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Adverse environmental exposures—war and violence, natural disasters, escalating heat, worsening air quality—experienced in pregnancy are consequential for multiple domains of well-being over the life course, including health, cognitive development, schooling, and earnings. Though these environmental exposures become embodied via biological processes, they are fundamentally sociological phenomena: Their emergence, allocation, and impact are structured by institutions and power. As a result, consequential early-life environmental exposures are a critical part of the sociological understanding of social stratification, intergenerational mobility, and individual and cohort life course trajectories. We review theory and evidence on prenatal exposures, describe enduring methodological issues and potential solutions for elucidating these effects, and discuss the importance of this evidence for the stratification of opportunity and outcomes in contemporary societies.
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Example of Adverse Outcome Pathway Concept Enabling Genome-to-Phenome Discovery in Toxicology
Synopsis The following article represents a mini-review of an intensive 10-year progression of genome-to-phenome (G2P) discovery guided by the adverse outcome pathway (AOP) concept. This example is presented as a means to stimulate crossover of this toxicological concept to enhance G2P discovery within the broader biological sciences community. The case study demonstrates the benefits of the AOP approach for establishing causal linkages across multiple levels of biological organization ultimately linking molecular initiation (often at the genomic scale) to organism-level phenotypes of interest. The case study summarizes a US military effort to identify the mechanism(s) underlying toxicological phenotypes of lethargy and weight loss in response to nitroaromatic munitions exposures, such as 2,4,6-trinitrotoluene. Initial key discoveries are described including the toxicogenomic results that nitrotoluene exposures inhibited expression within the peroxisome proliferator activated receptor α (PPARα) pathway. We channeled the AOP concept to test the hypothesis that inhibition of PPARα signaling in nitrotoluene exposures impacted lipid metabolic processes, thus affecting systemic energy budgets, ultimately resulting in body weight loss. Results from a series of transcriptomic, proteomic, lipidomic, in vitro PPARα nuclear signaling, and PPARα knock-out investigations ultimately supported various facets of this hypothesis. Given these results, we next proceeded to develop a formalized AOP description of PPARα antagonism leading to body weight loss. This AOP was refined through intensive literature review and polished through multiple rounds of peer-review leading to final international acceptance as an Organisation for Economic Cooperation and Development-approved AOP. Briefly, that AOP identifies PPARα antagonist binding as the molecular initiating event (MIE) leading to a series of key events including inhibition of nuclear transactivation for genes controlling lipid metabolism and ketogenesis, inhibition of fatty acid beta-oxidation and ketogenesis dynamics, negative energy budget, and ultimately the adverse outcome (AO) of body-weight loss. Given that the PPARα antagonism MIE represented a reliable indicator of AO progression within the pathway, a phylogenetic analysis was conducted which indicated that PPARα amino acid relatedness generally tracked species relatedness. Additionally, PPARα amino acid relatedness analysis using the Sequence Alignment to Predict Across Species Susceptibility predicted susceptibility to the MIE across vertebrates providing context for AOP extrapolation across species. Overall, we hope this illustrative example of how the AOP concept has benefited toxicology sows a seed within the broader biological sciences community to repurpose the concept to facilitate enhanced G2P discovery in biology.
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- Award ID(s):
- 1927470
- PAR ID:
- 10196270
- Date Published:
- Journal Name:
- Integrative and Comparative Biology
- Volume:
- 60
- Issue:
- 2
- ISSN:
- 1540-7063
- Page Range / eLocation ID:
- 375 to 384
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1093/icb/icaa064
