucopolysaccharidoses (Bredehorn et al., 2001). The phospholipids are stored in abnormal cytoplasmic inclusions with crystalloid substructure and are partially reversible upon discontinuation of treatment (Lullmann-Rauch, 1976; Bockhardt et al., 1978; Drenckhahn and Lullmann-Rauch, 1978; Bockhardt and Lullmann-Rauch, 1980; Lullmann-Rauch, 1981; D’Amico et al., 1985; Tabatabay et al., 1987; Duncker and Bredehorn, 1994; Bredehorn et al., 2001).

Desferrioxamine
Systemic administration of desferrioxamine, an iron-chelating agent, can significantly impair vision in patients treated for hemochromatosis. The retinal toxicity has been reproduced in rats and rabbits and was mainly assessed by electrophysiology. Morphological changes are poorly described but shall include lesions of the RPE (Arden, 1986; Leure-duPree and Connor, 1987; Good et al., 1990; Szwarcberg et al., 2002).

DL-(p-trifluoromethylphenyl) Isopropylamine Hydrochloride
In rats and dogs, high oral doses of dl-(p-trifluoromethylphenyl) isopropylamine hydrochloride have caused retinal toxicity, associated with loss of photoreceptors and RPE migration into the subretinal space (Delahunt et al., 1963).

Fluoride
Intravenous administration of near-lethal doses of sodium fluoride to rabbits results in very high fluoride concentrations in the eye. These concentrations are toxic to the retina, with destruction of the pigment epithelium and the POS (Sorsby and Harding, 1960,1966; Orzalesi et al., 1967a, 1967b; Vanysek et al., 1969).

Iodate
High intravenous doses of sodium or potassium iodate cause severe retinal damage in several mammalian species, including man (Grignolo et al., 1966; Grignolo, 1969; Orzalesi et al., 1970; Singalavanija et al., 1994, 2000; Burgi et al., 2001). Primarily, iodate exerts its effect on the RPE causing degeneration of the basal membrane, swelling of cell organelles, loss of apical microvilli, and finally necrosis of RPE cells (Suyama, 1967; Nilsson et al., 1977a; Kiuchi et al., 2002). As a consequence, the adhesion between RPE and Bruch’s membrane is weakened (Yoon and Marmor, 1993), and the blood-retinal barrier becomes leaky (Ringvold et al., 1981). Secondarily, POS become disorganized, photoreceptors degenerate, and the choriocapillaris atrophies (Nilsson et al., 1977b; Korte, 1984b). RPE cells proliferate as shown by proliferating cell nuclear antigen (PCNA) -immunoreactivity and some pigmented cells are found within the subretinal space (Kiuchi et al., 2002). The mechanism of toxicity is not clear, but inhibition of lysosomal enzymes may play an important pathogenetic role (Hayasaka et al., 1988).

Iodoacetate
Iodoacetate, an inhibitor of glycolysis, also shows severe retinotoxicity, but its action is different from sodium iodate. Iodoacetate has a high affinity for the retina, and intravenous administration of high doses of iodoacetate to rabbits causes retinal degeneration with marked injury of rods. Iodoacetate also affects RPE cells (most likely their phagocytic activity), and finally it may cause atrophy of the choriocapillaris (Grignolo, 1969; Orzalesi et al., 1970; Opas et al., 1986).

Lead
Systemic lead poisoning can induce swelling and lipofuscin accumulation in RPE cells of rabbits, eventually resulting in photoreceptor degeneration and in alteration of the blood-retinal barrier (Hass et al., 1964; Brown, 1974; Hughes and Coogan, 1974; Fox and Chu, 1988).

Methanol/Formic Acid
Oral methanol poisoning in man and nonhuman primates can result in permanent visual impairment. Methanol-induced retinal toxicity can be reproduced in rats by selectively inhibiting formate oxidation, which allows formate to accumulate to toxic concentrations comparable to primates (Murray et al., 1991; Eells et al., 1996, 2000). Methanol-intoxicated rats show mitochondrial disruption and vacuolation in the RPE, associated with lesions in POS and the optic nerve.

4,4'-Methylenedianiline
The chemical 4,4'-methylenedianiline is an intermediate in the production of isocyanates and polyurethanes. Inhalation causes degeneration of the photoreceptor inner and outer segments and degeneration of the RPE in both pigmented and unpigmented guinea pigs (Leong et al., 1987). Retinal degeneration has also been observed in cats poisoned via the peroral or percutaneous route (Schilling et al., 1966).

N-Methyl-N-nitrosurea
N-methyl-N-nitrosurea is a methylating agent and is therefore mutagenic. It causes dose- and time-dependent retinotoxicity after systemic administration in guinea pigs and rats (Herrold, 1976; Ogino et al., 1993; Nakajima et al., 1996). Morphological studies in rats suggest that photoreceptors may be damaged first, with subsequent vacuolization, degeneration, and migration of RPE cells (Nakajima et al., 1996).

Naphthalene
Naphthalene can cause severe cataracts in various species, but has also been reported to cause retinal damage in rabbits when administered orally. The retinal pigment epithelium appears to be primarily affected, but the pathomechanism of retinotoxicity is not known (Pirie, 1968).

Napthol
Naphthol was shown to cause ocular toxicity in man and rabbits. In the latter, retinal toxicity after systemic exposure is characterized by hypertrophy of the RPE, variable amounts of melanin in the RPE and degeneration of photoreceptors (van der Hoeve, 1913).

Nitroaniline
Oral administration of the rat poison N-3-pyridylmethyl-N'-p-nitrophenylurea (nitroanilin/pyriminil) caused ocular toxicity in humans, rabbits and hamsters causing primary alterations in the RPE and photoreceptors (Mindel et al., 1988; Taomoto et al., 1998).

Organophosphates
Few reports claim that cholinesterase-inhibiting organophosphate pesticides such as ethylthiometon, fenthion, and fenitrothion have the potential to harm the retina in man and experimental animal models (Boyes et al., 1994; Dementi, 1994). Although still controversial, there are reports of retinal degeneration and histological abnormalities of the pigment epithelium (Imai et al., 1983).

Oxalate
Rabbits that are subcutaneously treated with dibutyl oxalate develop intracellular needle-like birefringent crystalline deposits within RPE cells. Similar changes associated with hyperoxalemia are observed in various organs such as kidney, heart, and testis. The crystalline deposits in the RPE could be detected as white flecks on the retina by indirect ophthalmoscopy (Caine et al., 1975). Hyperoxalemia can be a sequela of methoxyflurane-treatment, which has rarely caused crystalline deposits in the RPE of man (Novak et al., 1988).

Phenothiazines
Phenothiazines are tranquilizers used for psychotic illness. If sufficiently high doses are administered for several weeks, some phenothiazine derivatives such as piperidylchlorophenothiazine, thioridazine, and chlorpromazine can cause clinically significant retinopathy in man (Sidall, 1968). Interestingly, retinal toxicity can be reproduced in cats, but not in rabbits, rats, guinea pigs or dogs (Goar and Fletcher, 1957; Verrey, 1956; Wagner, 1956). The main target of phenothiazine-induced retinal toxicity is probably the photoreceptor cell, particularly the rods. Outer segments disintegrate and the pigment epithelium has to cope with excessive shedding of POS. Individual RPE cells are larger than normal and contain increased amounts of lipofuscin, melanolysosomes, and curvilinear bodies, finally resulting in atrophy of the RPE layer (Miller et al., 1982). The mechanism of toxicity is unknown. Phenothiazines bind to melanin granules and accumulate within the uvea and RPE (Potts, 1962b), and they can dose-dependently inhibit phagocytosis in cultured chick RPE cells (Matsumura et al., 1986).

Quinolines
Quinoline derivatives are used as antimalarials and for the treatment of some autoimmune diseases. Chloroquine may adversely affect the retina in man, causing decreased visual acuity, blurred vision, diplopia, decreased color and night vision, and visual field defects (Berstein, 1968). Chloroquin retinopathy is dose-related (Berstein and Glinsberg, 1964), develops slowly, and is characterized by a fine mottling of the macula, arteriolar narrowing, peripheral retinal pigmentation, loss of the foveal reflex and, in advanced cases, by a depigmented macula surrounded by a pigmented ring (bull’seye macular pigmentation).

Chloroquine-induced retinal toxicity has been reproduced in several animal species, including rat, cat, dog, rabbit, pig, and monkey (Meier-Ruge, 1965; Gleiser et al., 1969; Abraham and Hendy, 1970; Berson, 1970; Gregory et al., 1970; Rosenthal et al., 1978). Morphological hallmark is the intracellular accumulation of membranous phospholipid inclusions (myeloid bodies) that occur in ganglion cells and (apparently to a lesser degree) in photoreceptors and RPE (Abraham and Hendy, 1970; Gregory et al., 1970; Perasalo et al., 1973; Ivanina et al., 1983; Duncker et al., 1995).

RPE cells largely remain intact, but eventually the POS deteriorate (Ivanina et al., 1983). Although it has been speculated that oxidative stress is a primary mechanism of chloroquine-induced retinal toxicity (Ivanina et al., 1987; Toler, 2004), there is extensive evidence suggesting that chloroquine primarily inhibits lysosomal degradation (Ivanina et al., 1989; Schraermeyer, 1992; Mahon et al., 2004; Peters et al., 2005). The high affinity of chloroquine for melanin and its potential to accumulate within the eye are thought to be an important pathogenic mechanism, but its significance is still obscure.

Streptozotocin
In rats and monkeys, streptozotocin can induce diabetes mellitus by selectively destroying pancreatic β-cells with subsequent formation of diabetic cataracts. Beside the cataracts, streptozotocin-treated rats show a significant deepening of basal infoldings of the RPE and a noticeable increase in the size of the extracellular space between the basal infoldings (Grimes and Laties, 1980; Aizu et al., 2002). These changes are not a toxic effect of streptozotocin but relate to the diabetic condition (Grimes et al., 1984).

Taurine Deficiency
Taurine is an amino acid that is essential for retinal function and shows highest concentrations in the photoreceptor layer (Orr et al., 1976; Schmidt et al., 1976; Lake 1982, Schuller-Levis and Park, 2003) to where it is transported via an energy-dependent transport system of the RPE (Lake et al., 1977). Reduced taurine concentrations in plasma and retina of cats result in disorientation of POS, progressive loss of the outer nuclear layer and the outer plexiform layer, and non-detectable electroretinograms (Hayes et al., 1975; Schmidt et al., 1976). Consequently, treatment of rats with guanidinoethyl sulfonate (GES), an inhibitor of taurine uptake, leads to severe reduction in retinal taurine concentration and degenerative changes in the retina (Lake and Malik, 1987).

Adult female albino rats treated with GES orally for 8 weeks exhibit vacuolization and swelling of the RPE. This is associated with disorganization of POS and finally with photoreceptor cell degeneration, formation of few retinal rosettes, and migration of RPE cells into the subretinal space (Lake and Malik, 1987). The mechanism of toxicity is still unknown, but impaired protection against oxidative stress is one proposed mechanism (Lake and Malik, 1987).

Urethane
Urethane is an antineoplastic and anaesthetizing substance that can cause retinal toxicity after repeated subcutaneous administration to rats (Korte et al., 1984a). Morphologically, the retina shows degeneration of photoreceptors, derangement of the RPE and ingrowth of vessels into the RPE (Bellhorn et al., 1973).

Zinc Deficiency Caused by Metal Chelators
Depletion of intracellular zinc can increase the vulnerability of cultured RPE cells to UV irradiation and may induce RPE cell apoptosis (Hyun et al., 2001). Zinc deficiency also appears to harm the RPE in vivo, since systemic administration of the zinc chelators dithizone or 1,10-phenanthroline to rats and dogs causes a dose-dependent accumulation of irregularly shaped, non-membrane bound, osmiophilic inclusion bodies in the basal portion of RPE cells (Leure-duPree, 1981; Leure-duPree and McClain, 1982; Leure-duPree and Bridges, 1982). Photoreceptors are not primarily affected, but chronic exposure may lead to disruption of POS (Leure-duPree and McClain, 1982). Inclusions are distinct from phagosomes, lysosomes, lipofuscin and peroxisomes, but their precise nature has not yet been clarified (Leure-duPree and McClain, 1982)

	Toxicologic Pathology of the Pigment Epithelium

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As summarized here, the RPE can exhibit distinct morphological features, which may depend not only on the duration and severity of the toxic injury, but also on the pathomechanism of injury. The following characteristics can be used to describe morphological abnormalities in the pigment epithelium of the retina as assessed by light and transmission electron microscopy.

Hypertrophy and Intracellular Accumulations
As previously mentioned, enlargement of RPE cells is not necessarily abnormal, but can be a prominent feature of early RPE toxicity. Hypertrophy may be associated with enlargement of the smooth endoplasmic reticulum, indicating increased metabolic activity of the cell (Figure 2). Hypertrophy may also occur with intracellular accumulation of normal or abnormal cellular components. Lysosomes can accumulate in the RPE, if degradation is impaired or POS are shed excessively (Figure 3). Chloroquin toxicity is associated with an increase in the number of lysosomes within the RPE and with an accumulation of large lysosomes with abundant whorls of membranes. This alteration has also been referred to as "retinal lipidosis," since the whorls are primarily composed of phospholipids. Inclusions are round to polygonal in shape, 0.3 to 1.5 µm in diameter and contain whorls of membranes which give a lamellated (fingerprint-like) structure (Ivanina et al., 1983) (Figure 4). The osmiophilic inclusions are referred to as "myeloid bodies" (Perasalo et al., 1973), "abnormal membranous cytoplasmic bodies" (Gregory et al., 1970; Matsumura et al., 1986), or "lamellar lysosome-like structures" (Gaafar et al., 1995), and closely resemble the inclusions observed in hepatocytes following chloroquine treatment. Within the retina, lamellated inclusions occur in the bipolar and ganglion cells (Abraham and Hendy, 1970), even before they appear in the RPE (Ivanina et al., 1983; Matsumura et al., 1986; Duncker et al., 1995).

View larger version (326K): [in this window] [in a new window]   Figure 2 Hypertrophic RPE cell with enlargement of the smooth endoplasmic reticulum (asterisk). Note the presence of mitochondria (M) at the basal portion of the cell and infoldings of the basal cell membrane. Arrowheads label the junction between two neighboring RPE cells. T = tight junction, POS = photoreceptor outer segments, TL = tapetum lucidum (within the choroid), B = Bruch’s membrane. Healthy adult Beagle dog. Eye fixed in glutaraldehyde and embedded in epon. Ultrathin section photographed by transmission electron microscopy. Original magnification: 10,080x.

View larger version (133K): [in this window] [in a new window]   Figure 3 RPE cells with intracellular accumulation of secondary lysosomes (S). There is also a mild enlargement of the smooth endoplasmic reticulum. Healthy adult Cynomolgus macaque. Eye fixed in glutaraldehyde and embedded in epon. Ultrathin section photographed by transmission electron microscopy. Scale bar = 2 µm.

View larger version (190K): [in this window] [in a new window]   Figure 4 Accumulation of residual bodies (arrowheads) and incompletely degraded phagosomes (asterisks) in the RPE. BM = Bruch’s membrane. 2-month-old Long Evans rat intraperitoneally treated with chloroquine twice a week for 6 weeks. Eye fixed in glutaraldehyde and embedded in epon. Ultrathin section photographed by transmission electron microscopy. Scale bar = 1.1 µm.

Loss of Polarity/Dedifferentiation
As indicated here, differentiated RPE cells have a polarized structure with distinct morphology at the apical and basolateral site. Loss of apical microvilli and basal infoldings are early features of RPE toxicity. The loss of basal infoldings suggests that transport processes within the RPE cell are impaired. The loss of apical microvilli is indicative of impaired POS phagocytosis and consequently, cells reveal a reduced number of phagosomes (Figure 6).

View larger version (288K): [in this window] [in a new window]   Figure 6 RPE cell with loss of apical microvilli. Note the disorganization of photoreceptor outer segments (POS), and the lack of phagosomes in the apical cytoplasm of the RPE cell. The RPE cell is hypertrophic with accumulation of smooth endoplasmic reticulum (asterisk). There is accumulation of cellular debris (D) between POS. Adult Beagle dog treated orally with an unspecified severely retinotoxic agent. Eye fixed in glutaraldehyde and embedded in epon. Ultrathin section photographed by transmission electron microscopy. Original magnification: 5,000x.

Degeneration/Necrosis/Atrophy
Early degeneration of RPE cells is characterized by swelling and vacuolization of mitochondria and the endoplasmic reticulum. This is followed by nuclear disintegration. Finally, RPE cells are lost and there are areas of the retina that are devoid of an RPE cell lining (atrophy) (Figure 7).

View larger version (351K): [in this window] [in a new window]   Figure 7 Focal necrosis of the RPE cell layer. Note the lack of RPE cell nuclei between the 2 arrows. RPE cell cytoplasm is hyalinized (necrosis). POS = photoreceptor outer segments. ONL = outer nuclear layer. Adult Beagle dog treated orally with an unspecified retinotoxic agent for 12 months. Eye fixed in Davidson fixative and embedded in paraffin. Section stained with H&E.

View larger version (322K): [in this window] [in a new window]   Figure 8 Hyperplasia of RPE cells. Note the immature phenotype of cells with a large vesicular nucleus (asterisk). Photoreceptor outer segments (POS) are disorganized, as is the outer nuclear layer (ONL). INL = inner nuclear layer, CH = choroid. Adult Beagle dog treated orally for 12 months with an unspecified mild retinotoxic agent. Eye fixed in formalin, embedded in paraffin. Section was moderately bleached before staining with H&E.

View larger version (613K): [in this window] [in a new window]   Figure 9 Cellular infiltrate in the subretinal space. (a) Pigmented cells (arrows) in the subretinal space between photoreceptor outer segments (OS). ONL = outer nuclear layer. Cynomolgus macaque treated with an unspecified mild retinotoxic agent for 4 weeks. Eye fixed in Glutaraldehyde and embedded in paraffin. H&E-stained section. (b) Overlying the RPE are 2 polygonal cells that are larger than the RPE cells (arrows). The photoreceptors have detached arteficially. Rat treated with the same retinotoxic agent for 3 months. Eye fixed in glutaraldehyde and embedded in epon. Toluidin blue-stained semithin section.

View larger version (584K): [in this window] [in a new window]   Figure 10 Focal collagenous subretinal membrane. (a) There is a focally extensive membrane between RPE and Bruch’s membrane, composed of multiple cell layers (asterisk). Note the numerous pigmented cells within photoreceptor outer segments (POS). ONL = outer nuclear layer, INL = inner nuclear layer, CH = choroid. (b) The membrane is composed of collagen fibers that stain red with the picrosirius stain. Black arrow = Bruch’s membrane, open arrow = RPE. Eye fixed in glutaraldehyde and embedded in paraffin. (c) The subretinal membrane is composed of multiple cell layers between a relatively normal RPE and Bruch’s membrane (arrow heads). The choroid (CH) is normal. The membrane is composed of spindle-shaped cells, some of them heavily pigmented, and abundant extracellular matrix with regular 64 nm-periodicity, indicating collagen fibers. Adult Cynomolgus macaque treated orally with an unspecified mild retinotoxic agent for 4 weeks. Eye fixed in glutaraldehyde and embedded in epon. Ultrathin section photographed by transmission electron microscopy.

	Summary

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RPE cells have a limited potential to respond to toxic or any other kind of insult. Hyperplasia of the endoplasmic reticulum in RPE cells is indicative of increased metabolic capacity in the cell and is likely not to be of any functional significance for vision. Accumulation of intracytoplasmic inclusions such as phospholipids or crystals may also be of no functional consequence if its extent is limited. Drug-induced phospholipid inclusions are partially reversible (Lee and Valentine, 1991). First morphological features of an impaired RPE cell function are loss of apical microvilli and basal infoldings (Suyama, 1967; Nilsson et al., 1977a; Kiuchi et al., 2002).

Since the apical and basolateral membrane contain specific transport proteins for ions and other substances (such as taurine, glucose, etc.), these morphological features suggest an impaired transport function. The apical microvilli of the RPE embrace the POS and are essential for their maintenance (Bok, 1993). It must be assumed that POS function becomes impaired if RPE microvilli regress. Indeed, most cases in which apical microvilli of the RPE are lost also show ultrastructural disorganization of POS (Nilsson et al., 1977b; Korte, 1984b). Further features of RPE toxicity are swelling and vacuolization of mitochondria and the endoplasmic reticulum. As in other cell types, these are early features of cell degeneration that are considered to be reversible (Lee and Valentine, 1991; Kumar et al., 2005). If RPE function is impaired beyond a "point of no return," the cell is irreversibly damaged and undergoes degeneration, finally resulting in atrophy of the RPE cell layer, loss of photoreceptors, and retinal atrophy (Lee and Valentine, 1991).

Since RPE cells are highly specialized cells, their capacity for regeneration appears to be very limited. However, very little is actually known about RPE regeneration (Korte et al., 1994). RPE cells can undergo hyperplasia, which may lead to RPE regeneration comprising reorganization of the polarized plasma membranes and reestablishment of the blood-retinal barrier (Korte et al., 1994). In contrast, RPE hyperplasia may result in the formation of a multilayered epithelium between Bruch’s membrane and the photoreceptors (Machemer and Laqua, 1975).

The factors that govern differentiation of newly generated RPE cells are still obscure, but it is known that extracellular matrix components influence RPE membrane polarity (reviewed in Korte et al., 1994). RPE cells that do not differentiate can undergo metaplasia into fibroblasts and as such are capable of producing a collagen rich extracellular matrix. This leads to the formation of collagenous membranes between the RPE and Bruch’s membrane (Lee, 2002). It must be assumed that this membrane significantly impaires the retinal function and therefore has impact on vision.

A relatively common finding in retinal toxicity is the occurrence of nucleated, often pigmented cells within the sub-retinal space (Delahunt et al., 1963; Lake and Malik, 1987; Nakajima et al., 1996; Kiuchi et al., 2002). This space between the photoreceptor nuclei and the RPE is usually filled with photoreceptor inner and outer segments and does not contain cell nuclei. Cells that have migrated into the subretinal space are frequently pigmented and could either represent detached RPE cells or macrophages that have infiltrated the retina and have phagocytozed melanin from degenerating RPE cells. In most cases, it is difficult to distinguish between these two cell types, but TEM and immunohistology may help in the differentiation.

Clinically, the RPE can be assessed by indirect ophthalmoscopy, fluorescein angiography, and electrophysiology (Grant and Schuman, 1993). Impairment of fluid transport across the RPE will likely result in retinal edema, which can be assessed by indirect ophthalmoscopy, similar to a pigmentary retinopathy. The latter describes abnormal pigmentation of the ocular fundus and is most likely a correlate of RPE cell hyperpigmentation, necrosis and hyperplasia (Laqua and Machemer, 1975).

In addition to the above-mentioned techniques, morphology, particularly using transmission electron microscopy, is a very sensitive method to detect RPE cell injury (Heywood and Gopinath, 1990; Whiteley and Peiffer, 2002). Detailed knowledge on the pathophysiology of the retinal pigment epithelium will enable early detection of the potential of a compound to adversely affect the eye, which is of major importance for preclinical toxicity studies, given the prominence of vision as a cognitive sense in humans (Whitley and Peiffer, 2002).

	Acknowledgment

	References

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Toxicologic Pathology, Vol. 35, No. 2, 252-267 (2007)
DOI: 10.1080/01926230601178199


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