RESUMEN

Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.

Asunto(s)

Dopamina , Microglía , Embarazo , Femenino , Ratones , Masculino , Animales , Microglía/metabolismo , Dopamina/metabolismo , Conducta Social , Emisiones de Vehículos , Neuronas Dopaminérgicas

RESUMEN

Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.

RESUMEN

BACKGROUND: To determine the safety and efficacy of intravitreal sirolimus and adjunct aflibercept in subjects with persistent, exudative age-related macular degeneration despite previous intravitreal anti-vascular endothelial growth factor (VEGF) treatment. METHODS: This institutional review board approved, registered (NCT02732899), prospective, subject-masked, single center, randomized controlled trial in subjects with persistent, exudative age-related macular degeneration compared alternating monthly intravitreal sirolimus and aflibercept (combination) versus aflibercept monotherapy (control) every 2 months over the course of 36 weeks. The primary measure of efficacy in the study was the mean change in central subfield thickness. RESULTS: 20 subjects were enrolled in the study, with 10 subjects assigned to each treatment group. Subjects had an average of 38 previous anti-VEGF injections. Mean central subfield thickness decreased in the combination group by 54.0 µm compared to 0.1 µm in the control group (p = 0.28). Mean visual acuity improved in the combination group by 2.5 ETDRS letters versus 0.8 ETDRS letters in the control group (p = 0.42). There were no serious ocular adverse events in either group; however, there were three serious systemic events in the combination group, including hospitalizations due to pancreatitis, pneumonia, and worsening hypertension. CONCLUSION: There was no statistically significant difference in the mean central subfield thickness change between the combination and control groups. However, intravitreal sirolimus with adjunct aflibercept did appear to have potential anatomical benefits as a treatment for persistent, exudative age-related macular degeneration and requires further investigation with a larger cohort to better understand the potential risks and benefits. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02732899. Registered 11 March 2016, https://clinicaltrials.gov/ct2/show/NCT02732899 . This trial was approved by the institutional review board at Advarra. Funding was provided by an investigator-initiated grant from Santen. Santen played no role in the design or implementation of this study.