Abstract
Increasing evidence demonstrated that PM2.5 could cross the placenta and fetal blood–brain barrier, causing neurotoxicity of embryonic development. The retina, an embryologic extension of the central nervous system, is extremely sensitive and vulnerable to environmental insults. The adverse effects of PM2.5 exposure on the retina during embryonic neurodevelopment are still largely unknown. Our goal was to investigate the effect of PM2.5 on human retinal development, which was recapitulated by human embryonic stem cell (hESC)-derived retinal organoids (hEROs). In the present study, using the hEROs as the model, the influences and the mechanisms of PM2.5 on the developing retina were analyzed. It demonstrated that the formation rate of the hERO-derived neural retina (NR) was affected by PM2.5 in a concentration dosage-dependent manner. The areas of hEROs and the thickness of hERO-NRs were significantly reduced after PM2.5 exposure at the concentration of 25, 50, and 100 μg/ml, which was due to the decrease of proliferation and the increase of apoptosis. Although we did not spot significant effects on retinal differentiation, PM2.5 exposure did lead to hERO-NR cell disarranging and structural disorder, especially retinal ganglion cell dislocation. Transcriptome analysis showed that PM2.5 treatment was significantly associated with the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways and reduced the level of the fibroblast growth factors (FGFs), particularly FGF8 and FGF10. These results provided evidence that PM2.5 exposure potentially inhibited proliferation and increased apoptosis at the early development stage of the human NR, probably through the MAPK and PI3K/Akt pathway. Our study suggested that exposure to PM2.5 suppressed cell proliferation and promoted cell apoptosis, thereby contributing to abnormal human retinal development.
Highlights
Air pollution has caused extensive acute and chronic health issues (Cohen et al, 2017; Miyazaki et al, 2019)
PM2.5 treatment was set at day 18, the time neural retina (NR) were generated within hESC-Derived Retinal Organoids (hEROs) initially, continued to observe the formation and differentiation of NR for 1–3 weeks (Figure 1A)
P < 0.0001; 70.14 ± 9.45 μm, P < 0.0001; 69.71 ± 9.93 μm, P < 0.0001; 105.83 ± 11.90 μm, respectively; Figure 2C). These results suggested that the growth of hEROs and hERO-NR was suppressed by PM2.5 in a dosage-dependent manner, and the most significant effect was demonstrated at a concentration of 100 μg/ml for 3 weeks
Summary
Air pollution has caused extensive acute and chronic health issues (Cohen et al, 2017; Miyazaki et al, 2019). Several epidemiological investigations have demonstrated that people with short- or long-term exposure to PM2.5 may cause dry eye, keratitis, and conjunctivitis accompanied by ocular symptoms and signs (irritation, redness, itchiness, tearing, burning, etc.) (Chang et al, 2012; Fu et al, 2017; Gutiérrez et al, 2019; Lu et al, 2019; Mo et al, 2019). It demonstrated that the possible mechanisms lie in the proinflammatory response and cytotoxicity through DNA damage and oxidative stress caused by PM2.5 exposure (Chua et al, 2019; Tang et al, 2019). Most works described observations of the biological and toxicological influences of PM2.5 on the ocular surface through direct contact; fine specific matter can affect the retina through the blood–retina barrier (Hong et al, 2016; Lee et al, 2020; Lyu et al, 2020)
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