Dr. Mohamed L. Toumi is a lecturer at the Applied Neuroendocrinology Laboratory at the University of Badji Mokhtar in Annaba, Algeria, and first author of the paper that won the 2014 Algerian Paper of the Year Award in Biological Sciences, entitled “Quercetin alleviates predator stress-induced anxiety-like and brain oxidative signs in pregnant rats and immune count disturbance in their offspring” and which was published in the journal Pharmacology, Biochemistry and Behavior. Inspire Magazine speaks to Dr Toumi about his research and the work reported in the award winning paper.
Inspire magazine: Thank you for speaking to Inspire Magazine, and many congratulations for winning the 2014 Algerian Paper of the Year Award in Biological Sciences. How do you feel about winning this award?
Dr Toumi: I would like to express my thanks to members of anasr.org and my deep appreciation for their commitment to promote the scientific work of Algerian researchers. It is well known that academic awards are of great interest to any scientist worldwide. I am very happy with this award, satisfied for harvesting a precious fruit of my hard work, and proud of being rewarded by the Algerian scientific community.
IM: In simple terms, can you tell us what the winning paper is about?
Dr Toumi: The winning paper represents a first-step study about the protective potential of a plant-derived molecule, quercetin, against stress effects during pregnancy in rats. Female rats were simply exposed to a domestic cat during their late gestation to create an animal model of psychological stress. Unlike many curative studies in which the treatment is applied after the stressful event, we proceeded to supply rats with oral doses of quercetin a few days before the stressful event took place. Although the impact of this intervention was firstly evaluated in the pregnant dams, what attracted our attention was the immune responses of their neonates as a result of the “prenatal stress” experienced when the maternal organism is in danger. Interesting findings were drawn from the study, which will be followed by complementary experiments about the behavioural consequences of the neonatal immune changes from puberty to adulthood.
IM: Why is it interesting to study the effect of prenatal predator stress on pregnant rats?
Dr Toumi: The study deals with the fact that pregnant women might be exposed to traumatic events like natural disasters and how this is linked to their prenatally-stressed infants developing a wide range of physiological and neurological diseases in later life. The prenatal predator stress is a highly valid method to draw conclusions that could be extrapolated to what human beings do really experience. Exposing pregnant rats to their natural predator, the cat, is an intense stressful situation that induces short term changes in the maternal hormonal and immune systems. These changes, in relation to the extreme fear of being caught by the predator, are complicated by the fact that both fight and flight reactions are blocked due to the two-chamber apparatus of stress. One of the main consequences of this situation is the appearance of a neuropsychological variant of the so-called Post Traumatic Stress Disorder (PTSD) in humans. The relevance of these experiments lies in the ability to study different facets of the same aversive situation in order to better understand the relationship between stress and mental disorders (anxiety, depression, phobia, …), as well as to reveal how can the mental state of pregnant subjects influence the growth and behaviour of their progeny. In this respect, prenatally-stressed rats offer an interesting animal model to explore the current biological hypotheses about the developmental origins of adult diseases which speculate that the various human diseases are somehow linked to the prenatal environment in which the fetal development occurs.
IM: You mentioned that prenatal stress causes a decrease in immune cells count in the offspring. Could you please elaborate on what causes such an effect and how does this effect on immune cells count impact on the health state of the offspring. In other words, does this effect on cell count increase the risk of certain diseases in the offspring?
Dr Toumi: Our findings clearly point out a possible role of corticosterone (the stress hormone in rats) in these immune effects. It is widely accepted that this hormone has an immunosuppressive effect in the stressed subject, meaning that it decreases temporarily a few functions of the immune system, especially the inflammatory activity. . However, there is still uncertainty regarding the underlying mechanisms on the fetal side. The fetal immune system is immature and seems therefore to be very sensitive to any change in the hormonal status. Nevertheless, whether corticosterone has the same suppressive effect on the maternal-fetal immune network is still unknown to date.
Certainly, the decrease in the immune cells count negatively impacts on the health state of the offspring. At this early stage of development, the immune system needs to be as stable as possible to properly overcome the critical transition from the intrauterine pathogen-free environment to the extra-uterine life. We could demonstrate that prenatally-stressed neonates have a prominent decline in lymphocytes. These cells are extremely essential in acquiring an appropriate immunocompetence (i.e. the ability to recognise and destroy pathogens) and represent a basic element of the immune memory. By weakening these capacities, prenatal stress causes the offspring to be prone to postnatal sepsis and viral infections. Furthermore, as the immune and nervous systems are proved to be tightly connected, the risk of development of neurological disorders (anxiety, depression, temperament, memory and learning problems) in childhood or later adult periods is high.
IM: How do you explain that the effect of prenatal stress on immune cells count was gender specific?
Dr Toumi: One of the most important and ultimate aims of prenatal stress studies is to explain the gender specificity (sex differences) from the molecular to the behavioural level. Obviously, the immune count profile in both sexes is not the same even in absence of stress events. The genetic background that governs this native difference is also responsible of the physiological reactivity to stress in each gender. As the connection between the pregnant subject and the fetus is mainly humoral, the immune system seems to be the first target of maternal aversive stimuli. Based on the existing literature, researchers attribute much of this gender specific immune response to the intolerable increase in glucocorticoids. These stress hormones can cross the placental barrier and influence the rate of sexual hormones (mainly testosterone and estradiol), which results in nervous and immune changes according to the adaptive ability of the offspring. Our findings support in part these hypotheses as we found a considerable increase in corticosterone in the traumatised dams whose neonates suffered from serious immune disturbances. However, the gender specificity is much more complicated than what the available experimental results demonstrate because many biological factors may play a crucial role. Our study should therefore be developed to cover a wide range of possible factors, enabling us to unravel the mechanisms by which maternal stress differently affects male and female development.
IM: You mentioned that Quercetin might be beneficial in counteracting the negative effects of prenatal stress on both dams and their offspring. Can you please explain why does it have such an effect and whether there is a potential of using it as a medical intervention to counteract the effects of stress?
Dr Toumi: The promising beneficial effect of quercetin against prenatal stress outcomes is especially deduced from its ability to prevent the hazardous elevation of maternal corticosterone rate following a traumatic experience. By counteracting the trauma-related hyper-arousal, quercetin may indirectly stabilise the fetal immune milieu. Supposing that this positive effect is not sufficient to overcome the stressful insults, quercetin may contribute to the immune defense during the early postnatal life because of its proved antioxidant, antibacterial and antiviral actions. It is noteworthy that the ability of flavonoids (a class of plant molecules to which quercetin belongs) to cross the placental barrier is a potential for medical intervention against stress, but the appropriate use depends on the dose and duration of treatment in the pregnant women. The design of our study, as well as of many other similar studies, is an optimal start for demonstrating potential health effects of quercetin in human subjects. Besides a healthy and diverse diet for the harmonious offspring development, anti-stress supplements are expected to be beneficial. It is also necessary to take into consideration that quercetin is a major ingredient of the human diet; this is why even a minor amount of supplements is far from being useless. More research is required to properly identify the effective dose of quercetin that achieves the desired response.
IM: Are you aware of any studies on humans showing the effect of prenatal stress on mothers and their babies?
Dr Toumi: Prenatal stress in humans, particularly from mid-pregnancy onwards, was extensively studied. Because of the extreme variability of design and context, I summarise here the main findings of these studies. It is nowadays known that stress during pregnancy is associated with noxious outcomes in mothers and babies. The stressed pregnant women are especially at risk for neuropsychiatric diseases such as anxiety and depression, which can in turn compromise their prenatal care and predispose them to several gestational complications, leading in some cases to the preterm delivery (miscarriage). The impact on babies is much more serious even with a successful delivery. Prenatally-stressed babies can suffer from infectious diseases due to their weak immune responses (as stated above) and be at high risk for metabolic disorders (diabetes, dyslipidemia) and neurological disorders (emotional problems, impaired cognitive development, temperament, aggressive attitudes and autism). It is interesting to note that the incidence of the abnormalities indicated in babies, infants and even adults is enhanced by the persistent anxiety and depressive sequelae in their mothers during the critical period of lactation.
IM: How can you extrapolate from your study on pregnant rats to humans?
Dr Toumi: Before discussing how we can extrapolate our findings, it is important to clarify the core idea of the paper for lay people. While of course there is no treatment that can lower the chance of getting occasionally traumatised, our study indicates that pre-stress pharmacological prevention with natural substances may facilitate the post-stress medical intervention once the traumatic event occurs. In fact, the recent research orientations are going to explore methods of preventing anxiety-related disorders from occurring instead of treating these disorders after they have occurred. As for many pathological conditions (e.g. diabetes, cancer…), the preventative measures with nutritional agents for stress coping are of great importance. Therefore, our study also elucidates the relevance of the type of diet that mothers should have during pregnancy. A clear extrapolation from this study is the need for a controllable dietary regimen, that ensures adequate nutritional supplies of quercetin rich sources during pregnancy in order to alleviate or prevent the negative outcomes of any unpredictable stressful events. Quercetin rich foods include onions, parsley, beans, tea, apples, blackberries, citrus fruits, grapes and olive oil.. As none can expect the occurrence of a stressful situations for a given pregnant woman, clinical prospective studies are the best way to extrapolate.
IM: Do you have any idea on how significant is the impact of maternal stress on the health state of mothers and babies in Algeria? And do you think there is enough awareness among Algerian mothers to avoid stress?
Dr Toumi: Stress is an integral part of our daily life. What can make an important difference on its effect from one country to another has more to do with the social and medical support that women receive throughout their pregnancy. In Algeria, this support is relatively medium, which would significantly increase the impact of gestational stress comparatively to well-developed countries. I think that the awareness to avoid stress is still insufficient among a large part of Algerian mothers. Unfortunately, the Algerian society lacks the necessary awareness programs about the importance of social support and gestational dietary regimen for a pregnancy as stress-free as possible.
IM: Can you tell us about the kind of support that you have received to accomplish this work, whether from your university or from your collaborators?
Dr Toumi: The support that we have received to accomplish this study was mainly practical and technical at the laboratory. I would like here to acknowledge the infinite encouragement and help that I was given throughout the achievement of this work from a precious lab-mate, my wife Dr. Sameha Merzoug.
IM: Thank you again for speaking to Inspire Magazine and all the best with your future endeavours
Dr Toumi: Thank you very much for this opportunity. I wish you a great success .