RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release From Enteroendocrine Cells.

BACKGROUND & AIMS: RET tyrosine kinase is necessary for enteric nervous system development. Loss-of-function RET mutations cause Hirschsprung disease (HSCR), in which infants are born with aganglionic bowel. Despite surgical correction, patients with HSCR often experience chronic defecatory dysfunction and enterocolitis, suggesting that RET is important after development. To test this hypothesis, we determined the location of postnatal RET and its significance in gastrointestinal (GI) motility. METHODS: RetCFP/+ mice and human transcriptional profiling data were studied to identify the enteric neuronal and epithelial cells that express RET. To determine whether RET regulates gut motility in vivo, genetic, and pharmacologic approaches were used to disrupt RET in all RET-expressing cells, a subset of enteric neurons, or intestinal epithelial cells. RESULTS: Distinct subsets of enteric neurons and enteroendocrine cells expressed RET in the adult intestine. RET disruption in the epithelium, rather than in enteric neurons, slowed GI motility selectively in male mice. RET kinase inhibition phenocopied this effect. Most RET+ epithelial cells were either enterochromaffin cells that release serotonin or L-cells that release peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), both of which can alter motility. RET kinase inhibition exaggerated PYY and GLP-1 release in a nutrient-dependent manner without altering serotonin secretion in mice and human organoids. PYY receptor blockade rescued dysmotility in mice lacking epithelial RET. CONCLUSIONS: RET signaling normally limits nutrient-dependent peptide release from L-cells and this activity is necessary for normal intestinal motility in male mice. These effects could contribute to dysmotility in HSCR, which predominantly affects males, and uncovers a mechanism that could be targeted to treat post-prandial GI dysfunction.

Sublethal perfluorooctanoic acid and perfluorooctanesulfonic acid delay C. elegans larval development and population growth but do not alter egg hatching.

Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) are polyfluoroalkyl substances (PFAS) used as surface coatings in manufacturing. Exposure to PFAS was shown to be correlated with infertility, low birth weight, and delayed aspects of pubertal development in mammals. Despite many correlational studies, there have been few direct investigations examining the link between PFAS exposure and early animal development. The aim of this study was to (1) examine the effects of PFOA on development and reproduction using the roundworm Caenorhabditis elegans, a model with a high predictive value for human reproductive toxicity and (2) compare observations to exposure to PFOS. PFAS exposure did not markedly alter egg hatching but delayed population growth, in part due to slower larval development. PFAS-exposed worms took longer to progress through larval stages to reach reproductive maturity, and this was not attributed to PFOA-induced toxicity to their food. Our results provide a robust benchmark for testing developmental and reproductive toxicity for other PFAS and PFAS-alternatives which continue to be used in manufacturing and released into the environment.

A geospatial and binomial logistic regression model to prioritize sampling for per- and polyfluorinated alkyl substances in public water systems.

As health-based drinking water standards for per- and polyfluorinated alkyl substances (PFAS) continue to evolve, public health and environmental protection decision-makers must assess exposure risks associated with all public drinking water systems in the United States (US). Unfortunately, current knowledge regarding the presence of PFAS in environmental systems is limited. In this study, a screening approach was established to: (1) identify and direct attention toward potential PFAS hot spots in drinking water sources, (2) prioritize sampling locations, and (3) provide insights regarding the potential PFAS sources that contaminate groundwater and surface water. Our approach incorporates geospatial data from public sources, including the US Environmental Protection Agency's Toxic Release Inventory, to identify locations where PFAS may be present in drinking water sources. An indicator factor (also known as "risk factor") was developed as a function of distance between potential past and/or present PFAS users (e.g., military bases, industrial sites, and airports) and the public water system, which generates a heat map that visualizes potential exposure risks. A binomial logistic regression model indicates whether PFAS are likely to be detected in public water systems. The results obtained using the developed screening approach aligned well (with a 76% overall model accuracy) with PFAS sampling and chemical analysis data from 81 public drinking water systems in the state of Kentucky. This study proposes this screening model as an effective decision aid to assist key decision-makers in identifying and prioritizing sampling locations for potential PFAS exposure risks in the public drinking water sources in their service areas. Integr Environ Assess Manag 2023;19:163-174. © 2022 SETAC.

Diminished androgen levels are linked to irritable bowel syndrome and cause bowel dysfunction in mice.

Functional gastrointestinal disorders (FGIDs) have prominent sex differences in incidence, symptoms, and treatment response that are not well understood. Androgens are steroid hormones present at much higher levels in males than females and could be involved in these differences. In adults with irritable bowel syndrome (IBS), a FGID that affects 5% to 10% of the population worldwide, we found that free testosterone levels were lower than those in healthy controls and inversely correlated with symptom severity. To determine how this diminished androgen signaling could contribute to bowel dysfunction, we depleted gonadal androgens in adult mice and found that this caused a profound deficit in gastrointestinal transit. Restoring a single androgen hormone was sufficient to rescue this deficit, suggesting that circulating androgens are essential for normal bowel motility in vivo. To determine the site of action, we probed androgen receptor expression in the intestine and discovered, unexpectedly, that a large subset of enteric neurons became androgen-responsive upon puberty. Androgen signaling to these neurons was required for normal colonic motility in adult mice. Taken together, these observations establish a role for gonadal androgens in the neural regulation of bowel function and link altered androgen levels with a common digestive disorder.

MODELING FATE AND TRANSPORT OF VOLATILE ORGANIC COMPOUNDS (VOCs) INSIDE SEWER SYSTEMS.

Hazardous waste site investigations have shown that volatile organic compounds (VOCs) can be transported via sewer pipes and migrate into indoor spaces. Despite field data confirming the presence of this exposure pathway, there is lack of context-based numerical models that provide guidance to characterize and predict VOCs concentration in sewer gas at vapor intrusion sites. Particularly, this poses a challenge when assessing and mitigating risks associated with these exposure pathways. Therefore, a numerical model has been developed to simulate the concentration of VOCs in sewer gas in different stages throughout the sewer lines. The developed model considers various input parameters, including temperature, sewer liquid depth, groundwater depth, and sewer construction characteristics to incorporate local and operational conditions. The model's output is verified using field data from a sewer system constructed near a Superfund site. Moreover, a sensitivity analysis was conducted to evaluate the model's response to variation of the external input parameters. To the best of our knowledge, this study is the first attempt to model VOCs concentration in sewer gas, particularly to address vapor intrusion. The developed model can be used as a numerical tool to support the development of sewer assessment guidelines, risk assessment studies, and mitigation strategies.