OECD Series on Adverse Outcome Pathways

An Adverse Outcome Pathway (AOP) describes a logical sequence of causally linked events at different levels of biological organisation, which follows exposure to a stressor and leads to an adverse health effect in humans or wildlife. AOPs are the central element of a toxicological knowledge framework, promoted by member countries through OECD, built to support chemical risk assessment based on mechanistic reasoning. These AOPs are available in the AOP-Wiki, an interactive and virtual encyclopaedia for AOP development. Following their development and review, the endorsed AOPs are published in the OECD Series on Adverse Outcome Pathways. As scientific knowledge progresses, the publication of an AOP in this series does not preclude regular updates or new contributions to a given AOP. While the AOP-Wiki is a dynamic tool, only impactful changes to the AOP will be reflected in subsequent updates of the published AOP.


Adverse Outcome Pathway on histone deacetylase inhibition leading to testicular atrophy

The present AOP describes inhibition of histone deacetylase resulting in testicular atrophy. Histone deacetylase inhibitors (HDIs) are approved as anti-cancer drugs since HDIs have apoptotic effects in cancer cells. The intracellular mechanisms of induction of the spermatocyte apoptosis by HDIs are suggested as histone deacetylase (HDAC) inhibition as MIE, histone acetylation increase, disrupted cell cycle, apoptosis, and spermatocyte depletion as KEs. The adverse outcome has been defined as testicular atrophy. The HDIs inhibit deacetylation of the histone, leading to an increase in histone acetylation. The apoptosis induced by disrupted cell cycle leads to spermatocyte depletion and testis atrophy. Testicular toxicity is of interest for human health risk assessment especially in terms of reproductive and developmental toxicity, however, the testicular toxicity has not been fully elucidated. This AOP may be one of the pathways induced by HDIs, which suggests the pathway networks of protein hyperacetylations.


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