Table 3.

Changes in gene regulation of (i) eye-related cells subjected to r-µg, (ii) eye tissue isolated from animals exposed to microgravity conditions, or (iii) healthy human volunteers exposed to head-down tilt.

Source	Kind	Gene Regulation	Microgravity	Reference
(i) Cell line	ARPE-19	Analysis of 23.556 targets: more than 5.500 differentially expressed genes Approx. 100 pathways were affected, including cellular response to space environment adaptation/damage GO analysis revealed that r-µg impacts several critical cellular mechanisms, including response to unfolded proteins and ion binding Of 366 screened miRNAs, 19 displayed differential downregulation of target genes More than 250 lncRNAs were deregulated	Spaceflight to the ISS, 3 d	[99]
(ii) Mice	C57BL/6 Male 9-week-old	Several pathways involved in inflammation, cell repair, cell death, and metabolic stress were significantly changed Analysis of regulated protein expression revealed changes in retinal protein expression related to immune response, metabolic function, and cellular structure	Spaceflight to the ISS, 35 d	[101]
(ii) Mice	C57BL/6 Male 10-week-old	Pathways involved in, e.g., inflammation, cell death, and metabolic stress, were significantly altered	Spaceflight to the ISS, 35 d	[102]
(ii) Mice	C57BL/6 Male 10-week-old	600 DEGs were detected in the retinas of mice flown Genes related to the phototransduction pathway and visual perception were enriched Of 75 genes associated with retinitis pigmentosa, 12 were differentially expressed. For diabetic retinopathy, only one gene was differentially expressed No differentially regulated genes were detected for retinal-detachment disease-associated and AMD A number of transcription factors, including Cazs1, Kdm4a, Kdm4b, and Kdm6b, were differentially expressed	Spaceflight to the ISS, 35 d	[103]
(ii) Mice	C57BL/6 Female 16-week-old	Differential methylations of many genes were observed Retinal cell homeostasis was disturbed: several genes involved in inflammation, oxidative stress, tissue remodelling, mitochondrial function, and angiogenesis were impacted Reduced gravity decelerates the epigenetic clock in the mouse retina	Spaceflight to the ISS, 37 d	[104]
(ii) Mice	Strain N/A Female	13 gene targets of three miRNAs were identified Ag-treatment only altered the expression of Zcchc9	Hindlimb unloading	[105]
(iii) Human healthy volunteers	Eight male subjects*	Analysis of one-carbon pathway polymorphisms in MTRR and SHMT1 did not reveal any significant changes	1 h settings of seated, HDT, and HDT + CO2	[106]
(iii) Human healthy volunteers	Six men and five women *	MTRR 66G and SHMT1 1420C alleles were associated with a greater increase in total retinal thickness during	30 d of 6° HDT bed rest with 0.5% CO2 exposure	[107]

Abbreviations: Age-related macular degeneration (AMD); human adult retinal pigment epithelium cells (ARPE-19); days (d); differentially expressed genes (DEGs); gene ontology (GO); head-down tilt (HDT); hours (h); International Space Station (ISS). * Blood samples and non-invasive analysis of eye and/or brain.