The impact of maternal endocrine diseases on offspring health: The germline effects and beyond - Fellows' seminar by Qiaolin Deng

“We investigate how maternal endocrine diseases affect the germline and/or the foetal development by uterine environment, resulting in changes in cellular and physiological functions that shape offspring health and disease susceptibility,” explained Qiaolin Deng of the Department of Physiology and Pharmacology, Karolinska Institute and Wallenberg Academy Fellow. “Women's health remains significantly underfunded, partly due to the prevailing thoughts that these issues affect only women. Through our work, we aim not only to advance understanding in this research area but also to highlight the broader societal implications of women’s health.”

The immortal germline

Deng’s research group studies the developmental principles of germline specification in health and disease using mouse models and human stem-cell cultures coupled with state-of-the-art molecular and cellular tools. She explained that, broadly speaking, mammals have two cell types – somatic and germ cells. “Germ cells are often considered to be immortal, as they serve as the sole carriers of genetic and epigenetic information across generations, perpetuating life,” she said. “Germline development is a long, complicated process and errors that occur in the germline can lead to profound and enduring consequences for species fitness and survival.” Deng highlighted that the concept of the germline was proposed to argue against Lamarckism (named after French zoologist Jean-Baptiste Lamarck) which suggested that physical characteristics acquired through use or disuse during organism’s lifetime can be passes on to its offspring; as well as Charles Darwin’s pangenesis theory which proposed the existence of tiny particles − gemmules, which contribute to the germline and so influence the next generation. She then described the work of German evolutionary biologist August Weismann, regarded as the most notable evolutionary theorist after Darwin, who proposed the existence of an impenetrable, barrier to separate somatic and germ cells – known as the Weismann barrier resulted in the unidirectional flow of heritable information.  “To safeguard the integrity of the germline, Weismann's barrier is proposed as a protective mechanism, segregating germ cells from somatic cells to shield them from environmental fluctuations,” explained Deng. “And changes in the somatic cells cannot be transferred from to the germline and on to the next generation in mammals.”

Enter epigenetics − heritable changes without alterations in the DNA sequence

However, it is the advances in the field of epigenetics that have enhanced our understanding of inheritance substantially. Epigenetics is the study of changes in organisms caused by the modification of gene expression rather than alteration of the genetic code itself. Deng explained that we now know that “each cell has the same DNA but there are hundreds of different cell types – their morphology and function depends on how the genetic information is used when the cells respond to different external factors.” “Epigenetics is the Chef who decides how to use the cookbook,” she added. “The key feature is that it is reversible – changes in cellular function can be undone.” In this regard she pointed to the 2012 Nobel Prize in Physiology or Medicine which was awarded jointly to John B. Gurdon and Shinya Yamanaka for their work showing that mature cells can be reprogrammed to become pluripotent (meaning they are able to differentiate into different cell types). These discoveries completely changed views of development and cellular specialisation. The possibility of being able to reprogramme human cells offers new opportunities to study diseases and develop methods for regenerative medicine. “Advancements in technology have enabled studies of molecular mechanisms beyond DNA, such as non-coding RNAs, histone modifications and DNA methylation, which collectively orchestrate cellular identity,” she explained. “These epigenetic mechanisms have emerged as key players linking parental health conditions to the predisposition of offspring to diseases such as obesity, diabetes, cardiovascular disease and behavioural disorders, a process known as the epigenetic inheritance of disease.” Deng’s group specifically investigates how maternal diseases conditions impact the health outcomes of future offspring through the developmental programming by placentas and/or germline modulation, a process known as epigenetic inheritance of disease or developmental origins of health and disease (DOHaD). Some of the early research work in this area has included trying to understand the developmental origins of higher rates of cardiovascular disease in certain regions as well as the physiological consequences of undernutrition and famine (most notably the Dutch famine birth cohort study which was set up to investigate the effects of acute maternal undernutrition in the 1944–1945 Dutch famine during specific stages of gestation on later health, with a focus on chronic cardiovascular and metabolic diseases, ageing and mental health; and, similar work on the great Famine in Ukraine in 1932−33) And it’s not just about the mother’s health, Deng also highlighted that more evidence is being accumulated about the role of the father in healthy pregnancy outcomes. She highlighted a recent Nature article showing the link between the paternal microbiome and offspring fitness in mice models − “Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality, which is probably due to dysfunctional placentas. Therefore, adverse pregnancy sometimes is not just a female problem.”

Women’s health – it’s not just about women

Deng’s group’s research currently focuses on diabetes and polycystic ovarian syndrome (PCOS) in women using mouse models, human-cohort samples, single-cell sequencing and disease-derived placental organoids in microfluidic co-culture systems. Worldwide, the International Diabetes Federation (IDF) estimates that one in six live births (16.8%) are to women with some form of hyperglycaemia in pregnancy.  Her laboratory has recently shown that even mild hyperglycemia during pregnancy still posed challenges in placental function followed by developmental programming effects on the offspring. Notably, male and female offspring exhibited distinct, sex-dimorphic phenotypes. “This is extremely intriguing, and we will follow up by investigating the underlying mechanisms." She also explained that their collaborative work has also shown that daughters of women with polycystic ovary syndrome (PCOS) are five times more likely to be diagnosed with PCOS as adults, and that the generational transmission is driven by high levels of male sex hormones during pregnancy. And sons of women with PCOS also have a twofold increased risk of developing obesity. “All our work has emphasised that women’s health is not only about women but also concerning men and children. More and more studies are showing this,” said Deng. “In 2020, only 5% of global research and development funding was allocated to women’s health research. This was split into 4% for women’s cancers and 1% for all other women-specific health issues.” “In the Global South there is strikingly increase of diabetes and cardiometabolic diseases. In addition to urbanisation and lifestyle changes, our research highlights another contributing factor emphasising the importance on women’s health”. Adding to the complexity, she noted that “Therapies that target treatment during pregnancy remain significantly underexplored due to the lingering shadow of historical tragedies like thalidomide.” “But we need to embrace new technologies – like nanomedicine which represents the next frontier,” she concluded. “Nanomedicine provides possibilities for highly targeted and specific therapies. However, it’s expensive, very resource-consuming in general to perform experiments assessing health impacts on mothers and children, highlighting the critical need for supportive funding policies.”   Michelle Galloway: Part-time media officer at STIAS Photograph: SCPS Photography