Environmental Health Practice Challenges and Research Needs for U.S. Health Departments.

BACKGROUND: Environmental health (EH) professionals, one of the largest segments of the public health workforce, are responsible for delivery of essential environmental public health services. The challenges facing these professionals and research needs to improve EH practice are not fully understood, but 26% of EH professionals working in health departments of the United States plan to retire in 5 y, while only 6% of public health students are currently pursuing EH concentrations. OBJECTIVES: A groundbreaking initiative was recently launched to understand EH practice in health departments of the United States. This commentary article aims to identify priority EH practice challenges and related research needs for health departments. METHODS: A horizon scanning approach was conducted in which challenges facing EH professionals were provided by 1,736 respondents working at health departments who responded to a web-based survey fielded in November 2017. Thematic analyses of the responses and determining the frequency at which respondents reported specific issues and opportunities identified primary EH topic areas. These topic areas and related issues informed focus group discussions at an in-person workshop held in Anaheim, California. The purpose of the in-person workshop was to engage each of the topic areas and issues, through facilitated focus groups, leading to the formation of four to five related problem statements for each EH topic. DISCUSSION: EH professionals are strategically positioned to diagnose, intervene, and prevent public health threats. Focus group engagement resulted in 29 priority problem statements partitioned among 6 EH topic areas: a) drinking water quality, b) wastewater management, c) healthy homes, d) food safety, e) vectors and public health pests, and f) emerging issues. This commentary article identifies priority challenges and related research needs to catalyze effective delivery of essential environmental public health services for common EH program areas in health departments. An unprecedented initiative to revitalize EH practice with timely and strategic recommendations for student and professional training, nontraditional partnerships, and basic and translational research activities is recommended. https://doi.org/10.1289/EHP5161.

Assessment of Community Awareness and Practices Concerning Indoor Air Pollutants - Madison County, Alabama, June 2017.

The Alabama Department of Public Health (ADPH) conducts an annual community assessment to evaluate household preparedness and local public health concerns. In June 2017, ADPH conducted a Community Assessment for Public Health Emergency Response (CASPER), focusing on indoor air pollutants in seven neighborhoods in Madison County, Alabama, where a large percentage of homes were built before 1980. Local health partners had concerns about indoor air quality and environmental risks such as radon; however, limited information was available regarding community awareness, prevention, and mitigation measures related to potential exposures. Weighted response frequencies were calculated from assessment responses. Among 192 household interview respondents, 78.4% were aware of potential indoor lead exposures, but only 12.6% of respondents living in houses built before 1978 reported that the house had been tested for lead. Similarly, respondents in 70.2% of households had heard of radon; however, only 7.3% of houses had been tested for radon. Smoking was reported by residents of 45.7% of households; among those, 48.4% reported that smoking occurred inside the house. Identified gaps in exposure prevention and mitigation, including low lead and radon testing rates and a high prevalence of indoor smoking, were shared with the local health department, and recommendations for timely interventions and policy guidance (e.g., targeted education campaigns and smoking cessation programs) were presented. Results of this CASPER demonstrated its usefulness and efficiency in gathering community-level data to help guide public health policies and timely interventions.

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.

The current frontline symptomatic treatment for Alzheimer's disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR-selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.

Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction.

G protein-coupled receptors (GPCRs) are known to initiate a plethora of signaling pathways in vitro. However, it is unclear which of these pathways are engaged to mediate physiological responses. Here, we examine the distinct roles of Gq/11-dependent signaling and receptor phosphorylation-dependent signaling in bronchial airway contraction and lung function regulated through the M3-muscarinic acetylcholine receptor (M3-mAChR). By using a genetically engineered mouse expressing a G protein-biased M3-mAChR mutant, we reveal the first evidence, to our knowledge, of a role for M3-mAChR phosphorylation in bronchial smooth muscle contraction in health and in a disease state with relevance to human asthma. Furthermore, this mouse model can be used to distinguish the physiological responses that are regulated by M3-mAChR phosphorylation (which include control of lung function) from those responses that are downstream of G protein signaling. In this way, we present an approach by which to predict the physiological/therapeutic outcome of M3-mAChR-biased ligands with important implications for drug discovery.

An Antibody Biosensor Establishes the Activation of the M1 Muscarinic Acetylcholine Receptor during Learning and Memory.

Establishing the in vivo activation status of G protein-coupled receptors would not only indicate physiological roles of G protein-coupled receptors but would also aid drug discovery by establishing drug/receptor engagement. Here, we develop a phospho-specific antibody-based biosensor to detect activation of the M1 muscarinic acetylcholine receptor (M1 mAChR) in vitro and in vivo Mass spectrometry phosphoproteomics identified 14 sites of phosphorylation on the M1 mAChR. Phospho-specific antibodies to four of these sites established that serine at position 228 (Ser(228)) on the M1 mAChR showed extremely low levels of basal phosphorylation that were significantly up-regulated by orthosteric agonist stimulation. In addition, the M1 mAChR-positive allosteric modulator, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, enhanced acetylcholine-mediated phosphorylation at Ser(228) These data supported the hypothesis that phosphorylation at Ser(228) was an indicator of M1 mAChR activation. This was further supported in vivo by the identification of phosphorylated Ser(228) on the M1 mAChR in the hippocampus of mice following administration of the muscarinic ligands xanomeline and 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Finally, Ser(228) phosphorylation was seen to increase in the CA1 region of the hippocampus following memory acquisition, a response that correlated closely with up-regulation of CA1 neuronal activity. Thus, determining the phosphorylation status of the M1 mAChR at Ser(228) not only provides a means of establishing receptor activation following drug treatment both in vitro and in vivo but also allows for the mapping of the activation status of the M1 mAChR in the hippocampus following memory acquisition thereby establishing a link between M1 mAChR activation and hippocampus-based memory and learning.