Reanalysis of Trichloroethylene and Tetrachloroethylene Metabolism to Glutathione Conjugates Using Human, Rat, and Mouse Liver in Vitro Models to Improve Precision in Risk Characterization.

BACKGROUND: Both trichloroethylene (TCE) and tetrachloroethylene (PCE) are high-priority chemicals subject to numerous human health risk evaluations by a range of agencies. Metabolism of TCE and PCE determines their ultimate toxicity; important uncertainties exist in quantitative characterization of metabolism to genotoxic moieties through glutathione (GSH) conjugation and species differences therein. OBJECTIVES: This study aimed to address these uncertainties using novel in vitro liver models, interspecies comparison, and a sensitive assay for quantification of GSH conjugates of TCE and PCE, S-(1,2-dichlorovinyl)glutathione (DCVG) and S-(1,2,2-trichlorovinyl) glutathione (TCVG), respectively. METHODS: Liver in vitro models used herein were suspension, 2-D culture, and micropatterned coculture (MPCC) with primary human, rat, and mouse hepatocytes, as well as human induced pluripotent stem cell (iPSC)-derived hepatocytes (iHep). RESULTS: We found that, although efficiency of metabolism varied among models, consistent with known differences in their metabolic capacity, formation rates of DCVG and TCVG generally followed the patterns human≥rat≥mouse, and primary hepatocytes>iHep. Data derived from MPCC were most consistent with estimates from physiologically based pharmacokinetic models calibrated to in vivo data. DISCUSSION: For TCE, the new data provided additional empirical support for inclusion of GSH conjugation-mediated kidney effects as critical for the derivation of noncancer toxicity values. For PCE, the data reduced previous uncertainties regarding the extent of TCVG formation in humans; this information was used to update several candidate kidney-specific noncancer toxicity values. Overall, MPCC-derived data provided physiologically relevant estimates of GSH-mediated metabolism of TCE and PCE to reduce uncertainties in interspecies extrapolation that constrained previous risk evaluations, thereby increasing the precision of risk characterizations of these high-priority toxicants. https://doi.org/10.1289/EHP12006.

Advancements in Microfluidic Systems for the Study of Female Reproductive Biology.

The female reproductive tract is a highly complex physiological system that consists of the ovaries, fallopian tubes, uterus, cervix, and vagina. An enhanced understanding of the molecular, cellular, and genetic mechanisms of the tract will allow for the development of more effective assisted reproductive technologies, therapeutics, and screening strategies for female specific disorders. Traditional 2-dimensional and 3-dimensional static culture systems may not always reflect the cellular and physical contexts or physicochemical microenvironment necessary to understand the dynamic exchange that is crucial for the functioning of the reproductive system. Microfluidic systems present a unique opportunity to study the female reproductive tract, as these systems recapitulate the multicellular architecture, contacts between different tissues, and microenvironmental cues that largely influence cell structure, function, behavior, and growth. This review discusses examples, challenges, and benefits of using microfluidic systems to model ovaries, fallopian tubes, endometrium, and placenta. Additionally, this review also briefly discusses the use of these systems in studying the effects of endocrine disrupting chemicals and diseases such as ovarian cancer, preeclampsia, and polycystic ovarian syndrome.