Developmental toxicity and programming alterations of multiple organs in offspring induced by medication during pregnancy

Medication during pregnancy is widespread, but there are few reports on its fetal safety. Recent studies suggest that medication during pregnancy can affect fetal morphological and functional development through multiple pathways, multiple organs, and multiple targets. Its mechanisms involve direct ways such as oxidative stress, epigenetic modification, and metabolic activation, and it may also be indirectly caused by placental dysfunction. Further studies have found that medication during pregnancy may also indirectly lead to multi-organ developmental programming, functional homeostasis changes, and susceptibility to related diseases in offspring by inducing fetal intrauterine exposure to too high or too low levels of maternal-derived glucocorticoids. The organ developmental toxicity and programming alterations caused by medication during pregnancy may also have gender differences and multi-generational genetic effects mediated by abnormal epigenetic modification. Combined with the latest research results of our laboratory, this paper reviews the latest research progress on the developmental toxicity and functional programming alterations of multiple organs in offspring induced by medication during pregnancy, which can provide a theoretical and experimental basis for rational medication during pregnancy and effective prevention and treatment of drug-related multiple fetal-originated diseases.

Prenatal Maternal Distress and Allergic Diseases in Offspring: Review of Evidence and Possible Pathways

Recent studies have suggested a close association between prenatal maternal distress and allergic diseases in the offspring. We selected relevant birth-cohort or national registry studies using a keyword search of the PubMed database and summarized current evidence on the impact of prenatal maternal distress on the development of offspring's allergic diseases. Moreover, we postulated possible pathways linking prenatal distress and allergic diseases based on relevant human and animal studies. Both dysregulated hypothalamic-pituitary-adrenal axis and increased oxidative stress may cause structural (altered brain/lung development) and functional (skewed immune development) changes, which may predispose the fetus to developing allergic diseases during childhood. Although many facts are yet to be discovered, changes in the placental response and epigenetic modification are presumed to mediate the whole process from maternal distress to allergic diseases. Maternal prenatal distress can also interact with other physical or environmental factors, including familial or physical factors, indoor and outdoor pollutants, and early childhood psychological distress. The gut-microbiome-brain axis and the role of the microbiome as an immune modulator should be considered when investigating the stress-allergy relationship and exploring potential intervention modalities. Further research is needed, and particular attention should be given to defining the most vulnerable subjects and critical time periods. To this end, studies exploring relevant biomarkers are warranted, which can enable us to explore adequate intervention strategies.

Renin-angiotensin system and developmental programming for hypertension / 国际儿科学杂志

Numerous studies have proved the close relationship between early adverse exposure and hypertension in later life, as a result, the blood pressure developmental programming theory has been proposed.The renin-angiotensin system(RAS) is an important endocrine system for maintaining blood pressure and cardiovascular homeostasis, which also plays a key role in histogenesis in early period.Adverse environmental exposure in early life influences the expression of RAS in circulation and local tissue, and interferes the balance of RAS,therefore regulates the blood pressure in later life.This review focuses upon the influence of RAS by early adverse exposure,the relation between RAS and developmental programming for hypertension.

Estudo das alterações cardiovasculares e metabólicas em modelo experimental de programação metaboólica: efeito de extrato da casca de uva vitis vinífera / Study of cardiovascular and metabolic changes in experimental model of metabolic programming: effect of extract of grape skins vitis vinífera

Estudos epidemiológicos e experimentais têm sugerido que fatores de risco cardiovasculares podem ser parcialmente atribuídos às influências do ambiente em que vive o indivíduo, e que a nutrição materna influencia na programação de alterações metabólicas e cardiovasculares no indivíduo adulto e que caracterizam a síndrome metabólica (SM). Em contrapartida, estudos prévios de nosso laboratório demonstram que o extrato da casca de uva Vitis labrusca (GSE) possui efeito vasodilatador, antihipertensivo e antioxidante. Desta forma, o objetivo deste estudo foi avaliar o efeito do tratamento oral com GSE (200mg/kg/dia), sobre as alterações cardiovasculares e metabólicas e extresse oxidativo observados na prole adulta (fêmea e machos) com 3 e 6 meses, cujas mães foram submetidas a uma dieta rica em gordura (hiperlipídica) durante a lactação. Quatro grupos de ratas foram alimentados com dietas experimentais: controle (7% de gordura); controle + GSE (7% de gordura + GSE), hiperlipídica (24% de gordura); hiperlipídica + GSE (24% de gordura + GSE) durante a lactação. Após o desmame, todos os filhotes passaram a ser alimentados com uma dieta controle e foram sacrificados aos 3 ou 6 meses de idade. A pressão arterial sistólica (PAS) foi medida por pletismografia de cauda e o efeito vasodilatador da acetilcolina (ACh) foi avaliado em leito arterial mesentérico (LAM) perfundido. Foram avaliados o peso corporal, adiposidade (intra-abdominal e gonadal), níveis plasmáticos de colesterol total, triglicerídeos, glicose e insulina, e a resistência à insulina (RI) foi calculada pelo índice de HOMA IR. As expressões do IRS-1, Akt e GLUT-4 foram determinadas em músculo soleus. O dano oxidativo, níveis de nitritos e a atividade das enzimas antioxidantes: superóxido dismutase, catalise e glutationa peroxidase foram dosados no plasma e homogenato de LAM. A PAS e tecido adiposo foram aumentados nas proles adultas de ambos os sexos e idades do grupo hiperlipídico e revertidos...

Epidemiological and experimental studies have suggested that cardiovascular risk factors can be partly attributed to the influences of the environment in which the individual lives, and that maternal nutrition influences the programming of metabolic and cardiovascular diseases in adults characterizing the metabolic syndrome. On the other hand, previus studies from our laboratory show that the skin extract of grape Vitis labrusca (GSE) has antihypertensive, antioxidant and vasodilator effects. Thus, the aim of this study was to evaluate the effect of oral treatment with GSE (200mg/kg/day) on the cardiovascular and metabolic disorders and oxidative stress observed in adult offspring (female and male) at 3 or 6 months whose mothers were fed a high fat diet (HF) during lactation. Four groups of rats were fed experimental diets: control (7% fat), control + GSE (7% fat + GSE), diet (24% fat), HF + GSE (24% fat + GSE) during lactation. After weaning, all pups have become fed a control diet and were sacrificed at 3 or 6 months of age. Systolic blood pressure (SBP) was measured by plethysmography and the vasodilator effect of acethylcholine (ACh) was studied in perfused mesenteric arterial bed (MAB). We determined the body weight, adiposity, plasma total cholesterol, triglycerides, glucose, insulin, and insulin resistance was calculated by HOMA IR. The expression of IRS-1, Akt and GLUT-4 were determined in soleus muscle. Oxidative damage, nitrite levels and antioxidant enzyme activity: superoxide dismutase, catalase and glutathione peroxidase were measured in plasma and homogenate of mesentery bed. The SBP and adipose tissue were increased in adult offspring of both sex and ages of the HF group and reversed by treatment with GSE. The vasodilator response to ACh was not different between groups of both sex, but was reduced by aging. In offspring females and males of the HF group were also observed increased levels of triglycerides, glucose and insulin resistance...

Compuestos disruptores endocrinos y su participación en la programación del eje reproductivo / Endocrine disruptor compounds and their role on the developmental programming of the reproductive axis

Different perturbations during fetal and post natal development unleash endocrine adaptations that permanently alter metabolism, increasing the susceptibility to develop later disease, process known as "developmental programming"'. Endocrine disruptor compounds (EDC) are widely spread on the environment and display estrogenic, anti-estrogenic or anti-androgenic activity; they are lypophilyc and stored for long periods on the adipose tissue. Maternal exposure to EDC during pregnancy and lactation produces the exposure of the fetus and neonate through placenta and breast milk. Epidemiological and experimental studies have demonstrated reproductive alterations as a consequence of intrauterine and/or neonatal exposure to EDC. Diethystilbestrol (DES) is the best documented compound, this synthetic estrogen was administered to pregnant women at the BO and 60 to prevent miscarriage. It was implicated in urogenital abnormalities in children exposed in utero and withdrawn from the market. The "DES daughters" are women with high incidence of vaginal hypoplasia, spontaneous abortion, premature delivery, uterine malformation, menstrual abnormalities and low fertility. The "DES sons" show testicular dysgenesis syndrome, which is characterized by hypospadias, cryptorchidism and low semen quality. This entity is also associated to the fetal exposure to anti-androgens as flutamide. The effects on the reproductive axis depend on the stage of development and the window of exposure, as well as the dose and the compound. The wide distribution of EDC into the environment affects both human health and ecosystems in general, the study of their mechanisms of action is extremely important currently.

Diversas perturbaciones durante el desarrollo fetal y posnatal desencadenan adaptaciones endocrinas que modifican permanentemente el metabolismo, incrementando la susceptibilidad para el desarrollo de enfermedades, proceso conocido como "programación durante el desarrollo". Los compuestos disruptores endocrinos (CDE) se encuentran en el medio ambiente y presentan actividad estrogénica, antiestrogénica o antiandrogénica; son altamente lipofílicos y se almacenan por periodos prolongados en el tejido adiposo. La exposición materna a CDE durante el embarazo y la lactancia permite su paso al producto a través de la placenta y la leche materna. Estudios epidemiológicos y experimentales han demostrado alteraciones en el eje reproductivo como consecuencia de la exposición intrauterina y/o neonatal a CDE. El compuesto mejor documentado es el dietilestilbestrol (DES), este estrógeno sintético fue administrado a mujeres embarazadas durante los 50s y 60s y retirado del mercado por su implicación en anormalidades urogenitales de los bebés expuestos in útero. Las denominadas "hijas del DES" son mujeres con alta incidencia de hipoplasia vaginal, malformaciones uterinas, irregularidades menstruales, baja fertilidad y alta prevalencia de aborto espontáneo y parto prematuro. Por su parte, "los hijos del DES" presentan una entidad clínica conocida como síndrome de disgenesia testicular caracterizado por hipospadias, criptorquidia y baja calidad del semen. Este síndrome también se asocia a la exposición fetal a compuestos antiandrogénicos como la ñutamida. Los efectos en el eje reproductivo dependen del estadio de desarrollo y del tiempo de exposición, así como de la dosis y el compuesto del que se trate. La extensa presencia de CDE en el ambiente afecta la salud humana e impacta al ecosistema en general por lo cual es de suma importancia el estudio de los mecanismos involucrados en su acción.