Unconventional oil and natural gas extraction (UOG) combines directional drilling and hydraulic fracturing and produces billions of liters of wastewater per year. Herein, we review experimental studies that evaluated the potential endocrine-mediated health impacts of exposure to a mixture of 23 UOG chemicals commonly found in wastewater. The purpose of this manuscript is to synthesize and summarize a body of work using the same UOG-mix but with different model systems and physiological endpoints in multiple experiments. The studies reviewed were conducted in laboratory animals (mice or tadpoles) and human tissue culture cells. A key feature of the in vivo studies was the use of four environmentally relevant doses spanning three orders of magnitude ranging from concentrations found in surface and ground water in UOG dense areas to concentrations found in UOG wastewater. This UOG-mix exhibited potent antagonist activity for the estrogen, androgen, glucocorticoid, progesterone, and thyroid receptors in human tissue culture cells. Subsequently, pregnant mice were administered the UOG-mix in drinking water and offspring were examined in adulthood or to tadpoles. Developmental exposure profoundly impacted pituitary hormone concentrations, reduced sperm counts, altered folliculogenesis, and increased mammary gland ductal density and preneoplastic lesions in mice. It also altered energy expenditure, exploratory and risk-taking behavior, the immune system in three immune models in mice, and affected basal and antiviral immunity in frogs. These findings highlight the diverse systems affected by developmental EDC exposure and the need to examine human and animal health in UOG regions.

非常规石油和天然气开采（UOG）结合了定向钻井和水力压裂，每年产生数十亿升废水。在此，我们回顾了一些实验研究，这些研究评估了暴露于废水中常见的 23 种 UOG 化学物质混合物对内分泌介导的潜在健康影响。本手稿的目的是在多个实验中使用相同的 UOG 组合但具有不同的模型系统和生理终点来综合和总结一系列工作。所审查的研究是在实验室动物（小鼠或蝌蚪）和人体组织培养细胞中进行的。体内研究的一个关键特征是使用四种环境相关剂量，跨越三个数量级，范围从 UOG 密集区域的地表水和地下水中发现的浓度到 UOG 废水中发现的浓度。这种 UOG 混合物对人体组织培养细胞中的雌激素、雄激素、糖皮质激素、孕激素和甲状腺受体表现出有效的拮抗活性。随后，怀孕小鼠被给予饮用水中的 UOG 混合物，并在成年小鼠或蝌蚪中对后代进行检查。发育暴露严重影响了小鼠的垂体激素浓度、精子数量减少、卵泡发生改变、乳腺导管密度增加和癌前病变。它还改变了小鼠三种免疫模型的能量消耗、探索和冒险行为、免疫系统，并影响了青蛙的基础免疫和抗病毒免疫。这些发现强调了受发育性 EDC 暴露影响的不同系统，以及检查 UOG 地区人类和动物健康的必要性。