Cancer hygiene hypothesis: A test from wild captive mammals.

The hygiene hypothesis, according to which the recent reduction of exposure to infectious agents in the human species would be the origin of various diseases, including autoimmune diseases and cancer, has often been proposed but not properly tested on animals. Here, we evaluated the relevance of this hypothesis to cancer risk in mammals in an original way, namely by using information on zoo mammals. We predicted that a higher richness of parasitic cohorts in the species' natural habitat would result in a greater occurrence of evolutionary mismatch due to the reduction of parasites in captive conditions. This, in turn, could contribute to an increased risk of developing lethal cancers. Using a comparative analysis of 112 mammalian species, we explored the potential relationship between cancer risk and parasite species richness using generalized phylogenetic least squares regressions to relate parasite species richness to cancer risk data. We found no strong evidence that parasite species richness increased cancer risk in zoo mammals for any of the parasite groups we tested. Without constituting definitive proof of the irrelevance of the hygienic hypothesis, our comparative study using zoo mammals does not support it, at least with respect to cancer risks.

Cancer Prevalence Across Vertebrates.

Cancer is pervasive across multicellular species, but what explains differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades (amphibians, sauropsids and mammals) we found that neoplasia and malignancy prevalence increases with adult weight (contrary to Peto's Paradox) and somatic mutation rate, but decreases with gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%) the black-footed penguin (<0.4%), ferrets (63%) and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer.

The effect of environmental pollution on gene expression of seabirds: A review.

One of the biggest challenges for ecotoxicologists is to detect harmful effects of contaminants on individual organisms before they have caused significant harm to natural populations. One possible approach for discovering sub-lethal, negative health effects of pollutants is to study gene expression, to identify metabolic pathways and physiological processes affected by contaminants. Seabirds are essential components of ecosystems but highly threatened by environmental changes. Being at the top of the food chain and exhibiting a slow pace of life, they are highly exposed to contaminants and to their ultimate impacts on populations. Here we provide an overview of the currently available seabird-related gene expression studies in the context of environmental pollution. We show that studies conducted, so far, mainly focus on a small selection of xenobiotic metabolism genes, often using lethal sampling protocols, while the greater promise of gene expression studies for wild species may lie in non-invasive procedures focusing on a wider range of physiological processes. However, as whole genome approaches might still be too expensive for large-scale assessments, we also bring out the most promising candidate biomarker genes for future studies. Based on the biased geographical representativeness of the current literature, we suggest expanding studies to temperate and tropical latitudes and urban environments. Also, as links with fitness traits are very rare in the current literature, but would be highly relevant for regulatory purposes, we point to an urgent need for establishing long-term monitoring programs in seabirds that would link pollutant exposure and gene expression to fitness traits.

The effect of placentation type, litter size, lactation and gestation length on cancer risk in mammals.

Reproduction is a central activity for all living organisms but is also associated with a diversity of costs that are detrimental for survival. Until recently, the cost of cancer as a selective force has been poorly considered. Considering 191 mammal species, we found cancer mortality was more likely to be detected in species having large, rather than low, litter sizes and long lactation lengths regardless of the placentation types. However, increasing litter size and gestation length are not per se associated with an enhanced cancer mortality risk. Contrary to basic theoretical expectations, the species with the highest cancer mortality were not those with the most invasive (i.e. haemochorial) placentation, but those with a moderately invasive (i.e. endotheliochorial) one. Overall, these results suggest that (i) high reproductive efforts favour oncogenic processes' dynamics, presumably because of trade-offs between allocation in reproduction effort and anti-cancer defences, (ii) cancer defence mechanisms in animals are most often adjusted to align reproductive lifespan, and (iii) malignant cells co-opt existing molecular and physiological pathways for placentation, but species with the most invasive placentation have also selected for potent barriers against lethal cancers. This work suggests that the logic of Peto's paradox seems to be applicable to other traits that promote tumorigenesis.

Correlations between oxidative DNA damage and formation of hepatic tumours in two flatfish species from contaminated environments.

Many species in aquatic environments face increased exposure to oncogenic pollution due to anthropogenic environmental change which can lead to higher cancer prevalence. The mechanistic relationship connecting environmental pollution and cancer is multi-factorial and poorly understood, and the specific mechanisms are so far still uncharacterized. One potential mediator between pollutant exposure and cancer is oxidative damage to DNA. We conducted a study in the field with two flatfish species, European flounder (Platichthys flesus L.) and common dab (Limanda limanda L.) with overlapping distribution and similar ecological niche, to investigate if the link between oncogenic pollutants and cancer described in ecotoxicological literature could be mediated by oxidative DNA damage. This was not the case for flounders as neither polycyclic aromatic hydrocarbon (PAH) bile metabolites nor metallic trace element concentrations were related to oxidative DNA damage measurements. However, dabs with higher PAH concentrations did exhibit increased oxidative damage. High oxidative DNA damage also did not predict neoplasm occurrence, rather, healthy individuals tended to have higher oxidative damage measurements compared to fishes with pre-neoplastic tumours. Our analyses showed that flounders had lower concentrations of PAH bile metabolites, suggesting that compared to dab this species is less exposed or better at eliminating these contaminants.

Spontaneously occurring tumors in different wild-derived strains of hydra.

Hydras are freshwater cnidarians widely used as a biological model to study different questions such as senescence or phenotypic plasticity but also tumoral development. The spontaneous tumors found in these organisms have been so far described in two female lab strains domesticated years ago (Hydra oligactis and Pelmatohydra robusta) and the extent to which these tumors can be representative of tumors within the diversity of wild hydras is completely unknown. In this study, we examined individuals isolated from recently sampled wild strains of different sex and geographical origin, which have developed outgrowths looking like tumors. These tumefactions have common features with the tumors previously described in lab strains: are composed of an accumulation of abnormal cells, resulting in a similar enlargement of the tissue layers. However, we also found diversity within these new types of tumors. Indeed, not only females, but also males seem prone to form these tumors. Finally, the microbiota associated to these tumors is different from the one involved in the previous lineages exhibiting tumors. We found that tumorous individuals hosted yet undescribed Chlamydiales vacuoles. This study brings new insights into the understanding of tumor susceptibility and diversity in brown hydras from different origins.

Life history and cancer in birds: clutch size predicts cancer.

Cancer is a disease that affects nearly all multicellular life, including birds. However, little is known about what factors explain the variance in cancer prevalence among species. Litter size is positively correlated with cancer prevalence in managed species of mammals, and larger body size, but not incubation or nestling period, is linked to tumor prevalence in wild birds. Also, birds that produce more elaborate sexual traits are expected to have fewer resources for cancer defenses and thus higher cancer prevalence. In this study, we examined whether cancer prevalence is associated with a wide variety of life history traits (clutch size, incubation length, body mass, lifespan, and the extent of sexual dimorphism) across 108 species of managed birds in 25 different zoological facilities, sanctuaries, and veterinary clinics. We found that clutch size was positively correlated with cancer and neoplasia (both benign and malignant) prevalence, even after controlling for body mass. Cancer prevalence was not associated with incubation length, body mass, lifespan, or sexual dimorphism. The positive correlations of clutch size with cancer prevalence and neoplasia prevalence suggest that there may be life-history trade-offs between reproductive investment and somatic maintenance (in the form of cancer prevention mechanisms) in managed birds.

Cancer Prevalence Across Vertebrates.

Cancer is pervasive across multicellular species. Are there any patterns that can explain differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades (amphibians, sauropsids and mammals) we found that neoplasia and malignancy prevalence increases with adult weight and decreases with gestation time, contrary to Peto’s Paradox. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%) the black-footed penguin (<0.4%), ferrets (63%) and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer.

Carryover effects of winter mercury contamination on summer concentrations and reproductive performance in little auks.

Many animals migrate after reproduction to respond to seasonal environmental changes. Environmental conditions experienced on non-breeding sites can have carryover effects on fitness. Exposure to harmful chemicals can vary widely between breeding and non-breeding grounds, but its carryover effects are poorly studied. Mercury (Hg) contamination is a major concern in the Arctic. Here, we quantified winter Hg contamination and its carryover effects in the most abundant Arctic seabird, the little auk Alle alle. Winter Hg contamination of birds from an East Greenland population was inferred from head feather concentrations. Birds tracked with Global Location Sensors (GLS, N = 28 of the total 92) spent the winter in western and central North Atlantic waters and had increasing head feather Hg concentrations with increasing longitude (i.e., eastward). This spatial pattern was not predicted by environmental variables such as bathymetry, sea-surface temperature or productivity, and needs further investigation. Hg concentrations in head feathers and blood were strongly correlated, suggesting a carryover effect of adult winter contamination on the consequent summer concentrations. Head feather Hg concentrations had no clear association with telomere length, a robust fitness indicator. In contrast, carryover negative effects were detected on chick health, as parental Hg contamination in winter was associated with decreasing growth rate of chicks in summer. Head feather Hg concentrations of females were not associated with egg membrane Hg concentrations, or with egg volume. In addition, parental winter Hg contamination was not related to Hg burdens in chicks' body feathers. Therefore, we hypothesise that the association between parental winter Hg exposure and the growth of their chick results from an Hg-related decrease in parental care, and needs further empirical evidence. Our results stress the need of considering parental contamination on non-breeding sites to understand Hg trans-generational effects in migrating seabirds, even at low concentrations.

Wild animals as an underused treasure trove for studying the genetics of cancer.

Recent years have seen an emergence of the field of comparative cancer genomics. However, the advancements in this field are held back by the hesitation to use knowledge obtained from human studies to study cancer in other animals, and vice versa. Since cancer is an ancient disease that arose with multicellularity, oncogenes and tumour-suppressor genes are amongst the oldest gene classes, shared by most animal species. Acknowledging that other animals are, in terms of cancer genetics, ecology, and evolution, rather similar to humans, creates huge potential for advancing the fields of human and animal oncology, but also biodiversity conservation. Also see the video abstract here: https://youtu.be/UFqyMx5HETY.

Pesticide impacts on avian species with special reference to farmland birds: a review.

For decades, we have observed a major biodiversity crisis impacting all taxa. Avian species have been particularly well monitored over the long term, documenting their declines. In particular, farmland birds are decreasing worldwide, but the contribution of pesticides to their decline remains controversial. Most studies addressing the effects of agrochemicals are limited to their assessment under controlled laboratory conditions, the determination of lethal dose 50 (LD50) values and testing in a few species, most belonging to Galliformes. They often ignore the high interspecies variability in sensitivity, delayed sublethal effects on the physiology, behaviour and life-history traits of individuals and their consequences at the population and community levels. Most importantly, they have entirely neglected to test for the multiple exposure pathways to which individuals are subjected in the field (cocktail effects). The present review aims to provide a comprehensive overview for ecologists, evolutionary ecologists and conservationists. We aimed to compile the literature on the effects of pesticides on bird physiology, behaviour and life-history traits, collecting evidence from model and wild species and from field and lab experiments to highlight the gaps that remain to be filled. We show how subtle nonlethal exposure might be pernicious, with major consequences for bird populations and communities. We finally propose several prospective guidelines for future studies that may be considered to meet urgent needs.

Oxidative physiology is weakly associated with pigmentation in birds.

The mechanistic link between avian oxidative physiology and plumage coloration has attracted considerable attention in past decades. Hence, multiple proximal hypotheses were proposed to explain how oxidative state might covary with the production of melanin and carotenoid pigments. Some hypotheses underscore that these pigments (or their precursors, e.g., glutathione) have antioxidant capacities or function as molecules storing the toxic excess of intracellular compounds, while others highlight that these pigments can act as pro-oxidants under specific conditions. Most studies addressing these associations are at the intraspecific level, while phylogenetic comparative studies are still scarce, though needed to assess the generality of these associations. Here, we tested whether plumage and bare part coloration were related to oxidative physiology at an interspecific level by measuring five oxidative physiology markers (three nonenzymatic antioxidants and two markers of lipid peroxidative damage) in 1387 individuals of 104 European bird species sampled during the breeding season, and by scoring plumage eumelanin, pheomelanin, and carotenoid content for each sex and species. Only the plasma level of reactive oxygen metabolites was related to melanin coloration, being positively associated with eumelanin score and negatively with pheomelanin score. Thus, our results do not support the role of antioxidant glutathione in driving variation in melanin synthesis across species. Furthermore, the carotenoid scores of feathers and bare parts were unrelated to the measured oxidative physiology parameters, further suggesting that the marked differences in pigmentation across birds does not influence their oxidative state.

Fibropapillomatosis Prevalence and Distribution in Immature Green Turtles (Chelonia mydas) in Martinique Island (Lesser Antilles).

Fibropapillomatosis (FP) threatens the survival of green turtle (Chelonia mydas) populations at a global scale, and human activities are regularly pointed as causes of high FP prevalence. However, the association of ecological factors with the disease's severity in complex coastal systems has not been well established and requires further studies. Based on a set of 405 individuals caught over ten years, this preliminary study provides the first insight of FP in Martinique Island, which is a critical development area for immature green turtles. Our main results are: (i) 12.8% of the individuals were affected by FP, (ii) FP has different prevalence and temporal evolution between very close sites, (iii) green turtles are more frequently affected on the upper body part such as eyes (41.4%), fore flippers (21.9%), and the neck (9.4%), and (iv) high densities of individuals are observed on restricted areas. We hypothesise that turtle's aggregation enhances horizontal transmission of the disease. FP could represent a risk for immature green turtles' survival in the French West Indies, a critical development area, which replenishes the entire Atlantic population. Continuing scientific monitoring is required to identify which factors are implicated in this panzootic disease and ensure the conservation of the green turtle at an international scale.

Telomeres, the loop tying cancer to organismal life-histories.

Recent developments in telomere and cancer evolutionary ecology demonstrate a very complex relationship between the need of tissue repair and controlling the emergence of abnormally proliferating cells. The trade-off is balanced by natural and sexual selection and mediated via both intrinsic and environmental factors. Here, we explore the effects of telomere-cancer dynamics on life history traits and strategies as well as on the cumulative effects of genetic and environmental factors. We show that telomere-cancer dynamics constitute an incredibly complex and multifaceted process. From research to date, it appears that the relationship between telomere length and cancer risk is likely nonlinear with good evidence that both (too) long and (too) short telomeres can be associated with increased cancer risk. The ability and propensity of organisms to respond to the interplay of telomere dynamics and oncogenic processes, depends on the combination of its tissue environments, life history strategies, environmental challenges (i.e., extreme climatic conditions), pressure by predators and pollution, as well as its evolutionary history. Consequently, precise interpretation of telomere-cancer dynamics requires integrative and multidisciplinary approaches. Finally, incorporating information on telomere dynamics and the expression of tumour suppressor genes and oncogenes could potentially provide the synergistic overview that could lay the foundations to study telomere-cancer dynamics at ecosystem levels.

Quantitative meta-analysis reveals no association between mercury contamination and body condition in birds.

Mercury contamination is a major threat to the global environment, and is still increasing in some regions despite international regulations. The methylated form of mercury is hazardous to biota, yet its sublethal effects are difficult to detect in wildlife. Body condition can vary in response to stressors, but previous studies have shown mixed effects of mercury on body condition in wildlife. Using birds as study organisms, we provide the first quantitative synthesis of the effect of mercury on body condition in animals. In addition, we explored the influence of intrinsic, extrinsic and methodological factors potentially explaining cross-study heterogeneity in results. We considered experimental and correlative studies carried out in adult birds and chicks, and mercury exposure inferred from blood and feathers. Most experimental investigations (90%) showed a significant relationship between mercury concentrations and body condition. Experimental exposure to mercury disrupted nutrient (fat) metabolism, metabolic rates, and food intake, resulting in either positive or negative associations with body condition. Correlative studies also showed either positive or negative associations, of which only 14% were statistically significant. Therefore, the overall effect of mercury concentrations on body condition was null in both experimental (estimate ± SE = 0.262 ± 0.309, 20 effect sizes, five species) and correlative studies (-0.011 ± 0.020, 315 effect sizes, 145 species). The single and interactive effects of age class and tissue type were accounted for in meta-analytic models of the correlative data set, since chicks and adults, as well as blood and feathers, are known to behave differently in terms of mercury accumulation and health effects. Of the 15 moderators tested, only wintering status explained cross-study heterogeneity in the correlative data set: free-ranging wintering birds were more likely to show a negative association between mercury and body condition. However, wintering effect sizes were limited to passerines, further studies should thus confirm this trend in other taxa. Collectively, our results suggest that (i) effects of mercury on body condition are weak and mostly detectable under controlled conditions, and (ii) body condition indices are unreliable indicators of mercury sublethal effects in the wild. Food availability, feeding rates and other sources of variation that are challenging to quantify likely confound the association between mercury and body condition in natura. Future studies could explore the metabolic effects of mercury further using designs that allow for the estimation and/or manipulation of food intake in both wild and captive birds, especially in under-represented life-history stages such as migration and overwintering.

Parental age does not influence offspring telomeres during early life in common gulls (Larus canus).

Parental age can affect offspring telomere length through heritable and epigenetic-like effects, but at what stage during development these effects are established is not well known. To address this, we conducted a cross-fostering experiment in common gulls (Larus canus) that enabled us distinguish between pre- and post-natal parental age effects on offspring telomere length. Whole clutches were exchanged after clutch completion within and between parental age classes (young and old) and blood samples were collected from chicks at hatching and during the fastest growth phase (11 days later) to measure telomeres. Neither the ages of the natal nor the foster parents predicted the telomere length or the change in telomere lengths of their chicks. Telomere length (TL) was repeatable within chicks, but increased across development (repeatability = 0.55, intraclass correlation coefficient within sampling events 0.934). Telomere length and the change in telomere length were not predicted by post-natal growth rate. Taken together, these findings suggest that in common gulls, telomere length during early life is not influenced by parental age or growth rate, which may indicate that protective mechanisms buffer telomeres from external conditions during development in this relatively long-lived species.

The evolution and ecology of benign tumors.

Tumors are usually classified into two main categories - benign or malignant, with much more attention being devoted to the second category given that they are usually associated with more severe health issues (i.e., metastatic cancers). Here, we argue that the mechanistic distinction between benign and malignant tumors has narrowed our understanding of neoplastic processes. This review provides the first comprehensive discussion of benign tumors in the context of their evolution and ecology as well as interactions with their hosts. We compare the genetic and epigenetic profiles, cellular activities, and the involvement of viruses in benign and malignant tumors. We also address the impact of intra-tumoral cell composition and its relationship with the tumoral microenvironment. Lastly, we explore the differences in the distribution of benign and malignant neoplasia across the tree of life and provide examples on how benign tumors can also affect individual fitness and consequently the evolutionary trajectories of populations and species. Overall, our goal is to bring attention to the non-cancerous manifestations of tumors, at different scales, and to stimulate research on the evolutionary ecology of host-tumor interactions on a broader scale. Ultimately, we suggest that a better appreciation of the differences and similarities between benign and malignant tumors is fundamental to our understanding of malignancy both at mechanistic and evolutionary levels.

Tumors (re)shape biotic interactions within ecosystems: Experimental evidence from the freshwater cnidarian Hydra.

While it is often assumed that oncogenic processes in metazoans can influence species interactions, empirical evidence is lacking. Here, we use the cnidarian Hydra oligactis to experimentally explore the consequences of tumor associated phenotypic alterations for its predation ability, relationship with commensal ciliates and vulnerability to predators. Unexpectedly, hydra's predation ability was higher in tumorous polyps compared to non-tumorous ones. Commensal ciliates colonized preferentially tumorous hydras than non-tumorous ones, and had a higher replication rate on the former. Finally, in a choice experiment, tumorous hydras were preferentially eaten by a fish predator. This study, for the first time, provides evidence that neoplastic growth has the potential, through effect(s) on host phenotype, to alter biotic interactions within ecosystems and should thus be taken into account by ecologists.

Cancer risk across mammals.

Cancer is a ubiquitous disease of metazoans, predicted to disproportionately affect larger, long-lived organisms owing to their greater number of cell divisions, and thus increased probability of somatic mutations1,2. While elevated cancer risk with larger body size and/or longevity has been documented within species3-5, Peto's paradox indicates the apparent lack of such an association among taxa6. Yet, unequivocal empirical evidence for Peto's paradox is lacking, stemming from the difficulty of estimating cancer risk in non-model species. Here we build and analyse a database on cancer-related mortality using data on adult zoo mammals (110,148 individuals, 191 species) and map age-controlled cancer mortality to the mammalian tree of life. We demonstrate the universality and high frequency of oncogenic phenomena in mammals and reveal substantial differences in cancer mortality across major mammalian orders. We show that the phylogenetic distribution of cancer mortality is associated with diet, with carnivorous mammals (especially mammal-consuming ones) facing the highest cancer-related mortality. Moreover, we provide unequivocal evidence for the body size and longevity components of Peto's paradox by showing that cancer mortality risk is largely independent of both body mass and adult life expectancy across species. These results highlight the key role of life-history evolution in shaping cancer resistance and provide major advancements in the quest for natural anticancer defences.

Avian blood parasite richness decreases with major histocompatibility complex class I loci number.

Major histocompatibility complex (MHC) genes are among the most polymorphic in the vertebrate genome. The high allele diversity is believed to be maintained primarily by sexual and pathogen-mediated balancing selection. The number of MHC loci also varies greatly across vertebrates, most notably across birds. MHC proteins play key roles in presenting antigens on the cell surface for recognition by T cells, with class I proteins specifically targeting intracellular pathogens. Here, we explore the hypothesis that MHC class I diversity (measured as loci number) coevolves with haemosporidian parasite burden of the host. Using data on 54 bird species, we demonstrate that high-MHC class I diversity is associated with significantly lower richness of Plasmodium, Haemoproteus as well as overall haemosporidian parasite lineages, the former thus indicating more efficient protection against intracellular pathogens. Nonetheless, the latter associations were only detected when MHC diversity was assessed using cloning and not 454 pyrosequencing-based studies, nor across all genotyping methods combined. Our results indicate that high-MHC class I diversity might play a key role in providing qualitative resistance against diverse haemosporidian parasites in birds, but further clarification is needed for the origin of contrasting results when using different genotyping methods for MHC loci quantification.