Hot Testicle Hypothesis May Explain Why Elephants Evolved Anti-Cancer Genes

In Trends in Ecology & Evolution, University of Oxford Professor Fritz Vollrath puts forth his “hot testicle hypothesis”. Vollrath suggests that elephants may carry more copies of p53 encoding genes due to an evolutionary mechanism that functions to protect sperm against harsh temperatures, but serendipitously offers cancer protection.

Elephants a unique model for studying cancer biology

Vollrath, an evolutionary biologist in the department of biology at the University of Oxford, is the lead-author of the study. As a long-term trustee and chairman of the UK charity Save the Elephants, he has spent many years studying the ecology, evolution and behavior of the African elephant in its natural habitat.

Elephants offer a unique system for studying a scientific model known as Peto’s Paradox, named after its discoverer, British statistician Professor Richard Peto.

Peto identified a flaw in the longstanding theory that larger, multi-cellular organisms are at a greater risk of developing cancer. The proposed logic behind this theory was that cancer occurs as a product of mutations cropping up during cell division; therefore, the more cells an organism has, the greater its susceptibility to cancer. Peto’s paradox points out that, if anything, the opposite occurs – there is a lack of correlation between body size and cancer risk at the species level.

“Elephants (Elephantidae) have become a model organism to explore the implications of this paradox because elephants are not only very large but also, uniquely, carry more than one copy of the TP53 gene, which encodes for the p53 protein,” writes Vollrath.

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The p53 protein was dubbed the “Guardian of the Genome” by the oncologist Sir David Lane in 1979, due to its ability to detect and repair damaged DNA during somatic and germline cell division. If the DNA is beyond repair, p53 triggers a cellular cascade, ultimately leading to cell death.

Elephants carry 20 copies of the TP53 gene, unlike other species in the animal kingdom, which are thought to carry just one. “If nothing else, this feature already marks elephants out as an important natural experiment for anyone interested in the TP53 gene complex and the molecular biology of p53 protein,” Vollrath explains in the paper.

Beyond carrying a unique genotype, elephants carry other rare and interesting traits that may be significant for understanding germline instability, Vollrath says. Based on his time studying the giant mammal, he believes that one phenotype deserves particular focus – elephant’s nondescending testicles. Behold the “hot testicle” hypothesis.  

The “hot testicle” hypothesis  

The production of healthy sperm in most mammals is highly influenced by the temperature of the testes, which must be several degrees below body temperature – hence why the scrotum is found outside of the body.

“It seems that in all mammals the high turnover of proliferating cells requires metabolic temperatures 2–4 °C below body temperature. For example, a mouse’s core body temperature is 36.6 °C, while the testicles are at 34 °C; any sperm produced at 37 °C has low viability, with high levels of unrepaired DNA and compromised crossover formation, while sperm produced at 38°C will be killed by apoptosis because of excessive loads of mutated DNA,” Vollrath describes.

Elephants cannot descend their testicles, meaning their testes temperature tracks with their body temperature at approximately 36–37 °C.

Given that elephants also have a large body size compared to their surface area, thick skin and a blisteringly warm natural habitat, Vollrath suggests that elephants face conditions that are “impossibly hot” for producing healthy sperm.

“All things considered, it appears that the elephant’s testes may experience temperatures dangerously high for mammalian sperm production, even under normal body temperatures. High temperature metabolism tends to be coupled with cellular oxidative stress, which increases the probability of mutations. Such mutations could be gene duplications, including multiplications of the TP53 gene,” he says.

Vollrath’s theory proposes that, in elephant evolution, the p53 protein may have played a key role in ensuring the production of health sperm despite soaring testicle temperatures, which is why elephants carry many copies of the TP53 gene.

A testable hypothesis

The Oxford professor emphasizes that his opinion is one that can be tested, outlining numerous research avenues: “Tests would start with addressing the temperature range of elephant testicles and their links to body core temperatures. This topic has serious implications if climate change increases temperatures in the elephant’s natural range, with the potential of endangering whole populations,” Vollrath says.

“Next, one might examine how other taxa, related or not, with ascrotal testicles, compare concerning testes temperature and p53 isoforms. Finally, for cancer researchers, probably the most important question would focus on the mechanism by which the elephant’s various TP53 retrogenes and p53 protein isoforms are able to guard, or not, the soma,” he adds. 

Examining the mechanisms by p53 proteins safeguard cells could play an important role in uncovering novel approaches to cancer prevention, while also offering insights into potential connections between testicle temperature and reproductive well-being.

Reference: Vollrath F. Uncoupling elephant TP53 and cancer.Trends Ecol Evol. 2023. doi: 10.1016/j.tree.2023.05.011

This article is a rework of a press release issued by the University of Oxford. Material has been edited for length and content.