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Developmental Biology - Pregnancy Compensation Theory
Pregnancy Compensation Hypothesis
Why is there such a big difference between women and men when it comes to human diseases?...
Women get autoimmune diseases, such as multiple sclerosis, lupus and rheumatoid arthritis eight times more than men do. On the other hand, women have a smaller risk of getting non-reproductive cancers such as melanoma, colon, kidney and lung cancer.
While there are some exciting developments in cancer treatments, such as immunotherapies, research shows women responding more favorably than men to this type of intervention.
Why is there such a big difference between women and men when it comes to human diseases? An interdisciplinary team of scientists at Arizona State University believes it may have the answer.
In a paper published in the journal Trends in Genetics, this team presents a new hypothesis for the phenomenon, setting the stage for novel research focused specifically on treating autoimmune diseases and cancer.
"Until now, the differences between women and men in regards to human diseases have not been explained by existing theories. We are proposing a new theory called The Pregnancy Compensation Hypothesis.
Basically, women's immune systems evolved to facilitate their survival during the presence of an immunologically invasive placenta and pregnancy, to compensate and survive the assault of parasites and pathogens. Now, in modern, industrialized societies, women are not pregnant all the time and don't have a placenta pushing back against the immune system.
Changes in our reproductive ecology exacerbate an increased risk of autoimmune disease as our immune surveillance is heightened. At the same time, we see a reduction in some diseases, like cancer."
Melissa Wilson PhD, Assistant Pprofessor, School of Life Sciences, Arizona State University, and senior author of the paper.
In the opinion of Heini Natri, the lead author of the study and a postdoctoral scholar with the ASU Center for Evolution and Medicine, because the immune system varies between the sexes, it should be considered when developing immunotherapies and other treatments.
"We think the Pregnancy Compensation Hypothesis may explain why there is a big sex difference in these diseases. Going forward, understanding the evolutionary origin of sex bias in these diseases can help us better understand the mechanisms and particular pieces of the immune system to target.
"Our goal is to actually make treatments better for everyone as we realize cancer is different in men and women.
In the study of most cancers and other diseases, and so far in the development of cancer treatments, that difference has not really been taken into account."
Heini Natri PhD, School of Life Sciences, Arizona State University; Center for Evolution and Medicine, Arizona State University, Tempe, Arizona, USA.
Effects of industrialization
Another factor that may exacerbate this situation is living a modern-day, urban lifestyle.
In industrialized communities, autoimmune diseases appear to occur at a much higher rate than in non-industrialized populations. Researchers believe our human immune system evolved expecting a given load of parasites. In our modern environment, exposure to those parasites has diminished — so the immune system has fewer foreign targets. With this reduced load, the immune system attacks 'self.'
"There is a mismatch between the ancestral environment humans we were adapted for — and the industrialized environment many people currently live in. In terms of an evolutionary timescale, our environment has changed incredibly fast," explains Angela Garcia, a postdoctoral research fellow with the center.
"We have also shifted from an active lifestyle to a sedentary one. We now have an overabundance of calories available, which potentially allows us to maintain excessive levels of hormones, including the female hormone estradiol. Maintaining such high levels of hormones may increase the chance of triggering autoimmune diseases."
Angela R. Garcia, School of Life Sciences, Arizona State University; Center for Evolution and Medicine, Arizona State University, Tempe, Arizona, USA
Future treatments
The researchers suggest that by framing future research within the Pregnancy Compensation Hypothesis, scientists could dive deeper into characterization of genes, environmental context and the longitudinal history of people.
"We think this is more than a hypothesis. By using modern molecular biologic techniques in genetics and genomics, we can look at the differences between male and female immune systems, and between modern immune profiles and those in pre-industrial populations. By doing so, we may find new ways to prevent cancer and autoimmune diseases," Ken Buetow, a professor with the school and co-author of the study.
Researchers also suggest there are [other] places where genes are regulated uniquely in males and females, as well as across environmental contexts.
"Going forward, we need to systematically collect environmental variables like pathogenic exposure, levels of stress and reproductive hormones, and parity. We have to understand these areas better," said Wilson.
Highlights
There are major sex differences in human disease that cannot be explained by reproductive hormones or environmental exposures alone.
Genes on the sex chromosomes exhibit differences in expression that are independent of reproductive hormones, and could contribute to sex differences in disease.
We propose that the ancestral immune system was strongly shaped by the requirement to compensate for unique immune regulation during pregnancy.
Dimorphism in immune function in response to placentation and pregnancy occurs via direct impact of reproductive hormones on immune function, as well as through heritable variation in sex chromosome dosage.
Although evolution has shaped sex differences in immune function over millions of years, industrialized urban populations experience both exacerbated sex differences in hormonal composition as well as reduced pregnancies compared with nonindustrialized populations.
We hypothesize that, ancestrally, sex-specific immune modulation evolved to facilitate survival of the pregnant person in the presence of an invasive placenta and an immunologically challenging pregnancy – an idea we term the 'pregnancy compensation hypothesis' (PCH). Further, we propose that sex differences in immune function are mediated, at least in part, by the evolution of gene content and dosage on the sex chromosomes, and are regulated by reproductive hormones. Finally, we propose that changes in reproductive ecology in industrialized environments exacerbate these evolved sex differences, resulting in the increasing risk of autoimmune disease observed in females, and a counteracting reduction in diseases such as cancer that can be combated by heightened immune surveillance. The PCH generates a series of expectations that can be tested empirically and that may help to identify the mechanisms underlying sex differences in modern human diseases.
Authors
Heini Natri, Angela R. Garcia, Kenneth H. Buetow, Benjamin C. Trumble and Melissa A. Wilson.
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Jun 13 2019 Fetal Timeline Maternal Timeline News
MODERN | ARCHAIC  Although humans evolved in a mosaic of different environments, sedentary industrialized urban environments are evolutionarily novel. ASU scientists predict these shifts in the environment may contribute to mismatches between how our immune systems have been shaped by natural selection to respond to the environment and how they are now responding, resulting in human disease. CREDIT Trends in Genetics
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