Parental Preconception and Pre-Hatch Exposure to a Developmental Insult Alters Offspring's Gene Expression and Epigenetic Regulations: An Avian Model.

Parental exposure to insults was initially considered safe if stopped before conception. In the present investigation, paternal or maternal preconception exposure to the neuroteratogen chlorpyrifos was investigated in a well-controlled avian model (Fayoumi) and compared to pre-hatch exposure focusing on molecular alterations. The investigation included the analysis of several neurogenesis, neurotransmission, epigenetic and microRNA genes. A significant decrease in the vesicular acetylcholine transporter (SLC18A3) expression was detected in the female offspring in the three investigated models: paternal (57.7%, p < 0.05), maternal (36%, p < 0.05) and pre-hatch (35.6%, p < 0.05). Paternal exposure to chlorpyrifos also led to a significant increase in brain-derived neurotrophic factor (BDNF) gene expression mainly in the female offspring (27.6%, p < 0.005), while its targeting microRNA, miR-10a, was similarly decreased in both female (50.5%, p < 0.05) and male (56%, p < 0.05) offspring. Doublecortin's (DCX) targeting microRNA, miR-29a, was decreased in the offspring after maternal preconception exposure to chlorpyrifos (39.8%, p < 0.05). Finally, pre-hatch exposure to chlorpyrifos led to a significant increase in protein kinase C beta (PKCß; 44.1%, p < 0.05), methyl-CpG-binding domain protein 2 (MBD2; 44%, p < 0.01) and 3 (MBD3; 33%, p < 0.05) genes expression in the offspring. Although extensive studies are required to establish a mechanism-phenotype relationship, it should be noted that the current investigation does not include phenotype assessment in the offspring.

Whole transcriptome analysis in offspring whose fathers were exposed to a developmental insult: a novel avian model.

Although the effects of paternal exposure to insults on the offspring received limited attention in the past, it is currently gaining interest especially after understanding the mechanisms which may mediate such exposure effects. In the current study, the well-controlled avian model (Fayoumi) was utilized to investigate the effects of paternal exposure to the developmental insult, chlorpyrifos on the offspring's gene expression via mRNA and small RNA sequencing. Numerous mRNA gene expression changes were detected in the offspring after paternal exposure to the developmental insult, especially in genes related to neurogenesis, learning and memory. qPCR analysis of several genes, that were significantly changed in mRNA sequencing, confirmed the results obtained in mRNA sequencing. On the other hand, small RNA sequencing did not identify significant microRNA genes expression changes in the offspring after paternal exposure to the developmental insult. The effects of the paternal exposure were more pronounced in the female offspring compared to the male offspring. The results identified expression alterations in major genes (some of which were pertinent to the functional changes observed in other forms of early developmental exposure) after paternal insult exposure and provided a direction for future studies involving the most affected genes.

Reversal of prenatal heroin-induced alterations in hippocampal gene expression via transplantation of mesenchymal stem cells during adulthood.

Neurobehavioral teratology is the study of typically subtle neurobehavioral birth defects. Our previously described mouse model demonstrated septohippocampal cholinergic innervation-related molecular and behavioral deficits after prenatal exposure to heroin. Since the alterations are below malformation level, they are likely to represent consequences of regulatory processes, feasibly gene expression. Consequently, in the present study pregnant mice were injected with heroin on gestation days 9-18 and were transplanted with mesenchymal stem cells (MSC) on postnatal day (PD) 105. The hippocampi of the offspring were analyzed on PD120 for the expression of the pertinent genes. Heroin induced global gender-dependent statistically significant changes in the expression of several genes. Significant Treatment X Sex interaction occurred in D1 and SOX2 genes (p < 0.01). Transplantation of MSC reversed the prenatal heroin-induced alterations in approximately 80% of the genes. The reversal index (RI), shifting the score of the heroin-exposed offspring by transplantation back toward the control level, was 0.61 ± 0.10 for the difference from RI = 0 (p < 0.001), confirming the validity of the effect of the neuroteratogens across variations among different genes. The present study suggests that neurobehavioral defects induced by prenatal heroin exposure are likely to be a consequence of regulatory changes. This study on prenatal exposure to insults with subsequent MSC therapy provides a model for elucidating the mechanisms of both the neuroteratogenicity and the therapy, steps that are critical for progress toward therapeutic applications.

Paternal and/or maternal preconception-induced neurobehavioral teratogenicity in animal and human models.

Prenatal insult exposure effects on the offspring, have and are still considered the main interest of most teratological studies, while paternal and maternal preconception effects have received relatively little interest. Once thought to be a myth, paternal exposure to insults leading to numerous detrimental effects in the offspring, has been confirmed on several occasions and is gaining increased attention. These effects could be demonstrated molecularly, biochemically and/or behaviorally. Different epigenetic mechanisms have been proposed for these effects to occur, including DNA methylation, histone modification and sperm RNA transmission. Paternal insult exposure has been shown to cause several neurobehavioral and developmental defects in the offspring. Findings on parental insult exposure effects on the progeny will be discussed in this review, with the main focus being on neurobehavioral effects after parental preconceptional exposure. The exposure to the insults induced long-lasting, mostly marked, defects. A few pioneering, prevention and reversal studies were published. Interestingly, most studies were conducted on paternal exposure and, at the present state of this field, on animal models. Clinical translation remains the subsequent challenge.

Development of Gabapentin Expandable Gastroretentive Controlled Drug Delivery System.

Expandable drug delivery systems are one of many gastroretentive delivery systems which have emerged during the last few years. Expandable systems are usually folded in a capsule and expand to dimensions greater than the pyloric sphincter upon contact with gastric fluid. This prevents them from being evacuated by gastric emptying. The main objective of developing such systems is to increase the residence time of a specific drug in stomach; controlling its release, increasing its bioavailability and decreasing its side effects and dosing frequency. An expandable gastroretentive drug delivery system containing Gabapentin was developed using experimental design (D-optimal reduced quadratic design). This system was able to unfold at stomach pH in less than 15 minutes and obtain a controlled release of 78.1 ± 4.7% in 6 hours following zero-order release kinetic model. It is rigid in stomach and its rigidity decreases at intestinal pH. FTIR analysis indicated the occurrence of hydrogen bonding in Gabapentin when present in the developed system, which might be responsible for the drug's controlled release. XRD analysis indicated that Gabapentin physical properties changed from crystalline in the typical state to amorphous in the developed system.