Exploring practices, challenges, and priorities for human health and ecological risk assessments in Indigenous communities in Canada.

Indigenous peoples in Canada are disproportionately exposed to environmental contaminants and may face elevated health risks related to their unique cultural, spiritual, and economic relationships with the land, including the use of traditional food systems. However, to date, institutionalized approaches to assess risks to human and ecological health from contaminants have not been well developed or implemented with Indigenous community contexts in mind. There is regulatory interest in developing new approach methods for risk assessment, and thus an opportunity to increase their relevance to Indigenous communities in which they will be ultimately applied. Therefore, we conducted an anonymous mixed-methods survey of those involved with risk assessment in Indigenous communities in Canada to: (1) understand risk assessment practice in Indigenous communities, (2) explore challenges with conventional assessment methods and compare these across sectors, and (3) gather perspectives on the development of new approaches. In all, 38 completed survey responses were received (14% response rate). Respondents were from Indigenous community environment and health offices (21% of respondents), Indigenous governments (8%), federal and provincial governments (21%), and academia (45%). Risk communication was seen as the most challenging part of risk assessment (71% responded "difficult"), and nearly all respondents agreed that time (86%), cost (76%), and resource availability (86%) were "moderate" to "serious" problems. Few respondents (16%) had heard of "new approach methods" for risk assessment, and 76% of respondents (and 100% of community-based respondents) agreed on the need to develop improved risk assessment approaches. To modernize risk assessment, respondents recommended advancing cumulative risk assessment methods, improving risk communication, and promoting Indigenous leadership and Traditional Knowledge in assessment activities. Integr Environ Assess Manag 2024;00:1-16. © 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Contaminated sites and Indigenous peoples in Canada and the United States: A scoping review.

Indigenous communities are disproportionately exposed to contaminated sites, and this poses unique challenges as many Indigenous peoples consider land as an integral part of their culture and economy. This scoping review aimed to identify and map information on contaminated sites and Indigenous peoples in Canada and the United States, namely (1) the relationship between contaminated sites and Indigenous peoples and their land and food systems; (2) strategies, challenges, and successes for contaminated sites assessment and management on Indigenous land; and (3) Indigenous leadership and inclusion in contaminated site assessment and management. We followed a PRISMA-ScR (Transparent Reporting of Systematic Reviews and Meta-Analyses-Extension for Scoping Reviews) checklist to collect data that could be categorized into these three objectives. Between October 2021 and July 2023, information from three data streams was retrieved: a systematic literature search; a grey literature search; and federal site data retrieval (Canada's Federal Contaminated Sites Inventory, USEPA's contaminated sites databases, including Superfund). This search yielded 51 peer-reviewed articles, 21 grey literature articles, and 11 404 federal site records, evidencing the contamination of the lands of 875 Indigenous communities and the presence of 440 different contaminants or contaminant groups. The body of information was categorized into three themes within the above objectives: Objective 1: Indigenous communities and geographic patterns; Contaminated sites, sources, and media; Contaminated sites and Indigenous lands; Contaminated sites and Indigenous food systems; Contaminated sites and the health of Indigenous peoples; Objective 2: Site management and classification processes; Health risk assessment; Risk management; Long-term management; and Objective 3: Collaborative research, Collaborative site management; Traditional knowledge and contaminated sites. Results highlighted a need to prioritize holism, efficiency, and Indigenous leadership in site assessment, management, and research, including a focus on community-specific approaches to site assessment and management; a reconceptualization of risks that privileges Indigenous epistemologies; and greater collaboration between stakeholder networks. Integr Environ Assess Manag 2023;00:1-24. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Parental Preconception Exposures to Outdoor Neighbourhood Environments and Adverse Birth Outcomes: A Protocol for a Scoping Review and Evidence Map.

Parental preconception exposures to built and natural outdoor environments could influence pregnancy and birth outcomes either directly, or via a range of health-related behaviours and conditions. However, there is no existing review summarising the evidence linking natural and built characteristics, such as air and noise pollution, walkability, greenness with pregnancy and birth outcomes. Therefore, the planned scoping review aims to collate and map the published literature on parental preconception exposures to built and natural outdoor environments and adverse pregnancy and birth outcomes. We will search electronic databases (MEDLINE, EMBASE, Scopus) to identify studies for inclusion. Studies will be included if they empirically assess the relationship between maternal and paternal preconception exposures to physical natural and built environment features that occur outdoors in the residential neighbourhood and adverse pregnancy and birth outcomes. Two reviewers will independently screen titles and abstracts, and then the full text. Data extraction and assessment of study quality will be performed by one researcher and checked by a second researcher. Results will be summarised in a narrative synthesis, with additional summaries presented as tables and figures. The scoping review will be disseminated via a peer-reviewed publication, at academic conferences, and published on a website.

The use of fluorescently-tagged apoptolidins in cellular uptake and response studies.

The apoptolidins are glycomacrolide microbial metabolites reported to be selectively cytotoxic against tumor cells. Using fluorescently tagged active derivatives we demonstrate selective uptake of these four tagged glycomacrolides in cancer cells over healthy human blood cells. We also demonstrate the utility of these five fluorescently tagged glycomacrolides in fluorescent flow cytometry to monitor cellular uptake of the six glycomacrolides and cellular response.

Decoupling Activation of Heme Biosynthesis from Anaerobic Toxicity in a Molecule Active in Staphylococcus aureus.

Small molecules active in the pathogenic bacterium Staphylococcus aureus are valuable tools for the study of its basic biology and pathogenesis, and many molecules may provide leads for novel therapeutics. We have previously reported a small molecule, 1, which activates endogenous heme biosynthesis in S. aureus, leading to an accumulation of intracellular heme. In addition to this novel activity, 1 also exhibits toxicity towards S. aureus growing under fermentative conditions. To determine if these activities are linked and establish what features of the molecule are required for activity, we synthesized a library of analogs around the structure of 1 and screened them for activation of heme biosynthesis and anaerobic toxicity to investigate structure-activity relationships. The results of this analysis suggest that these activities are not linked. Furthermore, we have identified the structural features that promote each activity and have established two classes of molecules: activators of heme biosynthesis and inhibitors of anaerobic growth. These molecules will serve as useful probes for their respective activities without concern for the off target effects of the parent compound.

Fluorescent probes of the apoptolidins and their utility in cellular localization studies.

Apoptolidin A has been described among the top 0.1% most-cell-selective cytotoxic agents to be evaluated in the NCI 60 cell line panel. The molecular structure of apoptolidin A consists of a 20-membered macrolide with mono- and disaccharide moieties. In contrast to apoptolidin A, the aglycone (apoptolidinone) shows no cytotoxicity (>10 µM) when evaluated against several tumor cell lines. Apoptolidin H, the C27 deglycosylated analogue of apoptolidin A, displayed sub-micromolar activity against H292 lung carcinoma cells. Selective esterification of apoptolidins A and H with 5-azidopentanoic acid afforded azido-functionalized derivatives of potency equal to that of the parent macrolide. They also underwent strain-promoted alkyne-azido cycloaddition reactions to provide access to fluorescent and biotin-functionalized probes. Microscopy studies demonstrate apoptolidins A and H localize in the mitochondria of H292 human lung carcinoma cells.

A general, enantioselective synthesis of N-alkyl terminal aziridines and C2-functionalized azetidines via organocatalysis.

A short, high-yielding protocol involving the enantioselective α-chlorination of aldehydes has been developed for the enantioselective synthesis of C2-functionalized aziridines and N-alkyl terminal azetidines from a common intermediate. This methodology allows for the rapid preparation of functionalized aziridines in 50-73% overall yields and 88-94% ee, and azetidines in 22-32% overall yields and 84-92% ee. Moreover, we developed a scalable and cost-effective route to the key organocatalyst (54% overall yield, >95% dr).