Application of mouse embryonic stem cell test to detect gender-specific effect of chemicals: a supplementary tool for embryotoxicity prediction

Gender effect is an inherent property of chemicals, characterised by variations caused by chemical-biology interaction. It is widely existed, but the shortage of appropriate model restricts the study on gender-specific effect. The embryonic stem cell test (EST) has been utilised as an alternative test for developmental toxicity. Despite its numerous improvements, mouse embryonic stem cells with an XX karyotype have not been used in the EST, which restricts the ability of the EST to identify gender-specific effect during high-throughput-screening (HTS) of chemicals to date. To address this, embryonic stem cell (ESC) SP3 line with an XX karyotype was used to establish a “female” model as a complement to EST. The authors proposed a “double-objects in unison” (DOU)-EST, which consisted of male ESC and female ESC; a seven-day EST protocol was utilised, and the gender-specific effect of chemicals was determined and discriminated; the replacement of myosin heavy chain (MHC) with myosin light chain (MLC) provided a suitable molecular biomarker in the DOU-EST. New linear discriminant functions were given in the purpose of distinguishing chemicals into three classes, namely no gender-specific effect, male-susceptive and female-susceptive. For fifteen chemicals in training set, the concordances of prediction result as no gender effect, male susceptive and female susceptive were 86.67%, 86.67% and 93.33% respectively, the sensitivities were 66.67%, 83.33% and 83.33% respectively, and the specificities were 91.67%, 88.89% and 100% respectively; the total accuracy of DOU-EST was 86.67%. For three chemicals in test set, one was incorrectively predicted. The possible reason for misclassification may due to the absence of hormone environment in vitro. Leave-one-out cross validation (LOOCV) indicated a mean error rate of 18.34%. Taken together, these data suggested a good performance of the proposed DOU-EST. Emerging chemicals with undiscovered gender-specific effect are anticipated to be screened with the DOU-EST.

Authors: Cheng W, Zhou R, Liang F, Wei H, Feng Y, Wang Y. ;Full Source: Chemical Research in Toxicology. 2016 Jul 21. [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][Epub ahead of print] ;[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]