Tag: sex differences

Categories : Gender Medical Research & TechnologyTags :

A New Model of the Liver Will Help Improve Drug Safety for Women

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Improved modelling of male and female livers can help lead to safer drugs

Photo by Danilo Alvesd on Unsplash

Researchers report in PLOS Computational Biology that they developed a powerful new tool to understand how medications affect men and women differently, and that will help lead to safer, more effective drugs in the future.

Women are known to suffer a disproportionate number of liver problems from medications but also usually underrepresented in drug testing. To address this, University of Virginia scientists have developed sophisticated computer simulations of male and female livers and used them to reveal sex-specific differences in how the tissues are affected by drugs.

The new model has already provided unprecedented insights into the biological processes that take place in the liver, the organ responsible for detoxifying the body, in both men and women. But the model also represents a powerful new tool for drug development, helping ensure that new medications will not cause harmful side effects.

“There are incredibly complex networks of genes and proteins that control how cells respond to drugs,” said UVA researcher Jason Papin, PhD, one of the model’s creators. “We knew that a computer model would be required to try to answer these important clinical questions, and we’re hopeful these models will continue to provide insights that can improve healthcare.”

Harmful side effects

Papin, of UVA’s Department of Biomedical Engineering, developed the model in collaboration with Connor Moore, a PhD student, and Christopher Holstege, MD, a UVA emergency medicine physician and director of UVA Health’s Blue Ridge Poison Center. “It is exceedingly important that both men and women receive the appropriate dose of recommended medications,” Holstege noted. “Drug therapy is complex and toxicity can occur with subtle changes in dose for specific individuals.”

Before developing their model, the researchers first looked at the federal Food and Drug Administration’s Adverse Event Reporting System to evaluate the frequency of reported liver problems in men and women. The scientists found that women consistently reported liver-related adverse events more often than did men.

The researchers then sought to explain why this might be the case. To do that, they developed computer models of the male and female livers that integrated vast amounts of data on gene activity and metabolic processes within cells. These cutting-edge liver simulations provided important insights into how drugs (xenobiotics) affect the tissue differently in men and women and allowed the researchers to understand why.

They found that xenobiotic metabolism was more active in untreated males, while pentose and glucoronate interconversions were female-biased, suggesting a difference in pretreatment gene expression, which may result in different initial responses of phase I and phase II metabolism to hepatotoxic drugs. They also observed sex-bias in bile acid biosynthesis, which in combination with xenobiotic metabolism, this result may suggest differences in bacterial deconjugation driven by sex differences in the gut microbiome. Differences were also found in several essential metabolic pathways, such as glycolysis/gluconeogenesis, nucleotide metabolism, and lipid metabolism with supporting evidence in human or rat hepatocytes.

“We were surprised how many differences we found, especially in very diverse biochemical pathways,” said Moore, a biomedical engineering student in Papin’s lab. “We hope our results emphasise how important it is for future scientists to consider how both men and women are affected by their research.”

The work has already identified a key series of cellular processes that explain sex differences in liver damage, and the scientists are calling for more investigation of it to better understand “hepatotoxicity” — liver toxicity. Ultimately, they hope their model will prove widely useful in developing safer drugs.

“We’re hopeful these approaches will be help address many other questions where men and women have differences in drug responses or disease processes,” Papin said. “Our ability to build predictive computer models of complex systems in biology, like those in this study, is truly opening all kinds of new avenues for tackling some of the most challenging biomedical problems.”

Source: University of Virginia Health System

Categories : Diet and Nutrition Metabolic DisordersTags :

Diet Extremes of Carbohydrate and Fat Tied to Sex-specific Mortality Risks

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Photo by I Yunmai on Unsplash

New research suggests that extreme dietary habits involving carbohydrates and fats affect life expectancy. Results published in The Journal of Nutrition show that a low carbohydrate intake in men and a high carbohydrate intake in women are associated with a higher risk of all-cause and cancer-related mortality and that women with higher fat intake may have a lower risk of all-cause mortality. Their findings suggest that people should pursue a balanced diet rather than heavily restricting their carbohydrate or fat intake.

While low-carbohydrate and low-fat diets are becoming popular as a way to promote weight loss and improve blood glucose levels, their long-term effects on life expectancy are less clear. Interestingly, recent studies conducted in Western countries suggest that extreme dietary habits for carbohydrates and fats are associated with a higher risk of mortality. However, few studies have explored these associations in East Asian populations, including Japanese individuals who typically have relatively low fat and high-carbohydrate dietary intakes.

Researchers from Nagoya University Graduate School of Medicine in Japan led by Dr Takashi Tamura conducted a follow-up survey over a period of 9 years with 81 333 Japanese people (34,893 men and 46 440 women) to evaluate the association between carbohydrate and fat intakes and the risk of mortality. Daily dietary intakes of carbohydrates, fats, and total energy were estimated using a food frequency questionnaire and calculated as a percentage of total energy intake for carbohydrates and fats. Carbohydrate intake quality (ie, refined compared with minimally processed carbohydrate intake) and fat intake quality (ie, saturated compared with unsaturated fat intake) were also assessed to examine the impact of food quality on the association with mortality.

They found that men who consumed less than 40% of their total energy from carbohydrates experienced significantly higher risks of all-cause and cancer-related mortality. The trend was observed regardless of whether refined or minimally processed carbohydrate were considered. On the other hand, among women with 5 years or longer of follow-up, those with a high carbohydrate intake of more than 65% had a higher risk of all-cause mortality. No clear association was observed between refined or minimally processed carbohydrate intake and the risk of mortality in women.

For fats, men with a high fat intake of more than 35% of their total energy from fats had a higher risk of cancer-related mortality. They also found that a low intake of unsaturated fat in men was associated with a higher risk of all-cause and cancer-related mortality. In contrast, total fat intake and saturated fat intake in women showed an inverse association with the risk of all-cause and cancer-related mortality. They concluded that this finding does not support the idea that high fat intake is detrimental to longevity in women.

“The finding that saturated fat intake was inversely associated with the risk of mortality only in women might partially explain the differences in the associations between the sexes,” Dr Tamura stated. “Alternatively, components other than fat in the food sources of fat may be responsible for the observed inverse association between fat intake and mortality in women.”

This study is extremely important because restricting carbohydrates and fats, such as extremely low-carbohydrate and low-fat diets, are now popular dieting strategies aimed at improving health, including the management of metabolic syndrome. However, this study shows that low-carbohydrate and low-fat diets may not be the healthiest strategy for promoting longevity, as their short-term benefits could potentially be outweighed by long-term risk.

Overall, an unfavourable association with mortality was observed for low-carbohydrate intake in men and for high carbohydrate intake in women, whereas high fat intake could be associated with a lower mortality risk in women. The findings suggest that individuals should carefully consider how to balance their diet and ensure that they are taking in energy from a variety of food sources, while avoiding extremes.

Source: Nagoya University

Categories : Cardiovascular Disease GenderTags :

Women Have Double the Mortality Risk After Heart Attack

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The risk of dying after a heart attack is more than twice as high for women than it is for men, according to research presented at Heart Failure 2023, held by the European Society of Cardiology (ESC).

“Women of all ages who experience a myocardial infarction are at particularly high risk of a poor prognosis,” said study author Dr Mariana Martinho of Hospital Garcia de Orta. “These women need regular monitoring after their heart event, with strict control of blood pressure, cholesterol levels and diabetes, and referral to cardiac rehabilitation. Smoking levels are rising in young women and this should be tackled, along with promoting physical activity and healthy living.”

Previous studies have found that women with ST-elevation myocardial infarction (STEMI) have a worse prognosis during their hospital stay compared to men, and that this may be due to their older age, increased numbers of other conditions, and less use of stents (percutaneous coronary intervention; PCI) to open blocked arteries. This study compared short- and long-term outcomes after STEMI in women and men, and examined whether any sex differences were apparent in both premenopausal (55 years and under) and postmenopausal (over 55) women.

This was a retrospective observational study which enrolled consecutive patients admitted with STEMI and treated with PCI within 48 hours of symptom onset between 2010 and 2015. Adverse outcomes were defined as 30-day all-cause mortality, five-year all-cause mortality and five-year major adverse cardiovascular events (MACE; a composite of all-cause death, reinfarction, hospitalisation for heart failure and ischaemic stroke).

The study included 884 patients. The average age was 62 years and 27% were women. Women were older than men (average age 67 vs 60 years) and had higher rates of high blood pressure, diabetes and prior stroke. Men were more likely to be smokers and have coronary artery disease. The interval between symptoms and treatment with PCI did not differ between women and men overall, but women aged 55 and below had a significantly longer treatment delay after arriving at the hospital than their male peers (95 vs 80 minutes).

The researchers compared the risk of adverse outcomes between women and men after adjusting for factors that could influence the relationship including diabetes, high cholesterol, hypertension, coronary artery disease, heart failure, chronic kidney disease, peripheral artery disease, stroke and family history of coronary artery disease. At 30 days, 11.8% of women had died compared to 4.6% of men, for a hazard ratio (HR) of 2.76. At five years, nearly one-third of women (32.1%) had died versus 16.9% of men (HR 2.33). More than one-third of women (34.2%) experienced MACE within five years compared with 19.8% of men (HR 2.10).

Dr Martinho said: “Women had a two to three times higher likelihood of adverse outcomes than men in the short- and long-term even after adjusting for other conditions and despite receiving PCI within the same timeframe as men.”

The researchers conducted a further analysis in which they matched men and women according to risk factors for cardiovascular disease including hypertension, diabetes, high cholesterol and smoking. Adverse outcomes were then compared between matched men and women aged 55 years and under, and between matched men and women over 55 years old.

There were 435 patients in the matched analysis. In matched patients over 55 years of age, all adverse outcomes measured were more common in women than men. Some 11.3% of women died within 30 days compared with 3.0% of men, for an HR of 3.85. At five years, one-third of women (32.9%) had died compared with 15.8% of men (HR 2.35) and more than one-third of women (34.1%) had experienced MACE compared with 17.6% of men (HR 2.15). In matched patients aged 55 years and below, one in five women (20.0%) experienced MACE within five years compared to 5.8% of men (HR 3.91), while there were no differences between women and men in all-cause mortality at 30 days or five years.

Dr Martinho said: “Postmenopausal women had worse short- and long-term outcomes after myocardial infarction than men of similar age. Premenopausal women had similar short-term mortality but a poorer prognosis in the long-term compared with their male counterparts. While our study did not examine the reasons for these differences, atypical symptoms of myocardial infarction in women and genetic predisposition may play a role. We did not find any differences in the use of medications to lower blood pressure or lipid levels between women and men.”

She concluded: “The findings are another reminder of the need for greater awareness of the risks of heart disease in women. More research is required to understand why there is gender disparity in prognosis after myocardial infarction so that steps can be taken to close the gap in outcomes.”

Source: European Society of Cardiology

Categories : Addiction Mental HealthTags :

Young Males Most at Risk of Developing Schizophrenia from Cannabis Use

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A registry-based study on cannabis users in Denmark spanning 39 years found that young males were more than twice as likely to develop schizophrenia as young females. The researchers, who published their findings in Psychological Medicine, estimated that about 15% of schizophrenia in this population group is due to cannabis use.

Previous research suggests an increase in schizophrenia population attributable risk fraction (PARF) for cannabis use disorder (CUD). However, sex and age variations in CUD and schizophrenia suggest the importance of examining differences in PARFs in sex and age subgroups.

Moreover, cannabis potency measured by the percentage of delta-9-tetrahydrocannabinol (THC) (main psychoactive component of cannabis) has increased dramatically, eg from 13% in 2006 to 30% in 2016 in Denmark. CUD has also increased markedly – past-year CUD rose significantly from 4.9% in 2014 to 5.9% in 2018 among US 18–25-year-olds.

A growing body of evidence suggests that the relationship between CUD and schizophrenia may differ by sex. Male sex and early heavy or frequent cannabis use are associated with earlier onset of psychosis.

The researchers conducted a nationwide Danish register-based cohort study including all individuals aged 16–49 at some point during 1972–2021, identifying CUD and schizophrenia status.

The researchers examined 6 907 859 individuals, with 45 327 cases of incident schizophrenia during follow-up. Males had slightly higher risk for schizophrenia with CUD (142%) than females (102%). But among 16–20-year-olds, the risk for males (284%) was more than twice that for females (81%). They also found that during the 39-year study period, the annual average increase in PARF for CUD in schizophrenia incidence was 4.8% among males and 3.2% among females. In 2021, among males, this risk fraction was 15%; among females, it was around 4%.

Conclusions

The researchers concluded that “Young males might be particularly susceptible to the effects of cannabis on schizophrenia. At a population level, assuming causality, one-fifth of cases of schizophrenia among young males might be prevented by averting CUD. Results highlight the importance of early detection and treatment of CUD and policy decisions regarding cannabis use and access, particularly for 16–25-year-olds.”

Categories : Cardiovascular Disease GenderTags :

Atherosclerosis is a Greater Heart Attack Risk for Women

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Source: Wikimedia CC0

Postmenopausal women with atherosclerosis are at higher risk of heart attacks than men of similar age, according to research presented at EACVI 2023, a scientific congress of the European Society of Cardiology (ESC), and published in European Heart Journal – Cardiovascular Imaging. Researchers used imaging techniques to examine the arteries of nearly 25 000 patients and followed them for heart attacks and death.

“The study suggests that a given burden of atherosclerosis is riskier in postmenopausal women than it is in men of that age,” said study author Dr Sophie van Rosendael of Leiden University Medical Centre. “Since atherosclerotic plaque burden is emerging as a target to decide the intensity of therapy to prevent heart attacks, the findings may impact treatment. Our results indicate that after menopause, women may need a higher dose of statins or the addition of another lipid-lowering drug. More studies are needed to confirm these findings.”

While young women do have heart attacks, in general, women develop atherosclerosis (narrowing of arteries due to plaque buildup) later in life than men and have heart attacks at an older age than men, in part because of the protective effect of oestrogen. This study examined whether the prognostic importance of atherosclerotic plaques are the same for women and men at different ages as this could be important for selecting treatments to prevent heart attacks.

The study included 24 950 patients referred for coronary computed tomography angiography (CCTA) and enrolled in the CONFIRM registry, which was conducted in six countries in North America, Europe, and Asia. CCTA is used to obtain 3D images of the arteries in the heart.

Total atherosclerotic burden was rated using the Leiden CCTA score, which incorporates the following items for each coronary segment: plaque presence (yes/no), composition (calcified, noncalcified or mixed), location, and severity of narrowing, for a final value of 0 to 42. Patients were divided into three categories previously found to predict the risk myocardial infarction: low atherosclerotic burden (0 to 5), medium (6 to 20) and high (over 20). In addition, obstructive coronary artery disease was defined as 50% narrowing or more.

The primary outcome was the difference in Leiden CCTA score between women and men of similar age. The investigators also analysed sex differences in the rates of major adverse cardiovascular events (MACE), which included all-cause death and myocardial infarction, after adjusting for age and cardiovascular risk factors (hypertension, high cholesterol, diabetes, current smoking and family history of coronary artery disease).

A total of 11 678 women (average age 58.5 years) and 13 272 men (average age 55.6 years) were followed for 3.7 years. Regarding the primary outcome, the study showed an approximately 12 year delay in the onset of coronary atherosclerosis in women: the median Leiden CCTA risk score was above zero at age 64 to 68 years in women versus 52 to 56 years in men (p<0.001). In addition, the overall plaque burden as quantified by the Leiden CCTA score was significantly lower in women, who had more non-obstructive disease.

Dr. van Rosendael said: “The results confirm the previously reported delay in the start of atherosclerosis in women. We also found that women are more likely to have non-obstructive disease. It was formerly thought that only obstructive atherosclerosis caused myocardial infarction but we now know that non-obstructive disease is also risky.”
 
The burden of atherosclerosis was equally predictive of MACE in premenopausal women (aged under 55 years) and men of the same age group. However, in postmenopausal women (age 55 years and older), the risk of MACE was higher than men for a given score. In postmenopausal women, compared to those with a low burden, those with a medium and high burden had 2.21-fold and 6.11-fold higher risks of MACE. While in men aged 55 years and older, compared to those with a low burden, those with a medium and high burden had 1.57-fold and 2.25-fold greater risks of MACE.

Dr van Rosendael said: “In this study, the elevated risk for women versus men was especially observed in postmenopausal women with the highest Leiden CCTA score. This could be partly because the inner diameter of coronary arteries is smaller in women, meaning that the same amount of plaque could have a larger impact on blood flow. Our findings link the known acceleration of atherosclerosis development after menopause with a significant increase in relative risk for women compared to men, despite a similar burden of atherosclerotic disease. This may have implications for the intensity of medical treatment.”

Source: European Society of Cardiology

Categories : Gender Medical Research & TechnologyTags :

Study Reveals How Androgen Receptor Functions are Affected by Mutations

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Testosterone molecule
Model of a testosterone molecule. Source: Wikimedia CC0

The androgen receptor is a key transcriptional factor for proper sex development, especially in males and the physiological balance of all the tissues that express this receptor. The androgen receptor is involved in several pathologies and syndromes, such as spinal and bulbar muscular atrophy or androgen insensitivity syndrome, for which there is no specific treatment. Regarded as the main initial and progression factor in prostate cancer, this receptor has been the main therapeutic target for the treatment against this disease for decades.

Now, a study published in Science Advances describes the structural and functional effects of mutations on the androgen receptor, as well as how these changes lead to the development of prostate cancer.

Point mutations in the androgen receptor

The human androgen receptor is a key protein in the development and functioning of the prostate in response to male hormones, such as testosterone. Point mutations in the androgen receptor – specifically, one amino acid swapped for another – are one of the main mechanisms than can lead to structural and functional alterations in the receptor, which result in the development of diseases.

The results of the University of Barcelona-led study show that the analysed mutations affect several functional regions of the union domain of the androgen receptor to testosterone. In particular, these are mutations that alter a region of the receptor which is the target for posttranscriptional modifications (that is, modifications in the protein once this is produced).

This type of chemical alterations affect specific amino acids of the androgen receptor and are executed by regulating proteins which are critical for the proper functioning of the receptor. If this receptor’s regulation pathway is altered, such as the case of the presence of mutations described by the team, its function is deregulated and it can be dysfunctional and cause pathologies.

“In our study, we experimentally checked that these mutations deregulate a specific mutation, known as arginine methylation, which is one of the posttranscriptional modifications, due to the structural changes these alterations produce in a functional area of the receptor. Also, we could observe that the deregulation of the androgen receptor methylation involves relevant changes in its function within the cell,” the team concludes.

Source: University of Barcelona

Categories : Cardiovascular Disease GenderTags :

Female and Male Hearts may Respond Differently to Noradrenaline

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Source: Wikimedia CC0

A new study published in Science Advances shows that female and male hearts respond differently to the stress hormone noradrenaline. The study in mice may have implications for human heart disorders like arrhythmias and heart failure and how different sexes respond to various drugs.

Using fluorescence imaging, the researchers were able to see in real time and in vivo how a mouse heart responds to hormones and neurotransmitters, including noradrenaline.

The results reveal that male and female mouse hearts respond uniformly at first after exposure to noradrenaline. However, some areas of the female heart return to normal more quickly than the male heart, producing differences in the heart’s electrical activity.

“The differences in electrical activity that we observed are called repolarisation in the female hearts. Repolarisation refers to how the heart resets between each heartbeat and is closely linked to some types of arrhythmias,” said Jessica L. Caldwell, first author of the study.

“We know that there are sex differences in the risk for certain types of arrhythmias. The study reveals a new factor that may contribute to different arrhythmia susceptibility between men and women,” Caldwell said.

Methods

The novel imaging system uses a genetically modified ‘CAMPER’ mouse to emit light during a very specific chemical reaction in the heart: cAMP binding.

The cAMP molecule (an abbreviation of cyclic adenosine 3′,5;-monophosphate) is an intermediate messenger that turns signals from hormones and neurotransmitters, including noradrenaline, into action from heart cells.

The light signals from the CAMPER mouse are transmitted by a biosensor that uses a fluorescence signal that can be picked up at high speed and high resolution by a new imaging system specially designed for hearts. This allows the researchers to record the heart’s reaction to noradrenaline in real time, along with changes in electrical activity.

This new imaging approach revealed the differences in the breakdown of cAMP in female and male mice and the associated differences in electrical activity.

Including female mice leads to discoveries

The researchers had not planned to study sex-based responses, according to Crystal M. Ripplinger, senior author of the study. But the researchers started seeing a pattern of different reactions, which led them to realise the differences were sex-based.

When Ripplinger started her lab at the UC Davis School of Medicine over a decade ago, she exclusively used male animals. That was the norm for most research at the time. But several years ago, she began including male and female animals in her studies.

“Sometimes the data between the two sexes is the same. But if the data start to show variation, the first thing we do is look at sex differences. Using both male and female mice has revealed clues into differences we would never have suspected. Researchers are realising you can’t extrapolate to both sexes from only studying one,” Ripplinger said.

She notes that with the current study, it’s not clear what the differences in cAMP and electrical activity may mean.

“The response in the female mice may be protective – or it may not. But simply documenting that there is a measurable difference in the response to a stress hormone is significant. We are hoping to learn more in future studies,” Ripplinger said.

Source: University of California – Davis Health

Categories : Ageing GenderTags :

Sex and Age Influence the Circadian Rhythm

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In a new study published in the journal Science, researchers exploring circadian molecular rhythms were able to uncover the organisation of gene expression rhythms in particular human tissues, and found that sex and age are involved, with females having a more regular pattern of rhythms.

In model organisms, analysing molecular rhythms is usually done using time-stamped measurements, but such data are not readily available in humans. To work around this, the researchers used existing measurements from a large cohort of post-mortem donors, combined with a novel computer algorithm that was designed to assign internal clock times to nearly one thousand donors.

“Interestingly, the data-science algorithm we developed turned out to resemble models from magnetic systems, which are well studied in statistical physics,” says study leader Felix Naef at Ecole Polytechnique Fédérale de Lausanne. Using this innovative approach, the researchers obtained the first comprehensive and accurate whole-organism view of 24-hour gene expression rhythms in 46 human tissues.

While the core clock machinery properties are conserved across the body and do not change significantly with sex and age, their analysis also revealed extensive programs of gene expression rhythms across major compartments of metabolism, stress response pathways and immune function, and these programs peaked twice a day.

In fact, the emerging whole-body organisation of circadian timing shows that rhythmic gene expression occurs as morning and evening waves, with the timing in the adrenal gland peaking first, while brain regions displayed much lower rhythmicity compared to metabolic tissues.

Dividing the donors by sex and age revealed a previously unknown richness of sex- and age- specific gene expression rhythms spread across biological functions. Strikingly, gene expression rhythms were sex-dimorphic (different in males and females) and more sustained in females, while rhythmic programs were generally reduced with age across the body.

Sex-dimorphic rhythms were particularly noticeable in the liver’s “xenobiotic detoxification,” the process by which liver breaks down harmful substances. Additionally, the study found that with age, the rhythm of gene expression decreases in the heart’s arteries, which may explain why older people are more susceptible to heart disease. This information could be useful in the field of “chronopharmacology,” which is the study of how a person’s internal clock affects the effectiveness and side effects of medication.

This study provides new insights into the complex interplay between our body clock, sex, and age. By understanding these rhythms, we might find new ways of diagnosing and treating pathologies such as sleep disorders and metabolic diseases.

Source: Ecole Polytechnique Fédérale de Lausanne

Categories : Gender PulmonologyTags :

Why Many Lung Diseases are Sex-biased

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Anatomical model of lungs
Photo by Robina Weermeijer on Unsplash

By studying sex differences in expression across more than 2500 genes in mouse lung cells, researchers may have found an explanation for sex biases in the prevalence and severity of lung diseases, such as the greater severity of COVID for males. In particular, very high numbers of X-linked genes escape transcriptional silencing in lung alveolar type 2 (AT2s) cells, according to their study published in Stem Cell Reports.

“Our study is the first to compare male and female AT2 cells for gene expression, and our findings suggest that there are likely sex differences in lung repair following viral-induced injury,” says co-senior author Montserrat Anguera, an associate professor at the University of Pennsylvania.

Sex differences exist for many lung diseases, but the mechanistic basis for this remains unclear. “We started this project during the beginning of the pandemic, because we were curious about the sex bias with COVID disease, where more older men have increased morbidity, and wondered whether X-chromosome inactivation (XCI) might contribute to this sex bias,” Anguera says. “We realised that the SARS-CoV2 virus first encounters AT2 cells in the lung, and that the virus enters cells through the angiotensin-converting enzyme 2 (Ace2) receptor, which is located on the X chromosome.”

XCI is a process by which one of the copies of the X chromosome is inactivated in female mammals. The inactive X chromosome is silenced by being packaged into a transcriptionally inactive structure called heterochromatin. XCI prevents female mammals from having twice as many X-chromosome gene products as males, who only possess a single copy of the X chromosome.

In the new study, Anguera and co-senior author Andrew Vaughan, an assistant professor at the University of Pennsylvania, investigated XCI maintenance and sex-specific gene expression profiles using male and female AT2s. The results showed that approximately 68% of expressed X-linked genes in mouse AT2s escape XCI. These genes include Ace2, which serves as the entry point into cells for SARS-CoV-2, but is also involved in lung repair.

There were genome-wide expression differences between male and female AT2s, possibly contributing to sex differences in lung injury and repair in multiple settings. Taken together, the findings demonstrate that AT2 cells have the highest levels of XCI escape for mouse cells reported to date and support a renewed focus on AT2s as a potential contributor to sex-biased differences in lung disease.

In addition, the results showed that AT2 cells, similar to immune cells, do not strictly follow the classic rules of XCI. “We were surprised to find that female AT2 cells lack canonical epigenetic modifications that are typically enriched on the inactive X as a result of XCI. These include the long noncoding RNA Xist and heterochromatic histone modifications H3K27me3 and H2AK119-ubiquitin,” Anguera says. “Because the inactive X in female AT2 cells has fewer epigenetic marks, this enables more gene expression chromosome wide, including the Ace2 gene.”

For now, it remains an open question whether ACE2 escapes XCI in human AT2 cells. to The authors say this is a likely scenario because there are significantly higher numbers of XCI escape genes in human cells compared to mouse cells.

Moving forward, the authors plan to investigate how expression from the inactive X in AT2 cells is affected by SARS-CoV2 infections. They also will continue to study how expression from the X chromosome is regulated in other cell types that do not exhibit conventional XCI maintenance. “Our findings open the door to future work investigating the genetic and epigenetic basis, residing within the X chromosome, of sex differences in immune responses to inhaled viruses,” Anguera says.

Source: Science Daily

Categories : Gender Metabolic DisordersTags :

Why Obesity’s Health Impacts are Worse for Males

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Toilet sign male and female
Photo by Tim Mossholder on Unsplash

A newly published study in iScience sheds light on the biological underpinnings in sex differences in obesity-related disease, with researchers observing “striking” differences in the cells that build blood vessels in the fatty tissue of male versus female mice.

Men are more likely than women to develop conditions associated with obesity such as cardiovascular disease, insulin resistance and diabetes, says study leader Professor Tara Haas at York University.

“People have used rodent models to study obesity, and the diseases that are associated with obesity – like diabetes – but they’ve typically always studied male rodents, because females are resistant to developing the same kinds of diseases,” says Haas. “We were really interested in exploring that difference because, to us, it spoke of something really fascinating happening in females that protects them.”

In earlier work, Haas and her team saw that when mice become obese, females grow a lot of new blood vessels to supply the expanding fat tissue with oxygen and nutrients, whereas males grow a lot less. For this study, Haas and her co-authors focused on differences in the endothelial cells that make up the building blocks of these blood vessels in fat tissue.

The team used software to help sift through thousands of genes to zero in on the ones that would be associated with blood vessel growth. They discovered that processes associated with the proliferation of new blood vessels were high in the female mice, whereas the males had a high level of processes associated with inflammation.

“It was very striking the extent of inflammation-associated processes that were prevalent in the males,” Haas recalls. “Other studies have shown that when endothelial cells have that kind of inflammatory response, they’re very dysfunctional, and they don’t respond to stimuli properly.”

York PhD student Alexandra Pislaru, who works in Haas’ lab and is a co-first author of the study, participated in this project as part of her dissertation.

“It is exciting to observe the continuing resilience that female endothelial cells display even when stressed by a long-term high-fat diet,” Pislaru says. “The findings from our study can help researchers to get a better understanding of why obesity manifests differently in men and women.”

The researchers also examined the behaviour of the endothelial cells when they were taken out of the body and studied in petri dishes.

“Even when we take them out of the body where they don’t have the circulating sex hormones or other kinds of factors, male and female endothelial cells still behave very differently from each other,” Haas explains.

Female endothelial cells replicated faster, while male endothelial cells displayed greater sensitivity to an inflammatory stimulus. By comparing with previously published data sets, the researchers found endothelial cells from aged male mice also displayed a more inflammatory profile compared to female cells.

“You can’t make the assumption that both sexes are going to respond to the same series of events the same way,” says Haas. “This isn’t just an obesity related issue – I think it’s a much broader conceptual problem that also encompasses healthy aging. One implication of our findings is that there will be situations where the treatment that is ideal for men is not going to be ideal for women and vice-versa.”

While humans and mice have different genes that may be turned up or down, Haas believes the general findings would likely apply and is interested studying the same cells in humans in future research.

Source: York University