Evidence for Reproductive Health Effects Following Exposures to Hydraulic Fracturing Chemical Mixtures.

Unconventional oil and natural gas (UOG) operations have emerged over the last four decades to transform oil and gas production in the United States and globally by unlocking previously inaccessible hydrocarbon deposits. UOG development utilizes many compounds associated with conventional oil and gas, as well as some specific to UOG extraction, particularly during hydraulic fracturing (HF). While research is increasing on UOG chemicals and their mixtures, this review discusses the current evidence for reproductive toxicity following exposures to UOG/HF mixtures. These complex chemical mixtures have been demonstrated to interact with numerous mechanisms known to influence reproductive health. A growing number of environmental and controlled laboratory testing studies have reported adverse reproductive health effects in animals exposed to various UOG chemical mixtures. An expanding body of epidemiological literature has assessed adverse birth outcomes, although none has directly examined reproductive measures such as time to pregnancy, semen quality, and other direct measures of fertility. The existing literature provides moderate evidence for decreased birth weights, increased risk of small for gestational age and/or preterm birth, increased congenital abnormalities, and increased infant mortality, though importantly, studies are widely variable in methods used. Most studies utilized distance from UOG operations as an exposure proxy and did not measure actual chemical exposures experienced by those living near these operations. As such, while there is growing evidence for effects on births in these regions and good mechanistic evidence for reproductive toxicity, there is much research still needed to make firm conclusions about UOG development and reproductive health.

Adipogenic and endocrine disrupting mixture effects of organic and inorganic pollutant mixtures.

Chronic health conditions are rapidly increasing in prevalence and cost to society worldwide: in the US, >42 % of adults aged 20 and older are currently classified as obese. Exposure to endocrine disrupting chemicals (EDCs) has been implicated as a causal factor; some EDCs, termed "obesogens", can increase weight and lipid accumulation and/or perturb metabolic homeostasis. This project aimed to assess the potential combination effects of diverse inorganic and organic contaminant mixtures, which more closely reflect environmentally realistic exposures, on nuclear receptor activation/inhibition and adipocyte differentiation. Herein, we focused on two polychlorinated biphenyls (PCB-77 and 153), two perfluoroalkyl substances (PFOA and PFOS), two brominated flame retardants (PBB-153 and BDE-47), and three inorganic contaminants (lead, arsenic, and cadmium). We examined adipogenesis using human mesenchymal stem cells and receptor bioactivities using luciferase reporter gene assays in human cell lines. We observed significantly greater effects for several receptor bioactivities by various contaminant mixtures relative to individual components. All nine contaminants promoted triglyceride accumulation and/or pre-adipocyte proliferation in human mesenchymal stem cells. Comparing simple component mixtures to individual components at 10 % and 50 % effect levels revealed putative synergistic effects for each of the mixtures for at least one of the concentrations relative to the individual component chemicals, some of which also exhibited significantly greater effects than the component contaminants. Our results support further testing of more realistic and complex contaminant mixtures that better reflect environmental exposures, in order to more conclusively define mixture responses both in vitro and in vivo.

Cetyl Alcohol Polyethoxylates Disrupt Metabolic Health in Developmentally Exposed Zebrafish.

Alcohol polyethoxylates (AEOs), such as cetyl alcohol ethoxylates (CetAEOs), are high-production-volume surfactants used in laundry detergents, hard-surface cleaners, pesticide formulations, textile production, oils, paints, and other products. AEOs have been suggested as lower toxicity replacements for alkylphenol polyethoxylates (APEOs), such as the nonylphenol and octylphenol polyethoxylates. We previously demonstrated that nonylphenol polyethoxylates induced triglyceride accumulation in several in vitro adipogenesis models and promoted adiposity and increased body weights in developmentally exposed zebrafish. We also demonstrated that diverse APEOs and AEOs were able to increase triglyceride accumulation and/or pre-adipocyte proliferation in a murine pre-adipocyte model. As such, the goals of this study were to assess the potential of CetAEOs to promote adiposity and alter growth and/or development (toxicity, length, weight, behavior, energy expenditure) of developmentally exposed zebrafish (Danio rerio). We also sought to expand our understanding of ethoxylate chain-length dependent effects through interrogation of varying chain-length CetAEOs. We demonstrated consistent adipogenic effects in two separate human bone-marrow-derived mesenchymal stem cell models as well as murine pre-adipocytes. Immediately following chemical exposures in zebrafish, we reported disrupted neurodevelopment and aberrant behavior in light/dark activity testing, with medium chain-length CetAEO-exposed fish exhibiting hyperactivity across both light and dark phases. By day 30, we demonstrated that cetyl alcohol and CetAEOs disrupted adipose deposition in developmentally exposed zebrafish, despite no apparent impacts on standard length or gross body weight. This research suggests metabolic health concerns for these common environmental contaminants, suggesting further need to assess molecular mechanisms and better characterize environmental concentrations for human health risk assessments.

Increasing Incidence of Spotted Fever Group Rickettsioses in the United States, 2010-2018.

Spotted fever group Rickettsia species are intracellular bacteria transmitted by tick or mite vectors and that cause human diseases referred to as spotted fever group rickettsioses, or spotted fevers. In the United States, the most recognized and commonly reported spotted fevers are Rocky Mountain spotted fever (RMSF) (Rickettsia rickettsii), Rickettsia parkeri rickettsiosis, Pacific Coast tick fever (Rickettsia species 364D), and rickettsialpox (Rickettsia akari). In this study, we summarize and evaluate surveillance data on spotted fever cases reported to the Centers for Disease Control and Prevention (CDC) through the National Notifiable Diseases Surveillance System from 2010 to 2018. During this period, there were 36,632 reported cases of spotted fevers with 95.83% (N = 35,104) reported as meeting the case definition as probable and 4.17% (N = 1528) reported as meeting the case definition as confirmed. The average national incidence of total cases, both probable and confirmed, was 12.77 cases per million persons per year. The highest statewide incidence was in Arkansas, with 256.84 per million per year, whereas the lowest incidence occurred in California, with 0.32 per million per year (note that spotted fevers were not notifiable in Hawaii and Alaska). Cases of spotted fevers were reported more frequently among males by gender, White by race, and non-Hispanic by ethnicity. The incidence of spotted fevers increased significantly from 2010 to 2018, but it is uncertain how many of the reported cases were RMSF and how many developed from more moderate spotted fevers. Improvement of the ability to differentiate between spotted fever group Rickettsia species is needed.

Evaluating Phenotypic and Transcriptomic Responses Induced by Low-Level VOCs in Zebrafish: Benzene as an Example.

Urban environments are plagued by complex mixtures of anthropogenic volatile organic compounds (VOCs), such as mixtures of benzene, toluene, ethylene, and xylene (BTEX). Sources of BTEX that drive human exposure include vehicle exhaust, industrial emissions, off-gassing of building material, as well as oil spillage and leakage. Among the BTEX mixture, benzene is the most volatile compound and has been linked to numerous adverse health outcomes. However, few studies have focused on the effects of low-level benzene on exposure during early development, which is a susceptible window when hematological, immune, metabolic, and detoxification systems are immature. In this study, we used zebrafish to conduct a VOC exposure model and evaluated phenotypic and transcriptomic responses following 0.1 and 1 ppm benzene exposure during the first five days of embryogenesis (n = 740 per treatment). The benzene body burden was 2 mg/kg in 1 ppm-exposed larval zebrafish pools and under the detection limit in 0.1 ppm-exposed fish. No observable phenotypic changes were found in both larvae except for significant skeletal deformities in 0.1 ppm-exposed fish (p = 0.01) compared with unexposed fish. Based on transcriptomic responses, 1 ppm benzene dysregulated genes that were implicated with the development of hematological system, and the regulation of oxidative stress response, fatty acid metabolism, immune system, and inflammatory response, including apob, nfkbiaa, serpinf1, foxa1, cyp2k6, and cyp2n13 from the cytochrome P450 gene family. Key genes including pik3c2b, pltp, and chia.2 were differentially expressed in both 1 and 0.1 ppm exposures. However, fewer transcriptomic changes were induced by 0.1 ppm compared with 1 ppm. Future studies are needed to determine if these transcriptomic responses during embryogenesis have long-term consequences at levels equal to or lower than 1 ppm.

A Review of Volatile Organic Compound Contamination in Post-Industrial Urban Centers: Reproductive Health Implications Using a Detroit Lens.

Volatile organic compounds (VOCs) are a group of aromatic or chlorinated organic chemicals commonly found in manufactured products that have high vapor pressure, and thus vaporize readily at room temperature. While airshed VOCs are well studied and have provided insights into public health issues, we suggest that belowground VOCs and the related vapor intrusion process could be equally or even more relevant to public health. The persistence, movement, remediation, and human health implications of subsurface VOCs in urban landscapes remain relatively understudied despite evidence of widespread contamination. This review explores the state of the science of subsurface movement and remediation of VOCs through groundwater and soils, the linkages between these poorly understood contaminant exposure pathways and health outcomes based on research in various animal models, and describes the role of these contaminants in human health, focusing on birth outcomes, notably low birth weight and preterm birth. Finally, this review provides recommendations for future research to address knowledge gaps that are essential for not only tackling health disparities and environmental injustice in post-industrial cities, but also protecting and preserving critical freshwater resources.