Systems for rating bodies of evidence used in systematic reviews of air pollution exposure and reproductive and children's health: a methodological survey.

BACKGROUND: Translating findings from systematic reviews assessing associations between environmental exposures and reproductive and children's health into policy recommendations requires valid and transparent evidence grading. METHODS: We aimed to evaluate systems for grading bodies of evidence used in systematic reviews of environmental exposures and reproductive/ children's health outcomes, by conducting a methodological survey of air pollution research, comprising a comprehensive search for and assessment of all relevant systematic reviews. To evaluate the frameworks used for rating the internal validity of primary studies and for grading bodies of evidence (multiple studies), we considered whether and how specific criteria or domains were operationalized to address reproductive/children's environmental health, e.g., whether the timing of exposure assessment was evaluated with regard to vulnerable developmental stages. RESULTS: Eighteen out of 177 (9.8%) systematic reviews used formal systems for rating the body of evidence; 15 distinct internal validity assessment tools for primary studies, and nine different grading systems for bodies of evidence were used, with multiple modifications applied to the cited approaches. The Newcastle Ottawa Scale (NOS) and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework, neither developed specifically for this field, were the most commonly used approaches for rating individual studies and bodies of evidence, respectively. Overall, the identified approaches were highly heterogeneous in both their comprehensiveness and their applicability to reproductive/children's environmental health research. CONCLUSION: Establishing the wider use of more appropriate evidence grading methods is instrumental both for strengthening systematic review methodologies, and for the effective development and implementation of environmental public health policies, particularly for protecting pregnant persons and children.

Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment.

Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.

Prenatal exposure to ambient air pollutants and congenital heart defects: An umbrella review.

BACKGROUND: Prenatal exposure to ambient air pollutants has been linked to congenital heart defects (CHD), but findings of existing systematic reviews have been mixed. OBJECTIVE: To assess the epidemiological evidence on associations between prenatal exposure to ambient air pollutants and CHD subtypes, based on a systematic overview of reviews ("umbrella review"). METHODS: We conducted a systematic search for reviews assessing associations between prenatal exposure to criteria air pollutants and CHD. The risk of bias was evaluated using the Risk of Bias in Systematic Reviews (ROBIS) tool. The certainty of the systematic review findings was graded using the Navigation Guide methodology. RESULTS: We identified eleven systematic reviews, including eight with meta-analyses, assessing in total 35 primary studies of prenatal exposure to criteria air pollutants and various CHD subtypes. The certainty of the findings of four meta-analyses indicating an increased risk for coarctation of the aorta associated with nitrogen dioxide exposure was rated as moderate. The certainty of findings indicating positive, inverse, or null associations for other pollutant-subtype combinations was rated as very low to low, based on low precision and high statistical heterogeneity of summary odds ratios (SOR), substantial inconsistencies between review findings, and methodological limitations of the systematic reviews. DISCUSSION: The inconsistent findings and high statistical heterogeneity of many SOR of the included systematic reviews may partly be traced to differences in methodological approaches, and the risk of bias across included reviews (e.g., inclusion criteria, systematic search strategies, synthesis methods) and primary studies (e.g., exposure assessment, diagnostic criteria). Adherence to appropriate systematic review guidelines for environmental health research, as well as rigorous evaluation of risk of bias in primary studies, are essential for future risk assessments and policy-making. Still, our findings suggest that prenatal exposure to ambient air pollutants may increase risks for at least some CHD subtypes.