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Review
. 2022 Mar 21;14(6):1585.
doi: 10.3390/cancers14061585.

The Role of ROS as a Double-Edged Sword in (In)Fertility: The Impact of Cancer Treatment

Sara Mendes  1   2 , Rosália Sá  3   4 , Manuel Magalhães  4   5 , Franklim Marques  5 , Mário Sousa  3   4 , Elisabete Silva  6   7
Affiliations
Review

The Role of ROS as a Double-Edged Sword in (In)Fertility: The Impact of Cancer Treatment

Sara Mendes et al. Cancers (Basel). .

Abstract

Tumor cells are highly resistant to oxidative stress resulting from the imbalance between high reactive oxygen species (ROS) production and insufficient antioxidant defenses. However, when intracellular levels of ROS rise beyond a certain threshold, largely above cancer cells' capacity to reduce it, they may ultimately lead to apoptosis or necrosis. This is, in fact, one of the molecular mechanisms of anticancer drugs, as most chemotherapeutic treatments alter redox homeostasis by further elevation of intracellular ROS levels or inhibition of antioxidant pathways. In traditional chemotherapy, it is widely accepted that most therapeutic effects are due to ROS-mediated cell damage, but in targeted therapies, ROS-mediated effects are mostly unknown and data are still emerging. The increasing effectiveness of anticancer treatments has raised new challenges, especially in the field of reproduction. With cancer patients' life expectancy increasing, many aiming to become parents will be confronted with the adverse effects of treatments. Consequently, concerns about the impact of anticancer therapies on reproductive capacity are of particular interest. In this review, we begin with a short introduction on anticancer therapies, then address ROS physiological/pathophysiological roles in both male and female reproductive systems, and finish with ROS-mediated adverse effects of anticancer treatments in reproduction.

Keywords: (in)fertility; chemotherapy; oxidative stress; reactive oxygen species (ROS); targeted agents.

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Conflict of interest statement

We here state that the material contained in the submitted manuscript has not been published previously, and has not being submitted elsewhere for publication. We declare that we all participated in the present study and that we have seen and approved the final version. We also declare that if this publication is accepted, it will not be published elsewhere including electronically in the same form, in English or in any other language, without the written consent of the copyright-holder. There was also no Fabrication, falsification, plagiarism, repetitive publications, obfuscation, no human research or experimentation. All authors also agree the order of authorship. All Authors disclose any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence their work, such as manufacturers of pharmaceuticals, laboratory supplies, and/or medical devices. It also includes employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding, including any financial arrangement with a company whose product is prominent in the submitted manuscript or with a company making a competing product, and any commercial affiliations.

Figures

Figure 1
Figure 1
ROS-mediated activation of cell signaling pathways. Major sites of reactive oxygen species (ROS) production in cells, enzymes responsible for ROS production at each of the cellular compartments, and principal signaling pathways activated.
Figure 2
Figure 2
Spermatogenesis and spermiogenesis. The diagram describes the different stages of spermatogenesis and spermiogenesis.
Figure 3
Figure 3
Oogenesis and folliculogenesis. The diagram describes the different stages of oogenesis and folliculogenesis.
Figure 4
Figure 4
Spermatogenesis dysfunction after anticancer treatment. ROS overproduction due to treatments depletes the antioxidant systems, leading to OS. Both the normal and abnormal spermatozoa can be damaged by ROS; however, in the treatment case (right side), damage is more prevalent since ROS are present/produced in higher quantity due to anticancer treatments. OS impinges on spermatozoa (represented by the red stars) and damages to cell/sperm and mitochondria membranes, DNA damage, and defects in the sperm mid-piece and axonemal region can be observed. The establishment of this compromised process leads to abnormal semen characteristics and is responsible for the fertility decline present in men submitted to anticancer treatments. Reactive oxygen species (ROS).
Figure 5
Figure 5
Ovarian tissue dysfunction after anticancer treatments. Increase in OS-derived from anticancer treatment, due to increased ROS production and impaired antioxidant response leads to the establishment of an oxidative microenvironment. In a post-treatment ovarian stroma, a depletion in the number of primordial and primary follicles and the presence of collagen deposition can be observed (fibrosis). The establishment of this compromised microenvironment impairs ovarian function and is responsible for the fertility decline present in women submitted to anticancer treatments. Reactive oxygen species (ROS). Cisplatin and doxorubicin are two widely used chemotherapeutic drugs to treat several types of cancer, including those of the reproductive tract. Their ROS-mediated effects on fertility will now be revised.
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