This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) systematic review synthesized effects of background levels of per- and polyfluorylalkyl substance (PFAS) levels on reproductive health outcomes in the general public: fertility, preterm birth, miscarriage, ovarian health, menstruation, menopause, sperm health, and in utero fetal growth. The inclusion criteria included original research (or primary) studies, human subjects, and investigation of outcomes of interest following non-occupational exposures. It drew from four databases (Web of Science, PubMed, Embase and Health and Environmental Research Online (HERO)) using a standardized search string for all studies published between 1 January 2017 and 13 April 2022. Risk of bias was assessed by two independent reviewers. Data were extracted and reviewed by multiple reviewers. Each study was summarized under its outcome in terms of methodology and results and placed in context, with recommendations for future research. Of 1712 records identified, 30 were eligible, with a total of 27,901 participants (33 datasets, as three studies included multiple outcomes). There was no effect of background levels of PFAS on fertility. There were weakly to moderately increased odds of preterm birth with higher perfluorooctane sulfonic acid (PFOS) levels; the same for miscarriage with perfluorooctanoic acid (PFOA) levels. There was limited yet suggestive evidence for a link between PFAS and early menopause and primary ovarian insufficiency; menstrual cycle characteristics were inconsistent. PFAS moderately increased odds of PCOS- and endometriosis-related infertility, respectively. Sperm motility and DNA health were moderately impaired by multiple PFAS. Fetal growth findings were inconsistent. This review may be used to inform forthcoming drinking water standards and policy initiatives regarding PFAS compounds and drinking water. Future reviews would benefit from more recent studies. Larger studies in these areas are warranted. Future studies should plan large cohorts and open access data availability to capture small effects and serve the public. Funding: Great Lakes Water Authority (Detroit, MI), the Erb Family Foundation through Healthy Urban Waters at Wayne State University (Detroit, MI), and Wayne State University CLEAR Superfund Research (NIH P42ES030991).

Urban environments are afflicted by mixtures of anthropogenic volatile organic compounds (VOCs). VOC sources that drive human exposure include vehicle exhaust, industrial emissions, and oil spillage. The highly volatile VOC benzene has been linked to adverse health outcomes. However, few studies have focused on the later-in-life effects of low-level benzene exposure during the susceptible window of early development. Transcriptomic responses during embryogenesis have potential long-term consequences at levels equal to or lower than 1 ppm, therefore justifying the analysis of adult zebrafish that were exposed during early development. Previously, we identified transcriptomic alteration following controlled VOC exposures to 0.1 or 1 ppm benzene during the first five days of embryogenesis using a zebrafish model. In this study, we evaluated the adult-onset transcriptomic responses to this low-level benzene embryogenesis exposure (n = 20/treatment). We identified key genes, including col1a2 and evi5b, that were differentially expressed in adult zebrafish in both concentrations. Some DEGs overlapped at the larval and adult stages, specifically nfkbiaa, mecr, and reep1. The observed transcriptomic results suggest dose- and sex-dependent changes, with the highest impact of benzene exposure to be on cancer outcomes, endocrine system disorders, reproductive success, neurodevelopment, neurological disease, and associated pathways. Due to molecular pathways being highly conserved between zebrafish and mammals, developmentally exposed adult zebrafish transcriptomics is an important endpoint for providing insight into the long term-effects of VOCs on human health and disease.

The plasminogen activation system (PAS) is primarily responsible for the degradation of fibrin clots as well as extracellular matrix remodeling. Many components of the PAS are produced by the liver, and the expression of these proteins is altered during liver disease. Liver is a primary site for the synthesis of proteins in the PAS, including plasminogen, tPA (tissue-type plasminogen activator), and uPA (urokinase-type plasminogen activator), as well as several modulators of plasmin activation. Clinical studies have shown that liver injury profoundly changes levels of PAS components and fibrinolytic activity in plasma. Likewise, there is strong experimental evidence to suggest that components of the PAS play an important role in determining the severity of hepatic injury and, paradoxically, also contribute to repair and regeneration of the injured liver. Here, we review the dynamic connections between the PAS and liver injury/disease, including changes in PAS expression and function accompanying liver disease in patients and mechanism-centered studies in animal models. We focus on established models of acute hepatic injury, chronic liver disease, and repair/regeneration, and review the effect of gain or loss of function of PAS components on the liver. The review seeks to cover not only field-driving discoveries but also spotlights unexplained dichotomies, challenges with interpretation, and the need for further exploration of mechanisms using leading-edge tools. Critical gaps in our understanding of how the PAS contributes to liver pathophysiology, and vice versa, are identified, and future directions are considered.