Developmental chronodisruption alters placental signaling in mice.

Chronodisruption has been largely overlooked as a developmental exposure. The placenta, a conduit between the maternal and fetal environments, may relay circadian cues to the fetus. We have previously shown that developmental chronodisruption causes visual impairment and increased retinal microglial and macrophage marker expression. Here, we investigated the impacts of environmental chronodisruption on fetal and placental outcomes in a C57BL/6J mouse (Mus musculus) model. Developmental chronodisruption had no effect on embryo count, placental weight, or fetal sex ratio. When measured with RNAseq, mice exposed to developmental chronodisruption (CD) had differential placental expression of several transcripts including Serpinf1, which encodes pigment epithelium-derived factor (PEDF). Immunofluorescence of microglia/macrophage markers, Iba1 and CD11b, also revealed significant upregulation of immune cell markers in CD-exposed placenta. Our results suggest that in utero chronodisruption enhances placental immune cell expression, potentially programming a pro-inflammatory tissue environment.

Light Environment Influences Developmental Programming of the Metabolic and Visual Systems in Mice.

Purpose: Light is a salient cue that can influence neurodevelopment and the immune system. Light exposure out of sync with the endogenous clock causes circadian disruption and chronic disease. Environmental light exposure may contribute to developmental programming of metabolic and neurological systems but has been largely overlooked in Developmental Origins of Health and Disease (DOHaD) research. Here, we investigated whether developmental light exposure altered programming of visual and metabolic systems. Methods: Pregnant mice and pups were exposed to control light (12:12 light:dark) or weekly light cycle inversions (circadian disruption [CD]) until weaning, after which male and female offspring were housed in control light and longitudinally measured to evaluate differences in growth (weight), glucose tolerance, visual function (optomotor response), and retinal function (electroretinogram), with and without high fat diet (HFD) challenge. Retinal microglia and macrophages were quantified by positive Iba1 and CD11b immunofluorescence. Results: CD exposure caused impaired visual function and increased retinal immune cell expression in adult offspring. When challenged with HFD, CD offspring also exhibited altered retinal function and sex-specific impairments in glucose tolerance. Conclusions: Overall, these findings suggest that the light environment contributes to developmental programming of the metabolic and visual systems, potentially promoting a pro-inflammatory milieu in the retina and increasing the risk of visual disease later in life.

Impacts of high fat diet on ocular outcomes in rodent models of visual disease.

High fat diets (HFD) have been utilized in rodent models of visual disease for over 50 years to model the effects of lipids, metabolic dysfunction, and diet-induced obesity on vision and ocular health. HFD treatment can recapitulate the pathologies of some of the leading causes of blindness, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) in rodent models of visual disease. However, there are many important factors to consider when using and interpreting these models. To synthesize our current understanding of the importance of lipid signaling, metabolism, and inflammation in HFD-driven visual disease processes, we systematically review the use of HFD in mouse and rat models of visual disease. The resulting literature is grouped into three clusters: models that solely focus on HFD treatment, models of diabetes that utilize both HFD and streptozotocin (STZ), and models of AMD that utilize both HFD and genetic models and/or other exposures. Our findings show that HFD profoundly affects vision, retinal function, many different ocular tissues, and multiple cell types through a variety of mechanisms. We delineate how HFD affects the cornea, lens, uvea, vitreous humor, retina, retinal pigmented epithelium (RPE), and Bruch's membrane (BM). Furthermore, we highlight how HFD impairs several retinal cell types, including glia (microglia), retinal ganglion cells, bipolar cells, photoreceptors, and vascular support cells (endothelial cells and pericytes). However, there are a number of gaps, limitations, and biases in the current literature. We highlight these gaps and discuss experimental design to help guide future studies. Very little is known about how HFD impacts the lens, ciliary bodies, and specific neuronal populations, such as rods, cones, bipolar cells, amacrine cells, and retinal ganglion cells. Additionally, sex bias is an important limitation in the current literature, with few HFD studies utilizing female rodents. Future studies should use ingredient-matched control diets (IMCD), include both sexes in experiments to evaluate sex-specific outcomes, conduct longitudinal metabolic and visual measurements, and capture acute outcomes. In conclusion, HFD is a systemic exposure with profound systemic effects, and rodent models are invaluable in understanding the impacts on visual and ocular disease.

Seasonally variant gene expression in full-term human placenta.

Seasonal exposures influence human health and development. The placenta, as a mediator of the maternal and fetal systems and a regulator of development, is an ideal tissue to understand the biological pathways underlying relationships between season of birth and later life health outcomes. Here, we conducted a differential expression (DE) analysis of season of birth in full-term human placental tissue to evaluate whether the placenta may be influenced by seasonal cues. Of the analyzed transcripts, 583 displayed DE between summer and winter births (False Discovery Rate [FDR] q < .05); among these, BHLHE40, MIR210HG, and HILPDA had increased expression among winter births (Bonferroni P < .05). Enrichment analyses of the seasonally variant genes between summer and winter births indicated overrepresentation of transcription factors HIF1A, VDR, and CLOCK, among others, and of GO term pathways related to ribosomal activity and infection. Additionally, a cosinor analysis found rhythmic expression for approximately 11.9% of all 17 664 analyzed placental transcripts. These results suggest that the placenta responds to seasonal cues and add to the growing body of evidence that the placenta acts as a peripheral clock, which may provide a molecular explanation for the extensive associations between season of birth and health outcomes.

Maternal circadian disruption is associated with variation in placental DNA methylation.

Circadian disruption is a common environmental and occupational exposure with public health consequences, but not much is known about whether circadian disruption affects in utero development. We investigated whether maternal circadian disruption, using night shift work as a proxy, is associated with variations in DNA methylation patterns of placental tissue in an epigenome-wide association study (EWAS) of night shift work. Here, we compared cytosine-guanosine dinucleotide (CpG) specific methylation genome-wide of placental tissue (measured with the Illumina 450K array) from participants (n = 237) in the Rhode Island Child Health Study (RICHS) who did (n = 53) and did not (n = 184) report working the night shift, using robust linear modeling and adjusting for maternal age, pre-pregnancy smoking, infant sex, maternal adversity, and putative cell mixture. Statistical analyses were adjusted for multiple comparisons and results presented with Bonferroni or Benjamini and Hochberg (BH) adjustment for false discovery rate. Night shift work was associated with differential methylation in placental tissue, including CpG sites in the genes NAV1, SMPD1, TAPBP, CLEC16A, DIP2C, FAM172A, and PLEKHG6 (Bonferroni-adjusted p<0.05). CpG sites within NAV1, MXRA8, GABRG1, PRDM16, WNT5A, and FOXG1 exhibited the most hypomethylation, while CpG sites within TDO2, ADAMTSL3, DLX2, and SERPINA1 exhibited the most hypermethylation (BH q<0.10). Functional analysis indicated GO-terms associated with cell-cell adhesion and enriched GWAS results for psoriasis. Night shift work was associated with differential methylation of the placenta, which may have implications for fetal health and development. This is the first study to examine the epigenetic impacts of night shift exposure, as a proxy for circadian disruption, on placental methylation in humans, and, while results should be interpreted with caution, suggests circadian disruption may have epigenetic impacts.