Neonatal SSRI Exposure Programs a Hypermetabolic State in Adult Mice

Background. Selective serotonin reuptake inhibitor (SSRI) therapy complicates up to 10% of pregnancies. During therapy, SSRIs exert pleiotropic antidepressant, anorexigenic, and neurotrophic effects. Intrauterine SSRI exposure has been modeled by neonatal administration to developmentally immature rodents, and it has paradoxically elicited features of adult depression. We hypothesized neonatal SSRI exposure likewise programs a rebound hypermetabolic state in adult mice. Methods. C57BL/6 pups were randomized to saline or sertraline (5 mg/kg/d) from P1–P14. Because estrogen increases tryptophan hydroxylase 2 (TPH2) expression, a subset of female mice underwent sham surgery or bilateral ovariectomy (OVX). Metabolic rate was determined by indirect calorimetry. Results. In both male and female mice, neonatal SSRI exposure increased adult caloric intake and metabolic rate. SSRI-exposed female mice had significantly decreased adult weight with a relative increase in brain weight and melatonin excretion, independent of ovarian status. Cerebral cortex TPH2 expression was increased in SSRI-exposed male mice but decreased in OVX SSRI-exposed female mice. Conclusions. SSRI exposure during a critical neurodevelopmental window increases adult caloric intake and metabolic rate. Ovarian status modulated central TPH2 expression, but not adult energy balance, suggesting programmed neural connectivity or enhanced melatonin production may play a more important role in the post-SSRI hypermetabolic syndrome

Reduced blood pressure of CFTR-F508del carriers correlates with diminished arterial reactivity rather than circulating blood volume in mice.

The F508del mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common cause of cystic fibrosis (CF). Both CF patients and F508del carriers have decreased blood pressure. While this has been attributed to salt depletion, recent studies have shown F508del expression interferes with smooth muscle cell calcium mobilization. We tested the hypothesis that carriers of the F508del mutation have lower adult blood pressures and reduced aortic contractility without a reduction in circulating blood volume. By radiotelemetry, F508del heterozygous mice had significantly lower arterial pressures than wild-type C57BL/6 controls, with the greatest effect seen at the time of dark-to-light cycle transition (mean difference of 10 mmHg). To replicate the vascular effects of sympathetic arousal, isoproterenol and epinephrine were co-infused, and F508del mice again had significantly reduced arterial pressures. Aortas isolated from F508del heterozygous mice had significantly decreased constriction to noradrenaline (0.9 ± 0.2 versus 2.9 ± 0.7 mN). Inhibition of wild-type CFTR or the inositol triphosphate receptor replicated the phenotype of F508del aortas. CFTR carrier status did not alter circulating blood volume. We conclude the CFTR-F508del mutation decreases aortic contractility and lowers arterial pressures. As a cAMP-activated chloride channel that facilitates calcium mobilization, we speculate wild-type CFTR co-activation during adrenergic receptor stimulation buffers the vasodilatory response to catecholamines, and loss of this compensatory vasoconstrictor tone may contribute to the lower arterial pressures seen in heterozygote carriers of a CFTR-F508del mutation

Neonatal Leptin Levels Predict the Early Childhood Developmental Assessment Scores of Preterm Infants

Preterm infants have low circulating levels of leptin, a key trophic hormone that influences growth and development. While the clinical importance of prematurity-associated leptin deficiency is undefined, recent preclinical and clinical investigations have shown that targeted enteral leptin supplementation can normalize neonatal leptin levels. We tested the hypothesis that, independent of growth velocity, prematurity-related neonatal leptin deficiency predicts adverse cardiovascular and neurodevelopmental outcomes. In a planned 2-year longitudinal follow-up of 83 preterm infants born at 22 to 32 weeks’ gestation, we obtained blood pressures from 58 children and the Ages & Stages Questionnaire (ASQ-3) for 66 children. Based on univariate analysis, blood pressures correlated with gestational age at birth (R = 0.30, p p p as the criterion for model selection, higher systolic blood pressure was predicted by rapid postnatal weight gain, later gestation at delivery and male sex (Cp = 3.0, R = 0.48). Lower ASQ-3 was predicted by lower leptin levels at 35 weeks postmenstrual age, earlier gestation at delivery and male sex (Cp = 2.9, R = 0.45). Children that had leptin levels above 1500 pg/mL at 35 weeks postmenstrual age had the highest ASQ-3 scores at 2 years. In conclusion, independent of growth velocity, higher leptin levels at 35 weeks’ gestation are associated with better developmental assessment scores in early childhood. While longer-term follow-up of a larger cohort is needed, these findings support investigations that have suggested that targeted neonatal leptin supplementation could improve the neurodevelopmental outcomes of preterm infants

Breast Milk for Term and Preterm Infants—Own Mother’s Milk or Donor Milk?

Hormones are important biological regulators, controlling development and physiological processes throughout life. We investigated pituitary hormones such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) and total protein levels during the first 6 months of lactation. Breast milk samples were collected every fourth week of lactation from mothers who gave birth to preterm (n = 14) or term (n = 16) infants. Donor milk is suggested when own mother’s milk is not available; therefore, we collected breast milk samples before and after Holder pasteurization (HoP) from the Breast Milk Collection Center of Pécs, Hungary. Three infant formulas prepared in the Neonatal Intensive Care Unit of the University of Pécs were tested at three different time points. Our aim was to examine the hormone content of own mother’s milk and donor milk. There were no significant changes over time in the concentrations of any hormone. Preterm milk had higher PRL (28.2 ± 2.5 vs. 19.3 ± 2.3 ng/mL) and LH (36.3 ± 8.8 vs. 15.9 ± 4.1 mIU/L) concentrations than term milk during the first 6 months of lactation. Total protein and FSH concentrations did not differ between preterm and term breast milk. Holder pasteurization decreased the PRL concentration (30.4 ± 1.8 vs. 14.4 ± 0.6 ng/mL) and did not affect gonadotropin levels of donor milk. Infant formulas have higher total protein content than breast milk but do not contain detectable levels of pituitary hormones. Differences were detected in the content of pituitary hormones produced for preterm and term infants. Divergence between feeding options offers opportunities for improvement of nutritional guidelines for both hospital and home feeding practices