François Corbin

Maternal and Cord-Blood Thyroid Hormone Levels and Exposure to Polybrominated Diphenyl Ethers and Polychlorinated Biphenyls During Early Pregnancy

Thyroid hormones play a critical role in the growth of many organs, especially the brain. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) interact with the thyroid pathway and may disturb neurodevelopment. This prospective study was designed to examine associations between maternal blood PBDEs and PCBs in early pregnancy and levels of thyroid hormones in maternal and umbilical-cord blood. Levels of low-brominated PBDEs, 3 PCB congeners, total and free thyroid hormones (triiodothyronine (T3) and thyroxine (T4)), thyroid-stimulating hormone, thyroid peroxidase antibodies, iodine, selenium, and mercury were measured in 380 pregnant women in the first trimester who were recruited at the University Hospital Center of Sherbrooke (Quebec, Canada) between September 2007 and December 2008. Thyroid hormone levels were also assessed at delivery and in cord blood (n = 260). Data were analyzed on both a volume basis and a lipid basis. At less than 20 weeks of pregnancy, no relationship was statistically significant in volume-based analysis. In lipid-based models, an inverse association between maternal PBDEs and total T3 and total T4 and a direct association with free T3 and free T4 were observed. At delivery, in both analyses, we observed negative associations between maternal total T4, free T3, cord-blood free T4, and PBDEs and between maternal free T3 and PCBs. Our results suggest that exposure to PBDEs and PCBs in pregnancy may interfere with thyroid hormone levels.

Effect of lovastatin on behavior in children and adults with fragile X syndrome: an open-label study.

Fragile X syndrome (FXS) results from dynamic mutations leading ultimately to the absence of expression of the Fragile X Mental Retardation Protein (FMRP). It is characterized by synaptic upregulated protein synthesis and immature dendritic spines associated with altered brain plasticity and cognitive functions. Recent work in Fmr1 knockout mice has shown that lovastatin, an inhibitor of Ras‐ERK1/2, normalized hippocampus protein synthesis. We hypothesize that lovastatin, as a disease‐modifying drug, would counterweigh the absence of FMRP and improve behavior. Here we report a phase I study to assess the safety and efficacy of lovastatin in individuals with FXS. A total of 15 patients (13 males, 6–31 years old) were treated with escalating doses of lovastatin (up to 40 mg) for three months. Their behavior were assessed before and after treatment using the Aberrant Behavioral Checklist—Community (ABC‐C) total score (primary outcome), as well as domains of the FXS validated version of the ABC‐C (secondary outcomes). The treatment was well tolerated and minimal side effects were reported. Significant improvement in the primary outcome (P < 0.005), as well as in secondary outcomes, were observed in the majority of the subjects (12/15). We think that long‐term sustained treatment with diseased‐modifying drugs would be necessary in order to improve behavior and ultimately learning. Lovastatin, well known for its long‐term security profile, would be a good candidate for that purposes. Our study showing reassuring safety data along with potential functional benefit emphasizes the need of a placebo‐controlled trial to ascertain lovastatin efficacy in FXS individuals.

Quantitative measurement of FMRP in blood platelets as a new screening test for fragile X syndrome.

Lessard M, Chouiali A, Drouin R, Sébire G, Corbin F. Quantitative measurement of FMRP in blood platelets as a new screening test for fragile X syndrome.

Active renin mass concentration to determine aldosterone-to-renin ratio in screening for primary aldosteronism

Background: Active renin mass concentration (ARC) is independent of the endogenous level of angiotensinogen, and less variable and more reproducible than plasma renin activity. Reference values for the aldosterone-to-renin ratio (ARR) using ARC are still undefined. The objective of the present study was to determine the threshold of ARR using ARC measurement to screen for primary aldosteronism. Methods: A total of 211 subjects were included in the study, comprising 78 healthy normotensive controls, 95 patients with essential hypertension, and 38 patients with confirmed primary aldosteronism (20 with surgery-confirmed aldosterone-producing adenoma and 18 with idiopathic adrenal hyperplasia). Blood samples were drawn from ambulatory patients and volunteers in the mid-morning without specific dietary restriction for measuring plasma aldosterone concentration, ARC, and serum potassium. Results: Most normotensive controls and essential hypertension patients had ARR results below 100 pmol/ng, a value which corresponded to 3.3 times the median of these two groups. Conclusion: Patients with ARR values above this level should be considered for further investigation (confirmatory tests) or for repeat testing should ARR values be borderline. This study indicates that ARC can be used reliably in determining ARR for primary aldosteronism screening.

Variations in HDL-carried miR-223 and miR-135a concentrations after consumption of dietary trans fat are associated with changes in blood lipid and inflammatory markers in healthy men - an exploratory study

ABSTRACT A high consumption of trans fatty acids (TFAs) is associated with an increased risk of cardiovascular diseases (CVDs). High-density lipoproteins (HDLs) have many cardioprotective properties and transport functional microRNAs (miRNAs) to recipient cells. We hypothesized that dietary TFAs modify the HDL-carried miRNA profile, therefore modulating its cardioprotective properties. We assessed whether consumption of dietary TFAs modifies HDL-carried miR-223-3p and miR-135a-3p concentration and the inter-relationship between diet-induced changes in HDL-carried miRNA concentration and CVD risk markers. In a double blind, randomized, crossover, controlled study, 9 men were fed each of 3 experimental isoenergetic diets: 1) High in industrial TFA (iTFA; 3.7% energy); 2) High in TFA from ruminants (rTFA; 3.7% energy); 3) Low in TFA (control; 0.8% energy) for 4 weeks each. HDLs were isolated by ultracentrifugation and miRNAs were quantified by RT-qPCR. Variations in HDL-miR-223-3p concentration were negatively correlated with variations in HDL-cholesterol after the iTFA diet (rs = 0.82; P = 0.007), and positively correlated with variations in C-reactive protein concentration after the rTFA diet (rs = 0.75; P = 0.020). Variations in HDL-miR-135a-3p concentration were positively correlated with variations in total triglyceride (TG) concentration following the iTFA diet (rs = −0.82; P = 0.007), and with variations in low-density lipoprotein (LDL)-TG concentration following the rTFA diet (rs = 0.83; P = 0.005), compared to the control diet. However, the consumption of dietary TFAs has no significant unidirectional impact on HDL-carried miR-223-3p and miR-135a-3p concentrations. Our results suggest that the variability in the HDL-carried miRNAs response to TFA intake, by being associated with variations in CVD risk factors, might reflect physiological changes in HDL functions.

Lovastatin corrects ERK pathway hyperactivation in fragile X syndrome: potential of platelet’s signaling cascades as new outcome measures in clinical trials

Abstract Aim: To establish whether platelets from fragile X syndrome (FXS) individuals recapitulate FXS mouse neurons’ defects in ERK and Akt pathways, and to evaluate the effect of lovastatin on these pathways. Methods: ERK and Akt phosphorylation (pERK, pAkt) statuses were assessed with quantitative Western blotting before and after a 12-week lovastatin trial. Results: Levels of pERK and pAkt were increased in FXS platelets, and lovastatin specifically normalized ERK activity. Changes in ERK phosphorylation were correlated with clinical response to lovastatin. Conclusions: Platelets’ signaling pathways provide biomarkers that can be used as treatment outcome measures in FXS clinical trials.

Effects of Moderate Hyperbilirubinemia on Nutritive Swallowing and Swallowing-Breathing Coordination in Preterm Lambs.

Background: Hyperbilirubinemia (HB) occurs in 90% of preterm newborns. HB induces acute neurological disorders (somnolence, abnormal tone, feeding difficulties, auditory dysfunction) and alterations in respiratory control. These findings suggest brainstem neurotoxicity that could also affect swallowing centers. Objective: To test the hypothesis that HB impairs nutritive swallowing (NS) and swallowing-breathing coordination. Methods: Two groups of preterm lambs (born 14 days prior to term), namely control (n = 6) and HB (n = 5), were studied. On day 5 of life (D0), moderate HB (150-250 µmol/l) was induced during 17 h in the HB group. Swallowing was assessed via recording of pharyngeal pressure and respiration by respiratory inductance plethysmography and pulse oximetry. The effect of HB on NS was assessed during standardized bottle-feeding. A second recording was performed 48 h after recovery from HB (D3). Results: Swallows were less frequent (p = 0.003) and of smaller volume (p = 0.01) in HB lambs while swallowing frequency was decreased (p = 0.004). These differences disappeared after HB normalization. Swallowing-breathing coordination was impaired in HB lambs, with a decrease in percent time with NS burst-related apneas/hypopneas at D0 and D3. Simultaneously, HB lambs tended to experience more severe desaturations (<80%) during bottle-feeding. Finally, following bottle-feeding, the respiratory rate was significantly lower, along with an increased apnea duration in HB lambs. Conclusions: Swallowing and swallowing-breathing coordination are altered by acute moderate HB in preterm lambs. Decreased efficiency at bottle-feeding is accompanied by continuation of breathing during swallow bursts, which may promote lung aspiration.

Changes in high-density lipoprotein-carried miRNA contribution to the plasmatic pool after consumption of dietary trans fat in healthy men

AIM High-density lipoproteins (HDLs) are associated to cardioprotection and transport functional miRNAs in circulation. The aim of this study is to assess whether consumption of trans fatty acids (TFAs) modifies the HDL-carried miRNA concentration and their contribution to the plasmatic pool. METHODS In a double-blind, randomized crossover controlled study, nine healthy men were fed each of three isoenergetic 4-week diets: first, rich in industrial TFAs; second, rich in TFAs from ruminants; third, low in TFAs. miRNAs were extracted from plasma and purified HDLs, and quantified by the real-time quantitative PCR (n = 87). RESULTS Seven HDL-carried miRNAs contributed to more than 15% of the plasmatic pool. Although no significant difference in HDL-carried miRNA concentration among diets was observed after adjustment for multiple testing, changes in the contribution to the plasmatic pool between diets were observed for miR-124-3p, miR-375, miR-150-5p and miR-31-5p (p FDR < 0.05). These miRNAs were enriched in lipid metabolism pathways. CONCLUSION These microtranscriptomic variants might reflect physiological changes in HDL functions in response to diet.

Platelets as a surrogate disease model of neurodevelopmental disorders: Insights from Fragile X Syndrome

Abstract Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism spectrum disorders (ASD). Despite a large number of therapeutics developed in past years, there is currently no targeted treatment approved for FXS. In fact, translation of the positive and very promising preclinical findings from animal models to human subjects has so far fallen short owing in part to the low predictive validity of the Fmr1 ko mouse, an overly simplistic model of the complex human disease. This issue stresses the critical need to identify new surrogate human peripheral cell models of FXS, which may in fact allow for the identification of novel and more efficient therapies. Of all described models, blood platelets appear to be one of the most promising and appropriate disease models of FXS, in part owing to their close biochemical similarities with neurons. Noteworthy, they also recapitulate some of FXS neuron’s core molecular dysregulations, such as hyperactivity of the MAPK/ERK and PI3K/Akt/mTOR pathways, elevated enzymatic activity of MMP9 and decreased production of cAMP. Platelets might therefore help furthering our understanding of FXS pathophysiology and might also lead to the identification of disease-specific biomarkers, as was shown in several psychiatric disorders such as schizophrenia and Alzheimer’s disease. Moreover, there is additional evidence suggesting that platelet signaling may assist with prediction of cognitive phenotype and could represent a potent readout of drug efficacy in clinical trials. Globally, given the neurobiological overlap between different forms of intellectual disability, platelets may be a valuable window to access the molecular underpinnings of ASD and other neurodevelopmental disorders (NDD) sharing similar synaptic plasticity defects with FXS. Platelets are indeed an attractive model for unraveling pathophysiological mechanisms involved in NDD as well as to search for diagnostic and therapeutic biomarkers.

New insights of altered lipid profile in Fragile X Syndrome

Background Fragile X Syndrome (FXS) is the main genetic cause of autism and intellectual deficiency resulting the absence of the Fragile X Mental Retardation Protein (FMRP). Clinical picture is characterized by cognitive impairment associated with a broad spectrum of psychiatric comorbidities including autism spectrum disorders and attention-deficit/hyperactivity disorders. Some of these disorders have been associated with lipid abnormalities and lower cholesterol levels. Since lipids are important for neuronal development, we aim to investigate the lipid profile of French Canadian-FXS individuals and to identify the altered components of cholesterol metabolism as well as their association with clinical profile. Methods Anthropometric data were collected from 25 FXS individuals and 26 controls. Lipid assessment included: total cholesterol (TC), triglycerides, LDL, HDL, ApoB, ApoA1, PCSK9, Lp(a) and lipoprotein electrophoresis. Aberrant and adaptive behaviour of affected individuals was respectively assessed by the ABC-C and ABAS questionnaires. Results FXS participants had a higher body mass index as compared to controls while 38% of them had TC<10th percentile. Lower levels of LDL, HDL and apoA1 were observed in FXS group as compared to controls. However, PCSK9 levels did not differ between the two groups. As expected, PCSK9 levels correlated with total cholesterol (rs = 0.61, p = 0.001) and LDL (rs = 0.46, p = 0.014) in the control group, while no association was present in the FXS group. An inverse relationship was observed between total cholesterol and aberrant behaviour as determined by ABC-C total score. Conclusion Our results showed the presence of hypocholesterolemia in French Canadian-FXS population, a condition that seems to influence their clinical phenotype. We identified for the first time a potential underlying alteration of PCSK9 function in FXS that could result from the absence of FMRP. Further investigations are warranted to better understand the association between cholesterol metabolism, PCSK9, FMRP and clinical profile.