Epigenetic programming for obesity and noncommunicable disease: From womb to tomb.

Several epidemiological, clinical and experimental studies in recent decades have shown the relationship between exposure to stressors during development and health outcomes later in life. The characterization of these susceptible phases, such as preconception, gestation, lactation and adolescence, and the understanding of factors that influence the risk of an adult individual for developing obesity, metabolic and cardiovascular diseases, is the focus of the DOHaD (Developmental Origins of Health and Disease) research line. In this sense, advancements in molecular biology techniques have contributed significantly to the understanding of the mechanisms underlying the observed phenotypes, their morphological and physiological alterations, having as a main driving factor the epigenetic modifications and their consequent modulation of gene expression. The present narrative review aimed to characterize the different susceptible phases of development and associated epigenetic modifications, and their implication in the development of non-communicable diseases. Additionally, we provide useful insights into interventions during development to counteract or prevent long-term programming for disease susceptibility.

Protein Restriction in the Peri-Pubertal Period Induces Autonomic Dysfunction and Cardiac and Vascular Structural Changes in Adult Rats.

Perturbations to nutrition during critical periods are associated with changes in embryonic, fetal or postnatal developmental patterns that may render the offspring more likely to develop cardiovascular disease in later life. The aim of this study was to evaluate whether autonomic nervous system imbalance underpins in the long-term hypertension induced by dietary protein restriction during peri-pubertal period. Male Wistar rats were assigned to groups fed with a low protein (4% protein, LP) or control diet (20.5% protein; NP) during peri-puberty, from post-natal day (PN) 30 until PN60, and then all were returned to a normal protein diet until evaluation of cardiovascular and autonomic function at PN120. LP rats showed long-term increased mean arterial pressure (p = 0.002) and sympathetic arousal; increased power of the low frequency (LF) band of the arterial pressure spectral (p = 0.080) compared with NP animals. The depressor response to the ganglion blocker hexamethonium was increased in LP compared with control animals (p = 0.006). Pulse interval variability showed an increase in the LF band and LF/HF ratio (p = 0.062 and p = 0.048) in LP animals. The cardiac response to atenolol and/or methylatropine and the baroreflex sensitivity were similar between groups. LP animals showed ventricular hypertrophy (p = 0.044) and increased interstitial fibrosis (p = 0.028) compared with controls. Reduced protein carbonyls (PC) (p = 0.030) and catalase activity (p = 0.001) were observed in hearts from LP animals compared with control. In the brainstem, the levels of PC (p = 0.002) and the activity of superoxide dismutase and catalase (p = 0.044 and p = 0.012) were reduced in LP animals, while the levels of GSH and total glutathione were higher (p = 0.039 and p = 0.038) compared with NP animals. Protein restriction during peri-pubertal period leads to hypertension later in life accompanied by sustained sympathetic arousal, which may be associated with a disorganization of brain and cardiac redox state and structural cardiac alteration.

Neonatal metformin short exposure inhibits male reproductive dysfunction caused by a high-fat diet in adult rats.

Metformin (Met) is widely used to control blood glucose levels and acts on various organs, including reproductive tissues, to improve reproductive and lifespan. This study evaluated whether neonatal Met exposure prevented male reproductive dysfunction caused by being overweight during adulthood. Randomized Wistar rat pups received an intraperitoneal injection from postnatal days (PNDs) 1 to 12of saline (Sal; 0.9% NaCl/day in 2mL/kg) or Met (100 mg/kg/day in 2 mL/kg). From PNDs 60 to 90, the animals received a regular (R; 4.5% fat; Sal R and Met R groups) or a high-fat (HF; 35% fat; Sal HF and Met HF groups) diet. At PND 90, all animals were euthanized to evaluate their biometric and reproductive parameters. The Sal and Met groups with R showed similar body weights, however, the HF diet increased the body weight in both groups. The Sal HF group showed testicular damage regarding in antioxidant status and inflammatory profile in the epididymal cauda. The HF diet reduced Leydig and Sertoli cells numbers, with lower sperm quality. The Met R animals showed positive reproductive programming, due to improved antioxidant defense, inflammatory biomarkers, and sperm morphology. Met HF prevented HF diet damage to reproductive organs and sperm morphology, but not to sperm motility. Early Met exposure positively affected the male reproductive system of adult rats, preventing reproductive HF disorders. STATEMENT OF NOVELTY AND SIGNIFICANCE: Metformin is used to control type 2 diabetes mellitus and can act to improve metabolism and lifespan. Metformin avoidance is recommended during pregnancy, but there is no information regarding its use when breastfeeding. For the first time, we showed in this current study that metformin positively acts in the male reproductive tissues and helps involved in later life. These data showed a better antioxidant defense and anti-inflammatory profile of Metformin animals than Saline animals and might directly improve reproductive organs morphophysiology and sperm morphology. Also, the neonatal Met application programs the male reproduction to counterbalance damages from an obesogenic environment in later life.

COVID-19 During Development: A Matter of Concern.

A new infectious disease, COVID-19, has spread around the world. The most common symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are cough and fever, but severe cases can develop acute respiratory distress syndrome. The main receptor for SARS-CoV-2 in human tissue is angiotensin-converting enzyme 2, and the lungs, heart, and kidneys are the most affected organs. Besides the inflammatory process and tissue damage, the presence of a cytokine "storm" has been related to a higher mortality rate. Other infectious viral diseases, such as Zika, chikungunya, and influenza, were associated with complications in pregnant women, such as growth restriction, malformation, preterm birth, low birth weight, miscarriage, and death, although they can also cause developmental disorders in infants and adolescents. Evidence points out that stressors during pregnancy and infancy may lead to the development of obesity, diabetes, and cardiovascular disease. Therefore, we hypothesize that COVID-19 infection during the critical phases of development can program the individual to chronic diseases in adulthood. It is important that COVID-19 patients receive proper monitoring as a way to avoid expensive costs to public health in the future.

Pulmonary Emphysema Impairs Male Reproductive Physiology Due To Testosterone and Oxidative Stress Imbalance in Mesocricetus auratus.

This study evaluated whether pulmonary emphysema affects sperm quality, male reproductive organs, and testosterone levels in adult male hamsters. Mesocricetus auratus males (130-150 g) were subdivided into a control group (C group) and an emphysema group (E group). The C group received an intratracheal instillation of saline solution (0.3 mL/100 g of body weight), and the E group received papain (40 mg/100 g of body weight). After 60 days, the biometric, pulmonary, and reproductive parameters of each group were evaluated. The E group developed pulmonary emphysema, which decreased body weight and sperm quality compared to the C group. In oxidative stress-related assays, lipid peroxidation was increased in the testis and epididymis (caput and cauda) in the E group compared with the C group. However, only the caput epididymis showed a reduction in glutathione levels. Pulmonary emphysema also affected the testicle by inducing an increase in abnormal seminiferous tubules, accompanied by a decrease in seminiferous epithelium height. Spermatogenesis kinetics were also modified by pulmonary emphysema. The number of Leydig and Sertoli cells decreased in the E group, accompanied by an increase in the nuclear volume of Leydig cells. Testosterone concentration was increased in the E group. Similarly, pulmonary emphysema altered epididymal components in all regions. In conclusion, pulmonary emphysema affected the reproductive system in this experimental model, as shown by testicular and epididymal morphophysiology changes, hormonal alteration, and oxidative stress imbalance, inducing the loss of correct function in the male reproductive system.

Bisphenol A reduces testosterone production in TM3 Leydig cells independently of its effects on cell death and mitochondrial membrane potential.

Leydig cells are the major testosterone-producing cells of the male reproductive system, and damage to these cells can impair fertility of men. Bisphenol A (BPA) is one of the chemicals with the highest volume of production worldwide. The aim of this study was to evaluate the effects of BPA on the growth, viability, and testosterone production of TM3 murine Leydig cells after exposure to BPA for 24 or 48 h. BPA reduced testosterone production, cell viability and cell growth in a concentration-dependent manner. The highest tested concentration of BPA (100 µM) increased cellular death, as indicated by an increased sub-G1 phase population and a larger number of cells labeled with Hoechst 3342. This concentration of BPA also decreased the number of metabolically active mitochondria as revealed by rhodamine staining. Therefore, our data show that BPA is toxic to Leydig TM3 cells and impairs their steroidogenic function.