Annual Meeting of the Japanese Society of Toxicology

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　Redox signaling [e.g., PTP1B/EGFR signaling] through oxidation of cysteines in proteins is involved in maintaining intracellular homeostasis. Once SH group on PTP1B active cysteine undergoes oxidation by reactive oxygen species (ROS) to form reversible SOH, and further irreversible SO₃H, PTP1B activity is inhibited, resulting in EGFR phosphorylation. We found that 9,10-phenanthrenequinone (9,10-PQ), a major quinone in PM_2.5, produced ROS excess through its redox cycling. While 9,10-PQ-produced ROS drastically decreased recombinant PTP1B activity by irreversible oxidation of Cys, exposure of A431 cells to 9,10-PQ did not markedly inhibit intracellular PTP activity and caused transient EGFR activation, suggesting that the cells have a convenient system to block further oxidation of PTP1B. Hence, we investigated the involvement of persulfide (SSH) with high-nucleophilicity in the ROS-dependent modification of PTP1B caused by 9,10-PQ.

　To generate S-sulfhydrated Cys, PTP1B was reacted with sodium disulfide (Na₂S₂). As a result, Cys215, PTP1B active site, was converted to SSH, which was reversible. Although excessive ROS cause oxidation of SH to irreversible SO₃H, we postulated that reaction products of SSH with ROS are SSOH, SSO₂H, and SSO₃H that could be reduced by dithiothreitol (DTT) regenerating SH. Consistently, we succeeded in detecting SSOH conversion at Cys215 during a reaction of PTP1B with H₂O₂ or 9,10-PQ in Na₂S₂presence. As expected, SSOH was reduced to SH by DTT and PTP1B activity was restored. Under these conditions, oxidized PTP1B was decreased, suggesting a reversibility of SSO_nH (n = 1~3) associated with PTP1B activity recovery.

　This study indicates, for the first time, that persulfide-mediated S-sulfhydration at Cys215 of PTP1B appears to protect the active site against oxidation by excessive ROS. In other words, persulfides might repress further irreversible oxidation of protein thiols.

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The role of toxicologic pathologists is to translate the diverse range of morphologic changes observed in toxicity studies into a uniform and readily understood set of diagnostic terms that can be tabulated and summarized in peer-reviewed publications or reports for regulatory submissions.

The essential components of the INHAND project are the Rodent Organ System or Non-rodent Species Working Groups. The Rodent Organ System Working Groups have the responsibility to prepare the nomenclature guidelines for both proliferative and non-proliferative lesions of rats and mice for their assigned organ system – 15 total systems. The Non-rodent Species Working Groups cover terminology specific to a species as well as noting diagnostic criteria that may be different from rodents for common lesions. The Non-rodent Working Groups include non-human primate, dog, minipig, rabbit and fish.

Substantial progress has been made to date – twelve of the 15 rodent organ systems have been published. Soft Tissue, Integument, Female Reproductive System, Digestive System, Cardiovascular System and Skeletal System and Tooth have been published in the Journal of Toxicologic Pathology (official journal of JSTP). The Respiratory System, Hepatobiliary System, Urinary System, Nervous System, Mammary, Zymbal’s, Preputial and Clitoral Glands, and Male Reproductive System have been published in Toxicologic Pathology (official journal of STP, BSTP and ESTP). Recommendations from an Apoptosis/Necrosis Working Group were published in Toxicologic Pathology. The Endocrine and Special Senses Systems are scheduled for publication in the Journal of Toxicologic Pathology in 2018. The Hematopoietic and Lymphoid System draft is scheduled for 2018.

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BioCelerate, a subsidiary of TransCelerate, is a preclinical industry consortium driving initiatives to increase efficiency and productivity in early stage R&D. Motivated in part by the FDA’s Strategic Plan for Regulatory Science and binding guidance requiring CDISC SEND standard format for nonclinical data, the Toxicology Data Sharing (TDS) Initiative was launched to enable participants to make more informed decisions on compound progression based on increased understanding of on-target and off-target toxicity. Via access to a cloud-based data sharing platform, DataCelerate, participants will have the ability to share, search for, visualize, and export de-identified unstructured (PDF format for legacy studies) and structured (SEND-compliant format) data sets stored in curated toxicology and background control data repositories. Long term, the platform will support and link TransCelerate and BioCelerate data sharing initiatives, facilitating valuable insights across the entire drug development continuum. Presented here are the core capabilities, use cases, and system architecture for the data sharing platform as well as the principles guiding data sharing and collaboration amongst BioCelerate participants.

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