Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

Abstract

Modern living challenges female reproductive health. We are witnessing a rise in reproductive disorders and drop in birth rates across the world. The reasons for these manifestations are multifaceted and most likely include continuous exposure to an ever-increasing number of chemicals. The cause–effect relationships between chemical exposure and female reproductive disorders, however, have proven problematic to determine. This has made it difficult to assess the risks chemical exposures pose to a woman’s reproductive development and function. To address this challenge, this review uses the adverse outcome pathway (AOP) concept to summarize current knowledge about how chemical exposure can affect female reproductive health. We have a special focus on effects on the ovaries, since they are essential for lifelong reproductive health in women, being the source of both oocytes and several reproductive hormones, including sex steroids. The AOP framework is widely accepted as a new tool for toxicological safety assessment that enables better use of mechanistic knowledge for regulatory purposes. AOPs equip assessors and regulators with a pragmatic network of linear cause–effect relationships, enabling the use of a wider range of test method data in chemical risk assessment and regulation. Based on current knowledge, we propose ten putative AOPs relevant for female reproductive disorders that can be further elaborated and potentially be included in the AOPwiki. This effort is an important step towards better safeguarding the reproductive health of all girls and women.

Live birth achieved despite the absence of ejaculated spermatozoa and mature oocytes retrieved: a case report

“…Chromosome misalignment and precocious chromatid splitting could occur in oocytes featuring the MII spindle [28,37]. Therefore, younger patients with an unexpectedly inadequate response to ovarian stimulation due to specific genetic background and/or endocrine derangements [38][39][40] are more likely to benefit from PLM-navigated ICSI timing than women of advanced age.…”

A Pragmatic Approach to Adverse Outcome Pathway Development and Evaluation

“…This, alongside the lack of commensurate professional recognition of the scholarly effort invested in rigorous AOP development, is a major hurdle that prevents many potential AOP developers from either embarking on the task all together, or saps motivation once it becomes clear how much work is required. These points are also reflected in the discrepancy between “purely conceptual” or “putative” AOPs that have been published in the open literature, eg ( Barenys et al , 2020 ; Franssen et al , 2021 ; Johansson et al , 2020 ; Martinovic-Weigelt et al , 2017 ; Palermo et al , 2021 ; Vinken, 2020 ; Weiss et al , 2021 ; Yang et al , 2019 ), versus those that exist and are under active development in the AOP-wiki .…”

Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries

“…But if not due to disrupted steroid signaling, what then could help explain the observed associations between fetal exposure to endocrine disruptors and reproductive disorders in women? One obvious explanation could be disrupted ovary development, which, in turn, would give rise to disease later as a consequence of compromised ovary/endocrine function ( Johansson et al , 2020 ).…”