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Krüppel-like factor 9 (Klf9) is a feedforward regulator of glucocorticoid receptor (GR) signaling. Here we show that in zebrafish klf9 is expressed with GR-dependent oscillatory dynamics in synchrony with fkbp5, a GR target that encodes a negative feedback regulator of GR signaling. We found that fkbp5 transcript levels are elevated in klf9–/– mutants and that Klf9 associates with chromatin at the fkbp5 promoter, which becomes hyperacetylated in klf9–/– mutants, suggesting that the GR regulates fkbp5 via an incoherent feedforward loop with klf9. As both the GR and Fkbp5 are known to regulate metabolism, we asked how loss of Klf9 affects metabolic rate and gene expression. We found that klf9–/– mutants have a decreased oxygen consumption rate (OCR) and upregulate glycolytic genes, the promoter regions of which are enriched for potential Klf9 binding motifs. Our results suggest that Klf9 functions downstream of the GR to regulate cellular glucocorticoid responsivity and metabolic homeostasis.

Contaminated drinking water is an important public health consideration in New England where well water is often found to contain arsenic and other metals such as cadmium, lead, and uranium. Chronic or high level exposure to these metals have been associated with multiple acute and chronic diseases, including cancers and impaired neurological development. While individual metal levels are often regulated, adverse health effects of metal mixtures, especially at concentrations considered safe for human consumption remain unclear. Here, we utilized a multivariate analysis that examined behavioral outcomes in the zebrafish model as a function of multiple metal chemical constituents of 92 drinking well water samples, collected in Maine and New Hampshire. To collect these samples, a citizen science approach was used, that engaged local teachers, students, and scientific partners. Our analysis of 4016 metal-mixture combinations shows that changes in zebrafish behavior are highly mixture dependent, and indicate that certain combinations of metals, especially those containing arsenic, cadmium, lead, and uranium, even at levels considered safe in drinking water, are significant drivers of behavioral toxicity. Our data emphasize the need to consider low-level chemical mixture effects and provide a framework for a more in-depth analysis of drinking water samples. We also provide evidence for the efficacy of utilizing citizen science in research, as the broader impact of this work is to empower local communities to advocate for improving their own water quality.

Arsenic is a metalloid that contaminates drinking water supplies worldwide. Owing to concerns for human health, the World Health Organization and the US Environmental Protection Agency have established a safe level in drinking water of ≤10 ppb. Recently, arsenic exposure has also been linked to lower IQ values in children. The effect of arsenic on neurogenesis, specifically eye development, has not been widely explored. This study aimed to examine the effect of environmentally relevant concentrations of arsenic on early eye development by morphological and molecular analysis. The zebrafish, Danio rerio, was chosen to model the impact of arsenic on retinogenesis because of similarities to human eye development. Arsenic exposure to zebrafish embryos resulted in a significant increase in eye diameter at 14 days postfertilization. This was coupled with a trend in thinning of the retinal pigmented epithelium (RPE) layer in embryos exposed to 500 ppb arsenic. Reverse transcription‐quantitative polymerase chain reaction analysis of genes associated with eye development revealed differential expression of Pax6a, Pax2a, Ngn1, Sox2 and Shha relative to control. Pax6a, Pax2a and Sox2 are important in the formation of the RPE. Proper formation of the RPE is necessary for growth of the sclera, which, in turn, is responsible for maintaining the shape of the eye. This could potentially be explained by the disruption of gene expression under arsenic exposure during critical time points in early eye development. These results provide insight into the effects arsenic may be having on early eye development in children exposed to contaminated drinking water supplies.

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