̽��ֱ�� of Cambridge - Dino Giussani

Combined steroid and statin treatment could reduce ‘accelerated ageing’ in preterm babies, study in rats suggests

cg605 — Thu, 02 Feb 2023 09:20:05 +0000

Cambridge scientists gave new-born rats, which are naturally born prematurely, combined glucocorticoid steroids and statin therapy. ̽��ֱ��results, published today in Hypertension, show that the combined treatment led to the elimination of negative effects of steroids on the cardiovascular system while retaining their positive effects on the developing respiratory system.

Preterm birth (before 37 weeks) is one of the greatest killers in perinatal medicine today. One in ten babies is born preterm in high-income countries; this can increase to almost 40% in low- and middle-income countries.

Preterm babies are extremely vulnerable because they miss out on a crucial final developmental stage in which the hormone cortisol is produced and released exponentially into the unborn baby’s blood. Cortisol is vital to the maturation of organs and systems that are needed to keep the baby alive once born.

For example, in the lungs, cortisol ensures that they become more elastic. This allows the lungs to expand so the baby can take its first breath. Without cortisol the new-born lungs would be too stiff, which leads to respiratory distress syndrome (RDS) and could be fatal.

̽��ֱ��established clinical treatment for any pregnancy threatened with preterm birth is glucocorticoid therapy, given via the mother before the baby is born and/or directly to the baby after birth. These synthetic steroids mimic the natural cortisol by speeding up the development of organs – including the lungs – which means the preterm baby is much more likely to survive.

Lead author Professor Dino Giussani from the Department of Physiology, Development and Neuroscience at the ̽��ֱ�� of Cambridge said: “Glucocorticoids are a clear lifesaver, but the problem with steroids is that they speed up the maturation of all organs. For the baby’s lungs this is beneficial, but for the heart and circulation system it can be damaging – it resembles accelerated ageing.”

A previous clinical study by Professor Paul Leeson’s laboratory at Oxford ̽��ֱ�� found that people who had been exposed to glucocorticoid therapy as unborn babies, via their mothers, showed measures of cardiovascular health typical of people a decade older.

Cambridge researcher Dr Andrew Kane, involved in the rat study, thought that this accelerated ageing could result from steroids causing oxidative stress Steroids lead to an imbalance of molecules known as free radicals, which result in a reduction in nitric oxide. Nitric oxide is very beneficial to the cardiovascular system – it increases blood flow and has anti-oxidant and anti-inflammatory properties.

To test if a lack of nitric oxide could be the origin of the adverse negative cardiovascular side-effects associated with glucocorticoid therapy, the researchers combined the steroid treatment with statins, which are widely used to lower cholesterol and are known to increase nitric oxide.

Researchers gave the synthetic steroid, dexamethasone, combined with the statin, pravastatin, to rat pups. There were three other groups – one receiving dexamethasone alone, one receiving pravastatin alone and a control group that received saline. Measures of respiratory and cardiovascular function were then taken when the rats had grown to ‘childhood’.

̽��ֱ��Cambridge scientists found that steroids produced adverse effects on heart and blood vessels, and molecular indices associated with cardiovascular problems. But if statins were given at the same time, the rats were protected from these effects. Crucially, the statins did not affect any of the beneficial effects of steroids on the respiratory system.

“Our discovery suggests that combined glucocorticoid and statin therapy may be safer than glucocorticoids alone for the treatment of preterm babies,” said Professor Giussani.

“We’re not saying to stop using glucocorticoids, as they are clearly a life-saving treatment. We’re saying that to improve this therapy – to fine tune it – we could combine it with statins. This gives us the best of both worlds – we can maintain the benefits of steroids on the developing lungs, but ‘weed out’ their adverse side-effects on the developing heart and circulation, thereby making therapy much safer for the treatment of preterm birth.”

̽��ֱ��team plan to replicate the experiment in sheep, which have a similar physiology to humans, before conducting human clinical trials.

̽��ֱ��research was funded by the British Heart Foundation and the Biotechnology and Biological Sciences Research Council (BBSRC). Dr Andrew Kane was supported by the Frank Edward Elmore Fund and the James Baird Fund.

Giussani, DA et al. Combined statin and glucocorticoid therapy for the safer treatment of preterm birth. Hypertension; 1 Feb 2023; DOI: 10.1161/HYPERTENSIONAHA.122.19647

Potentially life-saving steroids commonly given to preterm babies also increase the risk of long-term cardiovascular problems, but a new study in rats has found that if given in conjunction with statins, their positive effects remain while the potential negative side-effects are ‘weeded out’.

We’re not saying to stop using glucocorticoids, as they are clearly a life-saving treatment. We’re saying that to improve this therapy – to fine tune it – we could combine it with statins.

IvanJekic / E+ via Getty Images

Mother is holding a tiny hand of her preterm baby that is in the NICU.

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Simple treatment during pregnancy can protect baby from memory problems in later life, study in rats suggests

jg533 — Tue, 20 Apr 2021 23:01:00 +0000

Low oxygen in the womb - known as chronic fetal hypoxia - is one of the most common complications in human pregnancy. It can be diagnosed when a routine ultrasound scan shows that the baby is not growing properly and is caused by a number of conditions including pre-eclampsia, infection of the placenta, gestational diabetes or maternal obesity.

̽��ֱ��new results show that chronic fetal hypoxia leads to a reduced density of blood vessels, and a reduced number of nerve cells and their connections in parts of the offspring’s brain. When the offspring reaches adulthood, its ability to form lasting memories is reduced and there is evidence of accelerated brain ageing.

Vitamin C, an anti-oxidant, given to pregnant rats with chronic fetal hypoxia was shown to protect the future brain health of the offspring. ̽��ֱ��results are published today in the journal FASEB J.

“It’s hugely exciting to think we might be able to protect the brain health of an unborn child by a simple treatment that can be given to the mother during pregnancy,” said Professor Dino Giussani from the ̽��ֱ�� of Cambridge’s Department of Physiology, Development and Neuroscience, who led the study.

̽��ֱ��researchers used Vitamin C because it is a well-established and used anti-oxidant. However, only high doses were effective, which could cause adverse side-effects in humans. Follow-up studies are now searching for alternative anti-oxidants to treat chronic fetal hypoxia in humans.

To conduct the research, a group of pregnant rats were kept in ambient air with 13% oxygen – causing hypoxic pregnancies. ̽��ֱ��rest were kept in normal air (21% oxygen). Half of the rats in each group were given Vitamin C in their drinking water throughout the pregnancy. Following birth, the baby rats were raised to four months old, equivalent to early adulthood in humans, and then performed various tests to assess locomotion, anxiety, spatial learning and memory.

̽��ֱ��study found that rats born from hypoxic pregnancies took longer to perform the memory task, and didn’t remember things as well. Rats born from hypoxic pregnancies in which mothers had been given Vitamin C throughout their pregnancy performed the memory task just as well as offspring from normal pregnancies.

Analysing the brains of the rat offspring, the researchers found that the hippocampus - the area associated with forming memories – was less developed in rats from hypoxic pregnancies.

In deeper analysis, the scientists showed that hypoxic pregnancy causes excess production of reactive oxygen species, called ‘free radicals’, in the placenta. In healthy pregnancy the body keeps the level of free radicals in check by internal anti-oxidant enzymes, but excess free radicals overwhelm these natural defences and damage the placenta in a process called ‘oxidative stress’. This reduces blood flow and oxygen delivery to the developing baby.

In this study, placentas from the hypoxic pregnancies showed oxidative stress, while those from the hypoxic pregnancies supplemented with Vitamin C looked healthy.

Taken together, these results show that low oxygen in the womb during pregnancy causes oxidative stress in the placenta, affecting the brain development of the offspring and resulting in memory problems in later life.

“Chronic fetal hypoxia impairs oxygen delivery at critical periods of development of the baby’s central nervous system. This affects the number of nerve connections and cells made in the brain, which surfaces in adult life as problems with memory and an earlier cognitive decline,” said Dr Emily Camm from Cambridge’s Department of Physiology, Development and Neuroscience, first author of the report, who has recently taken up a new position at ̽��ֱ��Ritchie Centre in Australia.

̽��ֱ��interaction between our genes and lifestyle plays a role in determining our risk of disease as adults. There is also increasing evidence that the environment experienced during sensitive periods of fetal development directly influences our long-term health - a process known as ‘developmental programming.’

Brain health problems that may start in the womb due to complicated pregnancy range from attention deficit hyperactivity disorder, to brain changes in later life that have been linked with Alzheimer’s disease.

“In medicine today there has to be a shift in focus from treatment of the disease, when we can do comparatively little, to prevention, when we can do much more. This study shows that we can use preventative medicine even before birth to protect long term brain health,” said Giussani.

̽��ֱ��research was funded by ̽��ֱ��British Heart Foundation and ̽��ֱ��Medical Research Council, and the programme of work was approved by the ̽��ֱ�� of Cambridge Animal Welfare and Ethical Review Board.

Reference
Camm et al: ‘Maternal antioxidant treatment protects adult offspring against memory loss and hippocampal atrophy in a rodent model of developmental hypoxia.’ ̽��ֱ��FASEB Journal, April 2021. DOI: 10.1096/fj.202002557RR

A new study in laboratory rats has discovered a direct link between low oxygen in the womb and impaired memory function in the adult offspring. It also finds that anti-oxidant supplements during pregnancy may protect against this.

This study shows that we can use preventative medicine even before birth to protect long term brain health.

Dino Giussani

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Set up for life

cjb250 — Wed, 25 Nov 2020 08:13:14 +0000

We’re used to the idea that as adults we have some control over our destiny: what we eat and drink and how much we exercise can affect our health. But the risks of heart disease and diabetes can be programmed much earlier – even before we are born.

Prevention of heart disease can start before birth

jg533 — Wed, 19 Aug 2020 18:00:40 +0000

Babies that experience low oxygen levels in the womb due to pregnancy complications often go on to develop heart disease in adulthood. A study using sheep has discovered that a specialised antioxidant called MitoQ can prevent heart disease at its very onset. ̽��ֱ��results are published today in the journal Science Advances.

Genetics, and their interaction with lifestyle risk factors such as smoking and obesity, play a role in determining heart disease risk in adults. But there is also strong evidence that the environment experienced during sensitive periods of fetal development directly influences long-term cardiovascular health - a process known as ‘developmental programming.’

Low oxygen in the womb - known as chronic fetal hypoxia - is one of the most common complications in human pregnancy. In a process termed ‘oxidative stress,’ low oxygen to the developing fetus can cause damage to its heart and blood vessels. Fetal hypoxia can be diagnosed when a scan during pregnancy shows the baby is not growing properly.

“Many people may be predisposed to heart disease as adults because of the low level of oxygen they received in the womb. By providing a specific mitochondria-targeted antioxidant supplement to mothers whose pregnancy is complicated by fetal hypoxia, we can potentially prevent this,” said Professor Dino Giussani from the ̽��ֱ�� of Cambridge’s Department of Physiology, Development and Neuroscience, who led the study.

Chronic hypoxia is common to many complications of pregnancy. It can be caused by a number of conditions including pre-eclampsia, infection of the placenta, gestational diabetes or maternal obesity.

Oxidative stress largely originates in the cells’ mitochondria - the ‘batteries’ that power our cells - where the processes of respiration and energy production occur. To target mitochondria the Cambridge team used MitoQ, developed by Professor Mike Murphy and his colleagues at the ̽��ֱ�� of Cambridge’s MRC-Mitochondrial Biology Unit. MitoQ selectively accumulates within mitochondria, where it works to reduce oxidative stress.

Having established the safety of the treatment, the researchers gave MitoQ to pregnant sheep under low oxygen conditions. They found that the mitochondrial therapy protects against fetal growth restriction and high blood pressure in the offspring as adults. Using chicken embryos they also showed that MitoQ protects against mitochondria-derived oxidative stress.

“MitoQ has already been used in a number of human trials, for example it was shown to lower hypertension in older subjects. It is very exciting to see the potential to use MitoQ to treat a baby during a problematic pregnancy and prevent problems arising far later in life. There's still a long way to go before this can be used by pregnant mothers, but our work points to new possibilities for novel treatments," said Professor Murphy, who was also involved in the study.

This is the first time that MitoQ has been tested during sheep pregnancy. Sheep are animals whose cardiovascular development resembles that of a human baby more closely than laboratory rats and mice. Chicken embryos were also used to isolate the direct effects of MitoQ therapy on the embryonic heart independent of any influence on the mother or placenta.

“Our cardiovascular health is influenced by the lifestyle choices we make in adult life, but can also be traced back to the conditions we experienced when developing inside the womb,” said Professor James Leiper, Associate Medical Director at the British Heart Foundation.

He added: “This study reveals a plausible way to reduce the future risk of high blood pressure and consequent heart disease in babies from complicated pregnancies. Further research is now needed to translate these findings from animals to humans and identify the most effective time in development to give the MitoQ supplement to ‘at risk’ babies - whether that’s a particular point during pregnancy or soon after birth. Overcoming this next hurdle will enable it to be tested in clinical trials.”

Cardiovascular disease is a group of disorders of the heart and blood vessels that can cause heart attacks and strokes. It claims the life of one in three people, and costs the United States and Canada US$130 billion and the United Kingdom over £30 billion every year. ̽��ֱ��majority of these costs are for treatments that improve outcomes, but do not cure the disease.

There are increasing calls within the public health community to change the focus of cardiovascular disease research from treatment to prevention. By looking at the specific circumstances that increase the risk of developing heart disease, interventions can be made as early as possible rather than waiting until disease has become irreversible.

“If we want to reduce the prevalence of cardiovascular disease, we need to think of prevention rather than a cure. Applying this concept to pregnancy complications, we can bring preventative medicine all the way back into the womb - it’s treatment before birth. It completely changes our way of thinking about heart disease,” said Giussani.

This research was funded by ̽��ֱ��British Heart Foundation, and the programme of work was approved by the ̽��ֱ�� of Cambridge Animal Welfare and Ethical Review Board.

Reference
Botting, K.J. et al: ‘Translatable mitochondria-targeted protection against programmed cardiovascular dysfunction.’ Science Advances, 19 August 2020. DOI:10.1126/sciadv.abb1929

Mitochondrial therapy in complicated pregnancies lowers the chance of cardiovascular problems in the offspring.

It completely changes our way of thinking about heart disease

Dino Giussani

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Premature babies could benefit from changes to drugs administered to at-risk mothers

cjb250 — Wed, 20 Mar 2019 18:20:22 +0000

While the current practice of using glucocorticoid therapy shows life-saving benefits for the preterm infant, the researchers say that combining them with antioxidants would overcome potential safety concerns associated with existing treatment.

One in ten babies is born prematurely and up to three-quarters of these are at significant risk of death or long-term illness because premature babies are born with immature lungs and hence are at risk of dying from respiratory problems.

̽��ֱ��clinical use of glucocorticoids both in mothers at risk of premature labour and in premature babies has become common practice in the last 40 years. ̽��ֱ��treatment is based on research which discovered the important role played by glucocorticoids in fetal development and that giving premature babies synthetic glucocorticoids could accelerate the development of their lungs and respiratory system.

Now, every mother at risk of preterm birth gets this treatment worldwide in developed societies. It is regarded as one of the best examples of successfully translating basic experimental science into efficient human clinical practice and it has saved millions of preterm children every year.

However, despite the very clear life-saving effects of antenatal and postnatal glucocorticoid therapy to accelerate lung maturation in the infant, new research has identified some potential adverse side effects on the offspring’s growth, central nervous and cardiovascular systems. Some of these effects will not be seen until the child is fully grown and is in adulthood.

“ ̽��ֱ��evidence supporting the life-saving benefits of glucocorticoid treatment for premature babies is overwhelming. Without it, preterm babies would mostly die or suffer significantly from conditions associated with prematurity, leaving them with significant disability,” says Professor Dino Giussani from the Department of Physiology, Development & Neuroscience at the ̽��ֱ�� of Cambridge.

“Unfortunately, there can be subtle adverse effects from the therapy that suggest we need to fine-tune current clinical therapy to maintain its beneficial effects but weed out any potential negative adverse effects later in life.”

In a review published online in the journal Trends in Endocrinology and Metabolism, Professor Giussani and PhD student Tessa Garrud propose that in future, combined therapy of glucocorticoids with specific antioxidants may be safer for the treatment of the premature baby.

In their article, the researchers argue that while much is known about the physiological mechanisms via which glucocorticoids have a beneficial effect, far less is understood about those mechanisms by which the treatment can cause subtle negative effects. In part this is because it is difficult to ascertain which long term health problems are as a result of glucocorticoid treatment and which are due to the detrimental effects of preterm birth.

Professor Giussani and Ms Garrud point to research that suggests one likely culprit mechanism is the capacity of synthetic glucocorticoids to induce what is so-called ‘oxidative stress’, caused by an imbalance in the body of unstable atoms known as free radicals. While the body needs a certain number of free radicals for cell signalling or to stimulate repair, an overabundance can cause damage. Oxidative stress has been shown to lead to restricted blood flow and can damage the cardiovascular system in the long-term.

“When we bring together the research out there on this issue, we find strong evidence to suggest that combined antioxidant and glucocorticoid therapy may be safer than glucocorticoid therapy alone for the treatment of preterm birth,” says Ms Garrud.

Professor Giussani adds: “We believe it is time to study these further potential benefits in clinical trials. Glucocorticoid therapy is clearly a life-saver and is here to stay, but we support that treatment could be improved even further to maintain benefits while improving safety.”

̽��ֱ��research was supported by the British Heart Foundation and Wellcome.

Reference
Garrud, TAC and Giussani, DA. Combined antioxidant and glucocorticoid therapy for safer treatment of preterm birth. Trends in Endocrinology and Metabolism; April 2019; DOI: 10.1016/j.tem.2019.02.003

Scientists at the ̽��ֱ�� of Cambridge have suggested that subtle changes to the drugs administered to mothers threatened with preterm birth or to premature babies could further improve clinical treatment and help increase their safety.

We need to fine-tune current clinical therapy to maintain its beneficial effects but weed out any potential negative adverse effects later in life

Dino Giussani

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Heart disease risk begins in the womb, study in sheep suggests

cjb250 — Tue, 22 Jan 2019 19:00:00 +0000

Heart disease is the greatest killer in the world today, and it is widely accepted that our genes interact with traditional lifestyle risk factors, such as smoking, obesity and/or a sedentary life to promote an increased risk of cardiovascular disease.

In addition to the effects of adult lifestyle, there is already evidence that the gene-environment interaction before birth may be just as, if not more, important in ‘programming’ future heart health and heart disease. For example, human studies in siblings show that children born to a mother who was obese during pregnancy are at greater risk of heart disease than siblings born to the same mother after bariatric surgery to reduce maternal obesity. Such studies have provided strong evidence in humans that the environment experienced during critical periods of development can directly influence long-term cardiovascular health and heart disease risk.

̽��ֱ��new research, funded by the British Heart Foundation and the Biotechnology and Biological Sciences Research Council, shows that adult offspring from pregnancies complicated by chronic hypoxia – lower-than-normal oxygen levels – have increased indicators of cardiovascular disease such as high blood pressure and stiffer blood vessels. Chronic hypoxia in the developing baby within the womb is one of the most common outcomes of complicated pregnancy in humans. It occurs as a result of problems within the placenta, as can occur in preeclampsia, gestational diabetes or maternal smoking.

̽��ֱ��study, led by Professor Dino Giussani from the Department of Physiology, Development and Neuroscience and published today in the journal PLOS Biology, used pregnant sheep to show that maternal treatment with the antioxidant vitamin C during a complicated pregnancy could protect the adult offspring from developing hypertension and heart disease. ̽��ֱ��work therefore not only provides evidence that a prenatal influence on later heart disease in the offspring is indeed possible but also shows the potential to protect against it by “bringing preventative medicine back into the womb,” as Dr Kirsty Brain, first author of the study, puts it.

It turns out that vitamin C is a comparatively weak antioxidant, and while the Cambridge study provides a proof-of-principle, future work will focus on identifying alternative antioxidant therapies that could prove more effective in human clinical practice.

“Our discoveries emphasise that when considering strategies to reduce the overall burden of heart disease, much greater attention to prevention rather than treatment is required,” adds Professor Giussani. “Treatment should start as early as possible during development, rather than waiting until adulthood when the disease process has become irreversible.”

Professor Giussani stresses that it is too soon to consider vitamin C as a potential supplement for mothers. Any mothers concerned about their baby’s development in the womb should speak to their doctor before changing their diet or using supplements.

̽��ֱ��work draws attention to a new way of thinking about heart disease with a much longer-term perspective, focusing on prevention rather than treatment.

Reference
Brain KL, Allison BJ, Niu Y, Cross CM, Itani N, Kane AD, et al. Intervention against hypertension in the next generation programmed by developmental hypoxia. PLoS Biol 17(1): e2006552. https://doi.org/10.1371/journal.pbio.2006552

Offspring whose mothers had a complicated pregnancy may be at greater risk of heart disease in later life, according to a new study in sheep. ̽��ֱ��research, led by a team at the ̽��ֱ�� of Cambridge, suggests that our cards may be marked even before we are born.

Our discoveries emphasise that when considering strategies to reduce the overall burden of heart disease, much greater attention to prevention rather than treatment is required

Dino Giussani

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Breath of life: how your risk of heart disease may stem back to your time in the womb

cjb250 — Tue, 11 Jul 2017 08:00:07 +0000

̽��ֱ��history of science is littered with self-experimenters so passionate about their work that they used themselves as human guinea pigs, however ill-advisedly.

Sir Joseph Barcroft (1872–1947) was one such character. Professor of Physiology at Cambridge, he was best known for his studies of the oxygenation of blood. He also led mountain expeditions where he analysed the oxygen content of his blood and that of other expedition members.

In the middle of his career, Barcroft built an airtight glass chamber in his laboratory in Cambridge. There, he could live and exercise at oxygen levels equivalent to 16,000 feet. Like many self-experimentation stories, things did not always go to plan: in one experiment, he had to be rescued by colleagues after spending six days in the chamber and reportedly turning blue.

Despite his occasional misguided venture, Barcroft’s scientific legacy was significant and so, in his honour, the ̽��ֱ�� of Cambridge has recently opened a new state-of-the-art facility in his name. Research at the Barcroft Centre focuses on farm animals – mainly sheep and chickens, but also pigs – to model important aspects of human physiology.

̽��ֱ��Centre’s work spans several areas including Professor Jenny Morton’s studies on understanding fatal neurodegenerative diseases such as Huntington’s disease and a similar childhood disease, Batten disease, and Dr Frances Henson’s work on bone diseases such as osteoarthritis.

However, a significant amount of its work focuses on how we develop in the womb and how this programmes us for increased risk of heart disease in later life. This seems fitting as, in later years, Barcroft became interested in fetal development, and in particular the effects of low levels of oxygen on the unborn baby in the womb.

Carrying on this legacy are Professor Dino Giussani and his postdocs Dr Kim Botting and Dr Youguo Niu. All are also members of the Centre for Trophoblast Research (CTR), which this year celebrates its tenth anniversary and focuses on the interactions between the pregnant mother and the fetus, as mediated by the placenta.

Low levels of oxygen – or hypoxia – can occur in high-altitude pregnancies. But, as Giussani explains, there are far more common causes. “Smoking, pre-eclampsia, even maternal obesity – these all increase the risk of hypoxia for the mother’s baby, as do inherited genetic variants,” he says.

Housed in the Barcroft Centre is a suite of hypoxia chambers – superficially similar, perhaps, to that in which Barcroft placed himself, but nowadays far more sophisticated (and much safer). These are not intended for humans, but rather for animals, each of which is very closely monitored, often remotely using technology developed by the team.

̽��ֱ��smallest of these chambers doubles as an incubator for fertilised hens’ eggs. Scientists can watch the development of the fetus directly. They can see how the heart grows, for example, how it is affected by hypoxia, and what effect potential drugs have in ameliorating possible complications.

Of course, we grow in a womb, with a placenta connecting us to our mother and controlling our nutritional intake. Mice and rats are the most commonly used mammals in research, but to model mammalian development in longer-living species with similar rates of development to humans, it is necessary to turn to larger animals. Sheep make a good model. Not only is their gestation – and postnatal life – more comparable to a human’s than to a rat’s, but a newborn lamb’s physiology is also similar in a crucial way to a newborn baby’s: its heart is mature at birth. By comparison, a newborn rat’s heart is still very immature.

For part of gestation, the sheep are placed in hypoxia chambers, which contain finely controlled, lower-than-normal levels of oxygen. “This reduces the amount of oxygen in the blood of the pregnant sheep and thereby in her fetus,” explains Botting. “This mimics conditions where the placenta is not working appropriately, as in pregnancy complicated by pre-eclampsia or maternal obesity.”

̽��ֱ��pregnant ewes deliver outside the chambers in normal ambient air. Once born, most of the lambs are put out to pasture in the paddocks adjacent to the Centre, where they grow to adulthood.

“ ̽��ֱ��lambs which were hypoxic in the womb are not noticeably different,” says Giussani. “ ̽��ֱ��sheep will effectively live a normal life. That is the very point, because underneath, a silent killer is brewing; we want to investigate what happens as they grow because there is a theory that a complicated pregnancy may increase the risk of heart disease in the offspring later in life.”

Professor Abby Fowden, Head of the School of the Biological Sciences, and another CTR member and user of the Barcroft Centre, says that the facilities are unique. “It’s probably the only centre in the UK that has the capacity – the surgical and care facilities – to do these kinds of long-term developmental and neurodegenerative studies,” she explains.

Like Giussani, Fowden and her collaborator Dr Alison Forhead are interested in how the early environment in the womb programmes us for disease in later life. They are particularly interested in the role of hormones – in both the mother and the fetus – and how they affect growth and development.

There are some conditions, such as hypothyroidism – whereby the body produces insufficient thyroid hormones – and maternal stress, that probably affect normal fetal development, but about which surprisingly little is understood. To model these conditions, Fowden and Forhead again turn to a range of mammals including sheep and pigs.

As Forhead explains, normal development of the fetus is crucial for health in later life. “In the case of many organs, you’re born with a certain number of functional units, and in postnatal life you don’t have the capacity to change that number. So the number you’re born with has long-lasting consequences.”

Take nephrons, for example. These are functional units of our kidneys that filter the blood and are responsible for how much salt and water is excreted into the urine. “If you’re born with fewer nephrons, this has consequences for how much salt you retain, setting you up in later life to be at greater risk of developing high blood pressure.”

What is apparent from this work is just how much of disease in later life is programmed in the womb. While our lifestyle – our diet, how much we exercise after birth – plays an important role in whether we develop heart disease or type 2 diabetes, for example, much of the risk is present before we are even born, programmed during pregnancy into how our DNA and tissues function.

And these effects don’t necessarily stop at the next generation, as Giussani is discovering in his parallel work with rodents, which allows two or more generations to be studied in a comparably short time.

“If we look at the ‘grandchildren’ of pregnant rats that had a hypoxic pregnancy, we see this disease risk being passed on again, but in a really interesting way,” he says. “A male ‘child’ passes on the cardiovascular risk to the ‘grandchild’, but female offspring confer protection. This is really exciting as inheritable protection against a future risk of heart disease has never been demonstrated in mammals.”

In other words, while we must still recognise our own contribution to our risk of developing certain diseases, some of this risk was programmed into us before we were born: in fact, even before our parents were born. Work at the Barcroft Centre – in monitoring animals for not just one generation but several – will be vital for understanding the consequences of pregnancy not only for our children but also for their children – and even their children’s children.

Inset image: Joseph Barcroft.

Smoking, lack of exercise, bad diet and our genes are all well-known risk factors for heart disease, cancer and diabetes. But, as researchers are beginning to understand, the environment in the womb as we first begin to grow may also determine our future.

Underneath, a silent killer is brewing... there is a theory that a complicated pregnancy may increase the risk of heart disease in the offspring later in life.

Dino Giussani

Ryan Melaugh

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Old before your time: Study suggests that ageing begins in the womb

cjb250 — Tue, 01 Mar 2016 15:11:52 +0000

However, the offspring of mothers with lower levels of oxygen in the womb – which, in humans, can be a consequence of smoking during pregnancy or of pregnancy at high altitude – aged more quickly in adulthood.

Our DNA is ‘written’ onto chromosomes, of which humans carry 23 pairs. ̽��ֱ��ends of each chromosome are known as telomeres and act in a similar way to the plastic that binds the ends of shoelaces, preventing the chromosomes from fraying. As we age, these telomeres become shorter and shorter, and hence their length can be used as a proxy to measure ageing.

In a study funded in the UK by the British Heart Foundation and published today in ̽��ֱ��FASEB Journal, scientists report a study that involved measuring the length of telomeres in blood vessels of adult laboratory rats born from mothers who were or were not fed antioxidants during normal or complicated pregnancy.

̽��ֱ��most common complication in pregnancy is a reduction in the amount of oxygen that the baby receives – this can be due to a number of causes, including expectant mothers who smoke or who experience preeclampsia. To simulate this complication, the researchers placed a group of pregnant laboratory rats in a room containing 7% less oxygen than normal.

̽��ֱ��researchers found that adult rats born from mothers who had less oxygen during pregnancy had shorter telomeres than rats born from uncomplicated pregnancies, and experienced problems with the inner lining of their blood vessels – signs that they had aged more quickly and were predisposed to developing heart disease earlier than normal. However, when pregnant mothers in this group were given antioxidant supplements, this lowered the risk among their offspring of developing heart disease.

Even the offspring born from uncomplicated pregnancies – when the fetus had received appropriate levels of oxygen – benefited from a maternal diet of antioxidants, with longer telomeres than those rats whose mothers did not receive the antioxidant supplements during pregnancy.

Professor Dino Giussani from the Department of Physiology Development & Neuroscience at the ̽��ֱ�� of Cambridge, the study’s senior author, says: “Our study in rats suggests that the ageing clock begins ticking even before we are born and enter this world, which may surprise many people.

“We already know that our genes interact with environmental risk factors, such as smoking, obesity and lack of exercise to increase our risk of heart disease, but here we’ve shown that the environment we’re exposed to in the womb may be just as, if not more, important in programming a risk of adult-onset cardiovascular disease.”

First author Dr Beth Allison adds: “Antioxidants are known to reduce ageing, but here, we show for the first time that giving them to pregnant mothers can slow down the ageing clock of their offspring. This appears to be particularly important when there are complications with the pregnancy and the fetus is deprived of oxygen. Although this discovery was found using rats, it suggests a way that we may treat similar problems in humans.”

Professor Jeremy Pearson, Associate Medical Director at the BHF, said: “Previous research funded by the BHF has shown that sub-optimal conditions within the mother’s womb can lead to an increased risk of cardiovascular disease in later life. However, the mechanisms involved are poorly understood. Although conducted in rats, this research emphasises the need for pregnant mothers to maintain a healthy lifestyle for the sake of their baby’s future heart health.”

Reference
Allison, BJ et al. Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease. FASEB; 1 March 2016

̽��ֱ��process of ageing begins even before we are born, according to an international team of researchers led by the ̽��ֱ�� of Cambridge. In a study using rats to model pregnancy and fetal development, the researchers also found that providing mothers with antioxidants during pregnancy meant that their offspring aged more slowly in adulthood.

Our study in rats suggests that the ageing clock begins ticking even before we are born and enter this world, which may surprise many people

Dino Giussani

Valentin Ottone

Portrait #122 - Coline - While she was smoking (cropped)

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