Topical brimonidine induced acute uveal effusion in a patient with nanophthalmos: a case report.

BACKGROUND: We report a case of uveal effusion in a nanophthalmic eye after topical use of brimonidine. CASE PRESENTATION: A 42-year-old male patient with nanophthalmos experienced sudden blurred vision in the right eye after using topical brimonidine when picking up tennis balls repeatedly 6 weeks after bilateral YAG peripheral iridotomy. Ocular examination showed wide choroidal and exudative retinal detachment in the temporal and inferior region, involving the macula. Acute uveal effusion in the right, bilateral nanophthalmos was diagnosed. Oral and topical corticosteroids, combined with topical nonsteroids and atropine led to a complete resolution of the uveal effusion after one month. CONCLUSION: This case suggested a possible causal relationship between the topical use of brimonidine and acute uveal effusion in patients with nanophthalmos. Topical brimonidine should be used with caution in nanophthalmic eyes.

Excess caffeine exposure impairs eye development during chick embryogenesis.

Caffeine has been an integral component of our diet and medicines for centuries. It is now known that over consumption of caffeine has detrimental effects on our health, and also disrupts normal foetal development in pregnant mothers. In this study, we investigated the potential teratogenic effect of caffeine over-exposure on eye development in the early chick embryo. Firstly, we demonstrated that caffeine exposure caused chick embryos to develop asymmetrical microphthalmia and induced the orbital bone to develop abnormally. Secondly, caffeine exposure perturbed Pax6 expression in the retina of the developing eye. In addition, it perturbed the migration of HNK-1(+) cranial neural crest cells. Pax6 is an important gene that regulates eye development, so altering the expression of this gene might be the cause for the abnormal eye development. Thirdly, we found that reactive oxygen species (ROS) production was significantly increased in eye tissues following caffeine treatment, and that the addition of anti-oxidant vitamin C could rescue the eyes from developing abnormally in the presence of caffeine. This suggests that excess ROS induced by caffeine is one of the mechanisms involved in the teratogenic alterations observed in the eye during embryogenesis. In sum, our experiments in the chick embryo demonstrated that caffeine is a potential teratogen. It causes asymmetrical microphthalmia to develop by increasing ROS production and perturbs Pax6 expression.

Ocular involvement in fetal alcohol spectrum disorder: a review.

Fetal Alcohol Syndrome (FAS), the most severe manifestation of Fetal Alcohol Spectrum Disorder (FASD) is considered the leading non-hereditary cause of mental retardation and neurological deficit in the Western world. There lie a huge associated human cost to both FASD victims and their families and a considerable financial burden. This problem is being tackled on many fronts including community awareness programs, biomarker development for fetal alcohol exposure, research into preventative treatments and the development of more robust diagnostic systems for the early detection of FASD. Although ethanol can affect many of the major systems of the body, the eye is a primary target. Ocular aberrations including optic nerve hypoplasia, tortuosity of retinal vessels, coloboma and microphthalmia are frequently observed in children diagnosed with FAS. In this regard, ocular involvement in FAS has gained importance, particularly in relation to early diagnosis and identification of FAS. Furthermore, our considerable knowledge of the molecular mechanisms underlying eye development has provided a powerful tool for the investigation of the teratogenic actions of ethanol. In this review, we initially provide an overview of FASD in terms of historical background, epidemiology and current status. Next, we explore the role of ocular involvement in FASD and the use of eye measurements in the diagnosis of FAS. Lastly, we review how current knowledge of early eye development can be used to gain new insights into the molecular mechanisms of ethanol teratogenicity with particular reference to the sonic hedgehog pathway.

Eye-specific gene expression following embryonic ethanol exposure in zebrafish: roles for heat shock factor 1.

The mechanisms through which ethanol exposure results in developmental defects remain unclear. We used the zebrafish model to elucidate eye-specific mechanisms that underlie ethanol-mediated microphthalmia (reduced eye size), through time-series microarray analysis of gene expression within eyes of embryos exposed to 1.5% ethanol. 62 genes were differentially expressed (DE) in ethanol-treated as compared to control eyes sampled during retinal neurogenesis (24-48 h post-fertilization). The EDGE (extraction of differential gene expression) algorithm identified >3000 genes DE over developmental time in ethanol-exposed eyes as compared to controls. The DE lists included several genes indicating a mis-regulated cellular stress response due to ethanol exposure. Combined treatment with sub-threshold levels of ethanol and a morpholino targeting heat shock factor 1 mRNA resulted in microphthalmia, suggesting convergent molecular pathways. Thermal preconditioning partially prevented ethanol-mediated microphthalmia while maintaining Hsf-1 expression. These data suggest roles for reduced Hsf-1 in mediating microphthalmic effects of embryonic ethanol exposure.

Developmental abnormalities in chicken embryos exposed to N-nitrosoatrazine.

Nitrate and atrazine (ATR) occur in combination in some drinking-water supplies and might react to form N-nitrosoatrazine (NNAT), which is reportedly more toxic than nitrate, nitrite, or ATR. Current evidence from population-based studies indicates that exposure to nitrate, nitrite, and nitrosatable compounds increases the risk of congenital defects and/or rate of embryo lethality. To test the hypothesis that NNAT induces malformations during embryogenesis, chicken embryos were examined for lethality and developmental abnormalities after treating fertilized eggs with 0.06-3.63 µg NNAT. After 5 d of incubation (Hamburger and Hamilton stage 27), 90% of embryos in NNAT-treated eggs were alive, of which 23% were malformed. Malformations included heart and neural-tube defects, caudal regression, gastroschisis, microphthalmia, anophthalmia, and craniofacial hypoplasia. The findings from this investigation suggest further studies are needed to determine the mechanisms underlying NNAT-induced embryotoxicity.

Dietary benzo(a)pyrene intake during pregnancy and birth weight: associations modified by vitamin C intakes in the Norwegian Mother and Child Cohort Study (MoBa).

BACKGROUND: Maternal exposure to polycyclic aromatic hydrocarbons (PAH) during pregnancy has been associated with reduced fetal growth. However, the role of diet, the main source of PAH exposure among non-smokers, remains uncertain. OBJECTIVE: To assess associations between maternal exposure to dietary intake of the genotoxic PAH benzo(a)pyrene [B(a)P] during pregnancy and birth weight, exploring potential effect modification by dietary intakes of vitamins C, E and A, hypothesized to influence PAH metabolism. METHODS: This study included 50,651 women in the Norwegian Mother and Child Cohort Study (MoBa). Dietary B(a)P and nutrient intakes were estimated based on total consumption obtained from a food frequency questionnaire (FFQ) and estimated based on food composition data. Data on infant birth weight were obtained from the Medical Birth Registry of Norway (MBRN). Multivariate regression was used to assess associations between dietary B(a)P and birth weight, evaluating potential interactions with candidate nutrients. RESULTS: The multivariate-adjusted coefficient (95%CI) for birth weight associated with maternal energy-adjusted B(a)P intake was -20.5g (-31.1, -10.0) in women in the third compared with the first tertile of B(a)P intake. Results were similar after excluding smokers. Significant interactions were found between elevated intakes of vitamin C (>85mg/day) and dietary B(a)P during pregnancy for birth weight (P<0.05), but no interactions were found with other vitamins. The multivariate-adjusted coefficients (95%CI) for birth weight in women in the third compared with the first tertile of B(a)P intake were -44.4g (-76.5, -12.3) in the group with low vitamin C intakes vs. -17.6g (-29.0, -6.1) in the high vitamin C intake group. CONCLUSION: The results suggest that higher prenatal exposure to dietary B(a)P may reduce birth weight. Lowering maternal intake of B(a)P and increasing dietary vitamin C intake during pregnancy may help to reduce any adverse effects of B(a)P on birth weight.

Histological characterisation of the ethanol-induced microphthalmia phenotype in a chick embryo model system.

The eye is a sensitive indicator of the teratogenic effects of ethanol with ophthalmic defects such as microphthalmia frequently observed in FAS children. In this study, we have optimised the chick-embryo model system to investigate ethanol-induced ocular defects. Injection of 20% ethanol (125µl) directly into the yolk sac of HH-stage 7 embryos resulted in an overall 30% incidence of eye anomalies including microphthalmia. Ocular measurements showed that this treatment regime caused a significant reduction in overall globe size. Histological examination of microphthalmic specimens revealed three subgroups: (1) all ocular structures developed but were significantly retarded compared to age matched controls, (2) the bi-layered optic cup developed but with no evidence of lens induction, and (3) the optic vesicle failed to invaginate but remained as a vesicular structure comprising of a single layer of retinal pigment cells with no evidence of a neuro-retinal cell layer or lens structure. Further analysis identified clusters of apoptotic bodies in the ventral telencephalon, a region responsible for the expression of important genes in ocular specification. These results support a growing body of evidence, indicating that ethanol targets inductive signals in early eye development involving lens formation and retinal ganglion cell differentiation. The possible involvement of Shh, Fgf8, Bmp4 and Pax6 is discussed in relation to these outcomes.

Ethanol-induced microphthalmia is not mediated by changes in retinoic acid or sonic hedgehog signaling during retinal neurogenesis.

BACKGROUND: Microphthalmia (reduced eye size), generally accompanied by vision defects, is a hallmark of fetal alcohol spectrum disorder (FASD) in humans. In zebrafish, embryonic ethanol exposure over the time of retinal neurogenesis also results in microphthalmia. This microphthalmia is in part the consequence of reduced retinal cell differentiation, including photoreceptors. Here we pursue 2 signaling pathways implicated in other aspects of FASD pathogenesis: retinoic acid (RA) and Sonic hedgehog (Shh). METHODS: We evaluated markers for RA and Shh signaling within the eyes of embryos treated with ethanol during the period of retinal neurogenesis. We also performed rescue experiments using administration of exogenous RA and microinjection of cholesterol, which augments Shh signaling. RESULTS: Using sequential or co-treatments, RA did not rescue ethanol-induced microphthalmia at any concentration tested. In addition, RA itself caused microphthalmia, although the underlying mechanisms were distinct from those of ethanol. Interestingly, RA treatment appeared to recover photoreceptor differentiation in a concentration-dependent manner. This may be an independent effect of exogenous RA, as ethanol treatment alone did not alter RA signaling in the eye. Cholesterol injection also did not rescue ethanol-induced microphthalmia at any concentration tested, and ethanol treatments did not alter expression of shh, or of ptc-2, which is normally regulated by Shh signaling. CONCLUSIONS: Together these findings indicate that, during the time of retinal neurogenesis, effects of ethanol on eye development are likely independent of the RA and Shh signaling pathways. These studies suggest that FASD intervention strategies based upon augmentation of RA or Shh signaling may not prevent ethanol-induced microphthalmia.

Developmental toxicity of glyceryl trinitrate in quail embryos.

BACKGROUND: Although glyceryl trinitrate (GTN) is used extensively to treat angina and heart failure, little is known about its effects on the conceptus during organogenesis. The goal of these studies was to investigate the effects of GTN in a model organism, the quail (Coturnix coturnix japonica) embryo. METHODS: To identify the effects of GTN on quail embryo development, fertilized quail eggs (n = 10-12 eggs/group) were injected with GTN (0, 4.4, 44, or 440 µM) at Hamburger-Hamilton (HH) stage 0, 9, or 19 and examined 7 days later. Next, HH 9 embryos were injected with GTN (0, 0.88, 4.4, 8.8, 44, 88, and 440 µM, in 20 µL per egg) and examined 24-hours, 48-hours, or 72-hours postinjection. Finally, the developing eye on one side was exposed to GTN (44 µM) ex ovo and the tissue was probed for the presence of nitrated proteins. RESULTS: In ovo GTN exposure induced a dose-dependent increase in the number of malformed viable quail embryos with a maximal effect in HH 9 embryos. Microphthalmia, craniofacial, heart, and neural tube defects were elevated in GTN-exposed embryos. An increase in nitrated proteins was observed in the developing eye region of embryos exposed ex ovo to GTN. CONCLUSIONS: GTN treatment induced a variety of malformations in quail embryos. The presence of nitrated proteins suggests that organic nitrates, such as GTN, generate reactive nitrogen species. We hypothesize that GTN perturbations in the redox status of the embryo may underlie its developmental toxicity.

Agrin function associated with ocular development is a target of ethanol exposure in embryonic zebrafish.

BACKGROUND: Alcohol (ethanol) is a teratogen known to affect the developing eyes, face, and brain. Among the ocular defects in fetal alcohol spectrum disorder (FASD) are microphthalmia and optic nerve hypoplasia. Employing zebrafish as an FASD model provides an excellent system to analyze the molecular basis of prenatal ethanol exposure-induced defects because embryos can be exposed to ethanol at defined developmental stages and affected genetic pathways can be examined. We have previously shown that disruption of agrin function in zebrafish embryos produces microphthalmia and optic nerve hypoplasia. METHODS: Zebrafish embryos were exposed to varying concentrations of ethanol in the absence or presence of morpholino oligonucleotides (MOs) that disrupt agrin function. In situ hybridization was used to analyze ocular gene expression as a consequence of ethanol exposure and agrin knockdown. Morphologic analysis of zebrafish embryos was also conducted. RESULTS: Acute ethanol exposure induces diminished agrin gene expression in zebrafish eyes and, importantly, combined treatment with subthreshold levels of agrin MO and ethanol produces pronounced microphthalmia, markedly reduces agrin gene expression, and perturbs Pax6a and Mbx gene expression. Microphthalmia produced by combined agrin MO and ethanol treatment was rescued by sonic hedgehog (Shh) mRNA overexpression, suggesting that ethanol-mediated disruption of agrin expression results in disrupted Shh function. CONCLUSIONS: These studies illustrate the strong potential for using zebrafish as a model to aid in defining the molecular basis for ethanol's teratogenic effects. The results of this work suggest that agrin expression and function may be a target of ethanol exposure during embryogenesis.

Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study.

OBJECTIVE: To estimate the association between antibacterial medications and selected birth defects. DESIGN, SETTING, AND PARTICIPANTS: Population-based, multisite, case-control study of women who had pregnancies affected by 1 of more than 30 eligible major birth defects identified via birth defect surveillance programs in 10 states (n = 13 155) and control women randomly selected from the same geographical regions (n = 4941). MAIN EXPOSURE: Reported maternal use of antibacterials (1 month before pregnancy through the end of the first trimester). MAIN OUTCOME MEASURE: Odds ratios (ORs) measuring the association between antibacterial use and selected birth defects adjusted for potential confounders. RESULTS: The reported use of antibacterials increased during pregnancy, peaking during the third month. Sulfonamides were associated with anencephaly (adjusted OR [AOR] = 3.4; 95% confidence interval [CI], 1.3-8.8), hypoplastic left heart syndrome (AOR = 3.2; 95% CI, 1.3-7.6), coarctation of the aorta (AOR = 2.7; 95% CI, 1.3-5.6), choanal atresia (AOR = 8.0; 95% CI, 2.7-23.5), transverse limb deficiency (AOR = 2.5; 95% CI, 1.0-5.9), and diaphragmatic hernia (AOR = 2.4; 95% CI, 1.1-5.4). Nitrofurantoins were associated with anophthalmia or microphthalmos (AOR = 3.7; 95% CI, 1.1-12.2), hypoplastic left heart syndrome (AOR = 4.2; 95% CI, 1.9-9.1), atrial septal defects (AOR = 1.9; 95% CI, 1.1-3.4), and cleft lip with cleft palate (AOR = 2.1; 95% CI, 1.2-3.9). Other antibacterial agents that showed associations included erythromycins (2 defects), penicillins (1 defect), cephalosporins (1 defect), and quinolones (1 defect). CONCLUSIONS: Reassuringly, penicillins, erythromycins, and cephalosporins, although used commonly by pregnant women, were not associated with many birth defects. Sulfonamides and nitrofurantoins were associated with several birth defects, indicating a need for additional scrutiny.

Maternal administration of anti-angiogenic agents, TNP-470 and Angiostatin4.5, induces fetal microphthalmia.

PURPOSE: Agents specifically targeting the vasculature as a mode of therapy are finding increasing use in the clinic, primarily in the treatment of colon cancer (Avastin) and age-related macular degeneration (Lucentis). We have previously shown that maternal administration of angiogenic inhibitors (TNP-470 [O-[chloroacetyl-carbamoyl]fumagillol, initially called AGM-1470], the first angiogenic inhibitor to undergo clinical trials, and Angiostatin(4.5), currently in phase I-III clinical trials) cause fetal growth restriction and/or placental abnormalities. During a rapid growth phase of ocular development in the mouse (embryonic days 12 to 19 [E12-E19]), the placenta mediates the metabolic requirements of the fetus and consequently may impact upon the growth of the highly oxygen sensitive fetal eye. METHODS: We injected pregnant dams (between E10.5 - E18.5) with anti-angiogenic agents, which caused either a placental insufficiency type of IUGR (intrauterine growth restriction; i.e., TNP-470) or frank placental pathology (Angiostatin(4.5) [AS(4.5)]), and assessed changes in absolute ocular dimensions, tissue types, and vascular profiles using stereological techniques. RESULTS: The experiments showed that ocular volumes were significantly reduced in fetal mice where dams were treated with either TNP-470 or AS(4.5). Furthermore, TNP-470 specifically caused a reduction in hyaloid blood vessel length and volume, the only intraocular vascular circulation in fetal mice. CONCLUSIONS: These experiments support the hypothesis that the angiogenic inhibitors (specifically TNP-470 and AS(4.5)) induce microphthalmia either indirectly by their known effects on placental morphology (and/or function) or directly via altering microvascular growth in the fetus. These results also warrant further investigation of a new experimental paradigm linking placental pathology-related fetal growth restriction and microphthalmia.

Microphthalmos associated with Dartmouth combination chemotherapy in pregnancy: a case report.

BACKGROUND: Use of Dartmouth combination chemotherapy in pregnancy is scarcely reported, with only 1 report of its use in the late second and third trimesters and no report of its use in the first trimester. CASE: This is the first reported case in which the Dartmouth combination chemotherapy regimen was inadvertently used in a pregnant woman during the first and second trimesters for treatment of metastatic melanoma. The infant was found to have isolated microphthalmos and severe hypermetropia at 1 year of age. CONCLUSION: Although a causal relationship cannot be established from a single case, this report does provide useful information to discourage the use of this chemotherapy regimen in the first trimester, which is the critical period for organogenesis.

Microencephaly and microphthalmia in rat fetuses by busulfan.

Microencephaly and microphthalmia in the embryos/fetuses from rats exposed to busulfan were histopathologically examined. Busulfan was intraperitoneally administered at 10 mg/kg on gestation days (Days) 12, 13 and 14, and then embryos/fetuses were harvested on Days 14.5, 15, 16 and 21. In the treated group on Day 21, all fetuses were small with reduced body weight, with microencephaly and microphthalmia. On Days 14.5, 15 and 16, apoptotic cells were increased in the neuroepithelium and the neural retina with a width reduction and a decrease in cell density, and the lens epithelial cells histopathologically. Mitotic inhibition was observed in the neuroepithelium, neural retina and equatorial zone of the lens. On Day 21, the cerebral cortex and the retina became markedly thinner. The lens fibers showed swollen, fragmentary and vacuolar formation in the cranial portion accompanied with small lens sizes. The anti-proliferative effects of busulfan brings about a lack of cell populations required for the normal organogenesis of the brain and eye, and leads to microencephaly and microphthalmia, featuring hypoplasia of cerebrum and hypoplasia of retina and lens with cataract, respectively.

Critical period and minimum single oral dose of ochratoxin A for inducing developmental toxicity in pregnant Wistar rats.

Ochratoxin A (OTA), a potent in vivo teratogen, has been tested in various laboratory animal species. Present investigation was conducted to determine critical dose and critical time for the developmental toxicity of OTA in pregnant Wistar rats after single oral dose administration. OTA at different graded dose levels (2-4 mg/kg body weight) and at different gestation days (6-15), caused variable developmental defects in developing fetuses. OTA at 2.75 mg/kg body weight, dissolved in 0.1 M sodium bicarbonate (vehicle) and administered by oral intubation as a single dose on one of the gestational days 6-15, caused significant maternal toxicity in the dams and various gross, visceral and skeletal anomalies in the fetuses. The major gross malformations were external hydrocephaly, incomplete closure of skull and omphalocele. Internal hydrocephaly, microphthalmia, enlarged renal pelvis and renal hypoplasia were the main internal soft tissue anomalies. Major skeletal defects were developmental defects in skull bones, sternebrae, vertebrae and ribs. The gestational days 6 and 7 were found to be the most critical for the induction of teratogenicity in rats. Single oral dose of 2.75 mg/kg body weight OTA was found to be the minimum effective teratogenic dose in pregnant Wistar rats.

Catalase and peroxiredoxin 5 protect Xenopus embryos against alcohol-induced ocular anomalies.

PURPOSE: To study the molecular mechanisms underlying alcohol-induced ocular anomalies in Xenopus embryos. METHODS: Xenopus embryos were exposed to various concentrations (0.1%-0.5%) of alcohol, and the subsequent effects in eye development and in eye marker gene expression were determined. To investigate the role of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in fetal alcohol syndrome (FAS)-associated ocular injury, two antioxidant enzymes, catalase and peroxiredoxin 5, were overexpressed in the two blastomeres of the two-cell stage Xenopus embryos. RESULTS: Exposure of Xenopus embryos to alcohol during eye development produced marked gross ocular anomalies, including microphthalmia, incomplete closure of the choroid fissure, and malformation of the retina in 40% of the eyes examined. In parallel, alcohol (0.1%-0.5%) dose dependently and significantly reduced the expression of several eye marker genes, of which TBX5, VAX2, and Pax6 were the most vulnerable. Overexpression of catalase and of cytosolic and mitochondrial peroxiredoxin 5 restored the expression of these alcohol-sensitive eye markers and significantly decreased the frequency of ocular malformation from 39% to 21%, 19%, and 13% respectively. All these enzymes reduced alcohol-induced ROS production, but only peroxiredoxin 5 inhibited RNS formation in the alcohol-treated embryos. CONCLUSIONS: The results suggest that oxidative and nitrosative stresses both contribute to alcohol-induced fetal ocular injury.

High exogenous homocysteine modifies eye development in early chick embryos.

BACKGROUND: Homocysteine is a nonessential aminoacid whose increase is related to the appearance of neural tube defects in humans. In chick embryos, high levels of homocysteine produce neural tube defects and alteration of neural crest cell migration. METHODS: In our study, 8 microl of L-homocysteine thiolatone (20 micromol) was added to chick embryos of Stages 3-8/10 (Hamburger and Hamilton, 1951), (1238 hr of incubation). Three days later, 50 embryos, externally normal or carrying isolated spinal neural tube defects, were sectioned and stained by hematoxilin-eosin or anti-fibrillin-1 antibody. RESULTS: The eye showed alterations of the optic cup as microphthalmia, or lens dislocation. In both cases, the incidence of alterations diminished with the age of the homocysteine-increased embryos. Optic cup modifications are probably associated with central nervous system alterations, because most of the affected embryos exhibited isolated spinal neural tube defects and had altered neural crest cells. We have shown for the first time that high exogenous homocysteine during early development could produce a caudally-displaced lens axis before the zonule is formed. Fibrillin-1 is the main component of elastic microfibrils, and in the adult human it is seen as a protein particularly susceptible to homocysteine attack. CONCLUSIONS: Antibody staining against fibrillin-1 showed no evident morphological differences in distribution between experimental and control embryos in the lens, suggesting that fibrillin-1 was not the cause, and malformations may be attributed to other mechanisms.

Exposure-disease continuum for 2-chloro-2'-deoxyadenosine, a prototype ocular teratogen. 3. Intervention with PK11195.

BACKGROUND: Treatment of pregnant mice with 2-chloro-2'-deoxyadenosine (2CdA) on Day 8 of gestation induces microphthalmia through a mechanism linked to the p53 tumor suppressor pathway. The present study defines the response of Day 8 mouse embryos through time with respect to pharmacologic intervention with PK11195, a ligand of the mitochondrial peripheral benzodiazepine receptor (Bzrp). METHODS: Pregnant CD-1 mice dosed with 2CdA with or without PK11195 on gestation Day 8 provided fetuses for teratologic evaluation on Day 14 and Day 17; HPLC measured pyridine nucleotides (NADH/NAD+) at 1.5 hr, RT-PCR measured mitochondrial 16S rRNA abundance at 3.0 hr, and p53 protein induction was assessed with immunostaining at 4.5 hr postexposure. RESULTS: The mean incidences of malformed fetuses were significantly higher in the 7.5 mg/kg 2CdA treatment group (50.2% malformed) vs. the 2CdA + 4.0 mg/kg PK11195 co-treatment group (4.4% malformed). Malformed fetuses displayed a range of ocular defects that included microphthalmia and keratolenticular dysgenesis (Peters anomaly). No malformations were observed in the control or PK11195 alone groups. PK11195 also protected litters from increased resorption rates and fetal weight reduction. It did not rescue early effects on NADH balance (1.5 hr) or 16S rRNA expression (3.0 hr); however, the p53 response (4.5 hr) was downgraded in 2CdA + PK11195 embryos vs. 2CdA alone. By delaying the administration of PK11195 in 1.5 hr intervals it was determined that the window for protection closed between 4.5 to 6.0 hr after 2CdA. CONCLUSIONS: The capacity of PK11195 to suppress the pathogenesis of microphthalmia implies a critical role for mitochondrial peripheral benzodiazepine receptors in the p53-dependent mode of action of 2CdA on ocular development.