While it is now widely acknowledged that numerous human activities promote cancerous pathologies in wildlife (Giraudeau et al. 2018, Sepp et al. 2019, Baines et al. 2021a), the exact magnitude of the resulting ecological and evolutionary consequences remains incompletely understood (Vittecoq et al. 2013, Thomas et al. 2017). Simply predicting the accelerated disappearance of animals that have developed tumors in ecosystems is an oversimplified viewpoint that overlooks other potential repercussions. For instance, at the ecosystem level, the ecological impacts of differing susceptibility to cancer among species will vary based on the functional traits of the most affected species (e.g. predators, prey, keystone species; Hamede et al. 2020, Perret et al. 2020). Phenotypic changes induced by oncogenic processes in hosts also have the potential to alter various interactions between affected organisms and other species within the ecosystem. For example, tumor-bearing hydra exhibit modified interactions with other species compared to their healthy counterparts – they capture more prey, are more susceptible to predation, and experience heavier colonization by commensal ciliates (Boutry et al. 2022a, Duneau and Buchon 2022). At the individual and species levels, Dujon and colleagues (submitted) have suggested that effects at different time scales should be considered in the case of sudden and chronic exposure to mutagenic substances. Initially, it is expected that organisms will over-activate their anticancer defenses, significantly impacting them because these defenses are energetically costly and may force energetic trade-offs (Thomas et al. 2019, Biro et al. 2020, Dujon et al. 2022, Klaassen et al. 2024). It is also anticipated that affected species may progressively alter their life history traits, for example favoring earlier investment in reproduction (Jones et al. 2008, Arnal et al. 2017, Boutry et al. 2022b). In the long term, natural selection may favor the development of more powerful anticancer defenses, such as duplications of tumor suppressor genes (Sulak et al. 2016, Trivedi et al. 2023). Thus, the consequences of anthropogenically induced oncogenic activities on wildlife are diverse and complex, warranting further in-depth research, especially in aquatic ecosystems that are particularly prone to pollution (Häder et al. 2020).
The zebrafish (Danio rerio) is a widely used model for studying cancer due to its ability to develop cancer after exposure to mutagens or gene manipulation (Bambino and Chu 2017). Many tumors that Danio develop are highly homologous with human cancers at histological, proteomic and genetic levels (Kobar et al. 2021). In addition, research has shown that a mixture of organic pollutants common in today's environments can affect development and behavior of zebrafish, highlighting the potential threats they represent for human and animal populations (Bambino and Chu 2017). However, the extent to which the higher incidence of tumors could have population-wide repercussions through changes in life-history traits (Boddy et al. 2015, Ujvari et al. 2016) such as sex ratios or reproductive investment has so far received little consideration.
In humans, offspring sex ratio has been proposed as an indicator of risk of developing certain cancers in both women and men. There is increasing evidence that reproductive hormones play a role in the process of sex ratio adjustment in mammals (Grant and Chamley 2010, Merkling et al. 2018). It has been suggested that hormone profile at the time when children are conceived is responsible for both the offspring sex ratio and the incidence of cancer (James 2006, 2013). For instance, the high proportion of sons among women with pre-menopausal breast cancer may reflect the high levels of estrogen at conception (James 2006). Men who develop testicular cancer have, prior to the cancer diagnosis, a lower proportion of boys compared with the general population (James 2006), possibly due to low testosterone concentrations at the time of conception. However, data regarding whether the children were conceived before or after disease diagnosis is not sufficient to determine how these variables directly influence each other because oncogenic processes frequently exist at a sub-clinical level earlier in life (Thomas et al. 2018). Thus, studies examining the consequence of cancer on sex allocation in model organisms are warranted.
The aim of this study was to provide one of the first experimental studies investigating the effects of cancer on biological traits relevant to evolutionary ecology. First, we examine the possibility that skin cancer occurring at a very early age of the host (i.e. embryonic) could affect sex-specific mortality and/or sex determination, which is partially influenced by the environment in zebrafish (Experiment 1). This bias may occur due to a higher mortality among male embryos developing cancer compared to female embryos (Poulin 1996, Wells 2000, Lary and Paulozzi 2001, Li et al. 2017). Because sex differences in juvenile mortality may influence the strength of selection for sex allocation (Cox and Calsbeek 2010), cancer may increase the likelihood of producing females rather than males. Next, we investigated whether adult females bearing tumors, compared to healthy females, have a sex ratio bias in their brood (Experiment 2). This hypothesis was motivated in part by the influence of toxic substances or high population density on the sex ratio of subsequent generations through epigenetic mechanisms in zebrafish (Pierron et al. 2021, Guirandy et al. 2022). A biased sex ratio favoring males could also occur due to the expectation that females with health issues will produce lower-quality eggs. Regarding the overall survival of offspring in experiment 2, a first potential prediction is that, being the progeny of mothers in poor health, these offspring start life with a disadvantage, potentially reducing their chances of survival. On the other hand, it cannot be dismissed that females with cancer, as observed in other species, allocate more resources to their immediate reproductive events (see references above). This, as a terminal investment in reproduction (Clutton-Brock 1984), may contribute to the enhanced survival of their offspring.