Adverse Reproductive and Developmental Health Outcomes Following Prenatal Exposure to a Hydraulic Fracturing Chemical Mixture in Female C57Bl/6 Mice

Abstract

Unconventional oil and gas operations using hydraulic fracturing can contaminate surface and groundwater with endocrine-disrupting chemicals. We have previously shown that 23 of 24 commonly used hydraulic fracturing chemicals can activate or inhibit the estrogen, androgen, glucocorticoid, progesterone, and/or thyroid receptors in a human endometrial cancer cell reporter gene assay and that mixtures can behave synergistically, additively, or antagonistically on these receptors. In the current study, pregnant female C57Bl/6 dams were exposed to a mixture of 23 commonly used unconventional oil and gas chemicals at approximately 3, 30, 300, and 3000 μg/kg·d, flutamide at 50 mg/kg·d, or a 0.2% ethanol control vehicle via their drinking water from gestational day 11 through birth. This prenatal exposure to oil and gas operation chemicals suppressed pituitary hormone concentrations across experimental groups (prolactin, LH, FSH, and others), increased body weights, altered uterine and ovary weights, increased heart weights and collagen deposition, disrupted folliculogenesis, and other adverse health effects. This work suggests potential adverse developmental and reproductive health outcomes in humans and animals exposed to these oil and gas operation chemicals, with adverse outcomes observed even in the lowest dose group tested, equivalent to concentrations reported in drinking water sources. These endpoints suggest potential impacts on fertility, as previously observed in the male siblings, which require careful assessment in future studies.

Unconventional oil and gas chemicals and wastewater-impacted water samples promote adipogenesis via PPARγ-dependent and independent mechanisms in 3T3-L1 cells

“…Concentrations tested were dependent on toxicity tested performed prior to bioassays to prevent potential erroneous interpretation of receptor antagonism due to toxicity; all concentrations tested exhibited no toxicity in MTT assay. Results for WV samples published previously; Kassotis et al, 2016, Endocrine disrupting activities of surface water associated with a West Virginia oil and gas industry wastewater disposal well; Science of the Total Environment. …”

“…>1000 different chemicals are used for hydraulic fracturing across the US (Waxman et al, 2011; Environmental Protection Agency (EPA), 2015), many of which have been demonstrated to act as endocrine disrupting chemicals (EDCs) both in vitro and in vivo (Kassotis et al, 2014; Webb et al, 2014; Bolden et al, 2015; Kassotis et al, 2016a; Kassotis et al, 2015; He et al, 2017a; He et al, 2017b; Blewett et al, 2017a). EDCs are exogenous chemicals or mixtures of chemicals that can interfere with any aspect of hormone action (Zoeller et al, 2012; The Endocrine Disruption Exchange (TEDX), 2017; Diamanti-Kandarakis et al, 2009) and may disrupt development and contribute to disease in both humans and animals, particularly during critical windows of development (Vandenberg et al, 2012; Welshons et al, 2003).…”

“…Specifically, we selected a mixture of 23 commonly used UOG chemicals that has previously been examined in vitro and in vivo (Kassotis et al, 2014; Kassotis et al, 2016a; Kassotis et al, 2015), a subset of surface water (n = 4) extracts near a UOG wastewater-impacted site in WV, USA (Kassotis et al, 2016b), a subset of surface water samples (n = 4) near UOG spill sites in CO, USA (Kassotis et al, 2018b), and two UOG wastewater samples from CO that we have previously analytically characterized (Kassotis et al, 2015). All samples were screened for potential adipogenic activity in 3T3–L1 cells, and PPARγ activity was interrogated using a FRET reporter gene assay to further delineate mechanism (likely molecular initiating event).…”

Underutilized and Under Threat: Environmental Policy as a Tool to Address Diabetes Risk

“…While the CPP was intended to address climate change by reducing greenhouse gas emissions, it would have also further affected ancillary air pollutants, including those linked to diabetes risk. Similarly, intriguing evidence now suggests that chemicals used in oil and gas extraction (e.g., hydraulic fracturing or “fracking”) function as EDCs with effects that include metabolic disruptions [61, 62]. Furthermore, these processes increase leaching of diabetogenic arsenic into groundwater [63].…”

Salting the Earth: The Environmental Impact of Oil and Gas Wastewater Spills

“…Reproductive effects were seen in pups at all exposures levels. Male pups showed signs of hormonal disruption including lower sperm counts, increased testis weight, and increased blood testosterone levels, 31 while females showed reduced levels of prolactin, follicle-stimulating hormone, and luteinizing hormone 32 …”