A study in rodents has uncovered a direct link between low oxygen in the uterus during pregnancy—causing fetal hypoxia—and impaired memory function in adult offspring. The research, carried out by a team at the University of Cambridge, found that chronic fetal hypoxia led to a reduced density of blood vessels, and a reduced number of nerve cells and their connections, in the hippocampus. Giving the mother antioxidant supplements—in this study high levels of vitamin C—during pregnancy protected the growing fetus from the harmful effects of low oxygen, and from hypoxia-related memory problems later in life.

“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 research lead Dino Giussani, PhD, from the University of Cambridge’s Department of Physiology, Development and Neuroscience, who led the study. “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.” The team acknowledged that while vitamin C is a well established antioxidant, the high doses required to be effective in their reported study could cause adverse side effects in humans, so follow-up work will be needed to identify alternative anti-oxidants that might treat chronic fetal hypoxia in humans.

Giussani and colleagues describe their studies in The FASEB Journal, in a paper titled, “Maternal antioxidant treatment protects adult offspring against memory loss and hippocampal atrophy in a rodent model of developmental hypoxia.”

The 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.

“During the last 40 years, significant evidence derived from human epidemiological studies as well as from preclinical animal models has accumulated to show that suboptimal intrauterine conditions can increase the risk of adverse health outcomes in the offspring; a process known as developmental programming,” the authors wrote.

Chronic fetal hypoxia—low oxygen in the uterus—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. However, just how gestational hypoxia might affect the long-term health of the brain in offspring isn’t well understood, the team continued.

For their newly reported studies, the researchers used a rat model to investigate more closely how chronic fetal hypoxia might affect brain development. “We investigated in rats whether hypoxic pregnancy affects brain structure and function in the adult offspring and explored underlying mechanisms with maternal antioxidant intervention,” they wrote.

To conduct the research, the researchers housed different groups of pregnant rats under conditions in which the ambient air contained either a normal level of oxygen (21%), or a low, 13% oxygen level, which caused hypoxic pregnancies. Half of the rats in each group were given the antioxidant 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 were then assessed using various tests to assess locomotion, anxiety, spatial learning and memory.

The results showed that rats born from hypoxic pregnancies took longer to perform the memory task, and didn’t remember things as well. However, 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.

Analyzing 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. “The data show that prenatal hypoxia reduced neuronal number, vascularity and synaptic density in the hippocampus and impaired memory function in the adult male offspring,” the investigators stated.

Further analyses then showed that hypoxic pregnancy caused excess production of reactive oxygen species, called ‘free radicals’, in the placenta. “Levels of oxidative stress in the placenta, but not in the fetal or adult offspring brain, were increased in hypoxic pregnancy,” they further noted. 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 defenses and damage the placenta in a process called ‘oxidative stress’. This reduces blood flow and oxygen delivery to the developing baby.

In the reported study, the researchers found that placentas from the hypoxic pregnancies showed oxidative stress, while those from the hypoxic pregnancies supplemented with Vitamin C looked healthy. The results showed that chronic fetal hypoxia led 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 then reached adulthood, its ability to form lasting memories becomes reduced and there is evidence of accelerated brain aging. Antioxidant treatment of the pregnant mothers effectively prevented these effects. “… maternal antioxidant treatment in hypoxic pregnancy restored placental oxidative stress to normal levels and prevented the programmed adverse effects on cerebral structure and function in the adult offspring, implicating placental oxidative stress as a mediating factor,” the team stated. “

Taken together, the study findings indicated 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. ” Maternal supplementation with vitamin C during hypoxic pregnancy protected against oxidative stress in the placenta and prevented the adverse effects of prenatal hypoxia on hippocampal atrophy and memory loss in the adult offspring,” the authors commented. “Therefore, these data provide a link between prenatal hypoxia, placental oxidative stress and offspring brain health in later life, providing insight into mechanism and identifying a therapeutic strategy.”

Study first author Emily Camm, PhD, from Cambridge’s Department of Physiology, Development and Neuroscience, further noted, “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.” Camm recently took up a new position at The Ritchie Centre in Australia.

The team does note that the dose of vitamin C used in the reported study is much higher than is used in pregnant women, so alternative antioxidants to vitamin C may need to be sought for human investigations. “We are aware that the dose of vitamin C given to the rodent dams (ca. 500mg/day/kg) far exceeds that given to pregnant women, for instance in clinical trials to ameliorate preeclampsia,” they noted “… future studies should focus on alternative antioxidant therapy of improved human translational potential, such as with melatonin, allopurinol or the mitochondria-targeted antioxidant MitoQ.”

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