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.

Implementation of a six-around-one optical probe based on diffuse light spectroscopy for study of cerebral properties in a murine mouse model of autism spectrum disorder.

Light reflectance spectroscopy (LRS) is a multispectral technique, sensitive to the absorption and scattering properties of biological molecules in tissues. It is used as a noninvasive tool to extract quantitative physiological information from human tissues and organs. A near-infrared LRS based on a single optical probe was used to monitor changes in optical and hemodynamic parameters in a mouse model of autism. A murine model of autism induced by developmental exposure to valproic acid (VPA) was used. Since autism could be attributed to neuroanatomical changes, we hypothesize that these changes can be detected using the LRS because spectral properties depend on both molecular composition and structural changes. The fiber-optic probe in the setup consisted of seven small optical fibers: six fibers for illumination placed in a circular manner around a central single collection fiber. Overall, measurements demonstrate changes in diffused reflectance spectra, cerebral optical tissue properties (absorption and scattering), and chromophore levels. Furthermore, we were able to identify differences between male and female groups. Finally, the effectiveness of S-Adenosylmethionine as a drug therapy was studied and found to improve the hemodynamic outcome. For the first time, to the best of our knowledge, the LRS is utilized to study variations in brain parameters in the VPA autism model mice through an intact scalp.

Gender Related Changes in Gene Expression Induced by Valproic Acid in A Mouse Model of Autism and the Correction by S-adenosyl Methionine. Does It Explain the Gender Differences in Autistic Like Behavior?

In previous studies we produced autism like behavioral changes in mice by Valproic acid (VPA) with significant differences between genders. S-adenosine methionine (SAM) prevented the autism like behavior in both genders. The expression of 770 genes of pathways involved in neurophysiology and neuropathology was studied in the prefrontal cortex of 60 days old male and female mice using the NanoString nCounter. In females, VPA induced statistically significant changes in the expression of 146 genes; 71 genes were upregulated and 75 downregulated. In males, VPA changed the expression of only 19 genes, 16 were upregulated and 3 downregulated. Eight genes were similarly changed in both genders. When considering only the genes that were changed by at least 50%, VPA changed the expression of 15 genes in females and 3 in males. Only Nts was similarly downregulated in both genders. SAM normalized the expression of most changed genes in both genders. We presume that genes that are involved in autism like behavior in our model were similarly changed in both genders and corrected by SAM. The behavioral and other differences between genders may be related to genes that were differently affected by VPA in males and females and/or differently affected by SAM.

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.

Reversal of chlorpyrifos neurobehavioral teratogenicity in mice by allographic transplantation of adult subventricular zone-derived neural stem cells.

Neurobehavioral teratogenicity can be reversed with transplantation of neural stem cells. However, the usefulness of this therapy would be greatly enhanced by employing adult stem cells. In pursuit of this this goal, we developed a model that uses subventricular zone (SVZ) cells. HS/Ibg mice were exposed prenatally to chlorpyrifos on gestational days 9-18 (3 mg/kg/day, SC) in order to induce deficits in their performance in the Morris water maze test. Both the control and the exposed offspring were transplanted with SVZ cells (or vehicle) on postnatal day 35; this actually represents an allogenic transplantation, because the HS/Ibg strain is a heterogeneous stock. The transplanted cells were later observed in the host brain by DiI tracing, and their initial differentiation to cholinergic neurons and astrocytes was ascertained. On postnatal day 80, animals that had been exposed prenatally to chlorpyrifos displayed impaired Morris water maze performance, requiring more time to reach the platform. Transplantation of adult SVZ-derived neural stem cells (NSC) reversed the deficits. Applying autologous transplantation provides an important demonstration that the methodological obstacles of immunological rejection and the ethical concerns related to using embryonic stem cells may be successfully bypassed in developing stem cell therapies for neurodevelopmental disorders.

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.

Survival, differentiation, and reversal of heroin neurobehavioral teratogenicity in mice by transplanted neural stem cells derived from embryonic stem cells.

Cell therapies in animal models of neurobehavioral defects are normally derived from neural stem cells (NSC) of the developing cortex. However, the clinical feasibility of NSC therapies would be greatly improved by deriving transplanted cells and from a tissue culture source that is self-renewing, containing cells that potentially differentiate into the desired neuronal phenotypes. These cultures can be engineered to contain the appropriate factors to support their therapeutic action and likely evoke lesser immune reactions. In the current study, we employed our model of mice neurobehaviorally impaired via prenatal exposure to heroin, to test the therapeutic efficacy of NSC derived from murine embryonic stem cells culture (ESC). The culture contained elongated bipolar cells, 90% of which are positive for nestin, the intermediate filament protein found in neural precursors. After removal of growth factors, the NSC differentiated into neurons (34.0% +/- 3.8% NF-160 positive), including cholinergic cells (ChAT positive), oligodendrocytes (29.9% +/- 4.2% O(4)), and astrocytes (36.1% +/- 4.7% GFAP positive). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis confirmed the immunocytochemical findings. Mice made deficient in Morris maze behavior by prenatal heroin exposure (10 mg/kg heroin s.c. on gestational days 9-18) were transplanted into the hippocampus region on postnatal day 35 with the ES culture-derived NSC (ES-NSC) labeled with dialkylcarbocyanine (Dil) cell tracker. Dil+ and NF160+ cells were detected in the hippocampal region (50% +/- 8% survival). The transplantation completely restored maze performance to normal; e.g., on day 3, transplantation improved the behavior from the deficient level of 11.9-sec latency to the control of 5.6-sec latency (44.5% improvement).

Reversal of neurobehavioral teratogenicity in animal models and human: Three decades of progress.

Early studies of behavioral teratology were mostly descriptive, fulfilling the necessary first requirement in a new field. The next obvious stage was put forward in the 80's as mechanism driven science enabled reversal of the teratogens-induced deficits. Three decades later a plethora of studies have been published demonstrating the success of the new direction. Complete and long-term (ostensibly permanent) reversal has been demonstrated in numerous animal models representing the realization of the ultimate goal of the field. Perhaps less sought after, but still significant, are the studies on recovery which needs consistent treatment for its persistence The studies reviewed here have been summarized in Tables 1 and 2. Clinically, the field is only in its incipient stage because of the paucity in translational findings for complete reversal or even complete alleviation. Human findings are emerging but in partial alleviation, noteworthy were the demonstration of FASD children who showed improvement after choline treatment while others showed no effect. Consequently, while further studies in an animal model on the mechanism by which the teratogen exerts its deleterious effects and the reversal procedure action are important, the main thrust of the research should now be translation of the animal model findings into a standard clinical routine. Indeed, first steps towards these goals are being made in children with various neurodevelopmental disorders via the application of a variety of rehabilitation programs by physiotherapists, occupational therapists and speech and language therapists, but the results are partial and may not be long-lasting.

S-adenosyl methionine prevents ASD like behaviors triggered by early postnatal valproic acid exposure in very young mice.

INTRODUCTION: A common animal model of ASD is the one induced by valproic acid (VPA), inducing epigenetic changes and oxidative stress. We studied the possible preventive effect of the methyl donor for epigenetic enzymatic reactions, S-adenosine methionine (SAM), on ASD like behavioral changes and on redox potential in the brain and liver in this model. METHODS: ICR albino mice were injected on postnatal day 4 with one dose of 300 mg/kg of VPA, with normal saline (controls) or with VPA and SAM that was given orally for 3 days at the dose of 30 mg/kg body weight. From day 50, we carried out neurobehavioral tests and assessment of the antioxidant status of the prefrontal cerebral cortex, liver assessing SOD and CAT activity, lipid peroxidation and the expression of antioxidant genes. RESULTS: Mice injected with VPA exhibited neurobehavioral deficits typical of ASD that were more prominent in males. Changes in the activity of SOD and CAT increased lipid peroxidation and changes in the expression of antioxidant genes were observed in the prefrontal cortex of VPA treated mice, more prominent in females, while ASD like behavior was more prominent in males. There were no changes in the redox potential of the liver. The co-administration of VPA and SAM alleviated most ASD like neurobehavioral symptoms and normalized the redox potential in the prefrontal cortex. CONCLUSIONS: Early postnatal VPA administration induces ASD like behavior that is more severe in males, while the redox status changes are more severe in females; SAM corrects both. VPA-induced ASD seems to result from epigenetic changes, while the redox status changes may be secondary.

Reversal of heroin neurobehavioral teratogenicity by grafting of neural progenitors.

A major objective in identifying the mechanisms underlying neurobehavioral teratogenicity in an animal model is the possibility of designing therapies that reverse or offset teratogen-induced neural damage. In our previous studies, we identified deficits in hippocampal muscarinic cholinergic receptor-induced translocation of protein kinase C (PKC) gamma as the likely central factor responsible for the adverse behavioral effects of pre-natal heroin exposure. Neural progenitors (NP) have the ability to recover behavioral deficits after focal hippocampal damage. Therefore, we explored whether behavioral and synaptic defects could be reversed in adulthood by neural progenitor grafting. Pregnant mice were injected daily with 10 mg/kg of heroin on gestational days 9-18. In adulthood, offspring showed deficits in the Morris maze, a behavior dependent on the integrity of septohippocampal cholinergic synaptic function, along with the loss of the PKCgamma and PKCbetaII responses to cholinergic stimulation. Mice that were exposed pre-natally to heroin and vehicle control mice were then grafted in adulthood with NP. Importantly, most grafted cells differentiated to astrocytes. NP reversed the behavioral deficits (p = 0.0043) and restored the normal response of hippocampal PKCgamma and PKCbetaII (p = 0.0337 and p = 0.0265 respectively) to cholinergic receptor stimulation. The effects were specific as the PKCalpha isoform, which is unrelated to the behavioral deficits, showed almost no changes. Neural progenitor grafting thus offers an animal model for reversing neurobehavioral deficits originating in septohippocampal cholinergic defects elicited by pre-natal exposure to insults.

Developmental neurotoxic effects of chlorpyrifos on acetylcholine and serotonin pathways in an avian model.

The developmental neurotoxicity of organophosphates such as chlorpyrifos (CPF) involves multiple mechanisms that ultimately compromise the function of specific neurotransmitter systems, notably acetylcholine (ACh) and serotonin (5-hydroxytryptamine, 5HT). Studies in mammalian models incorporate both direct effects on brain development and indirect effects mediated through maternal physiology and maternal/neonatal interactions. We examined the effects of CPF in an avian model, which does not share these potential confounds. Chick eggs were injected with CPF (10 or 20 mg/kg) on incubation days 2 and 6 and markers of ACh and 5HT systems were examined at hatching. The higher dose caused a reduction in cholinesterase activity but there was no consistent downregulation of m(2)-muscarinic ACh receptors as would have been expected from ACh hyperstimulation. Both doses evoked significant reductions in the presynaptic high-affinity choline transporter, the rate-limiting factor in ACh biosynthesis, as monitored by binding of hemicholinium-3. Choline acetyltransferase, a constitutive marker for ACh terminals, was unaffected. This suggests that CPF reduces ACh presynaptic activity rather than compromising the development of ACh projections per se. CPF exposure also reduced the expression of cerebrocortical 5HT(1A) receptors. These effects in the chick model recapitulate many of the actions of early gestational CPF exposure in rats, and thus suggest that CPF exerts direct actions on the immature brain to compromise the development of ACh and 5HT pathways.

Exposure of developing chicks to perfluorooctanoic acid induces defects in prehatch and early posthatch development.

There is increasing concern over the widespread use of perfluorinated chemicals, which accumulate in various tissues and penetrate the mammalian fetus. A chick model was established for the rapid evaluation of teratogenicity of these chemicals, an important issue because developmental defects often occur at lower exposures than those required for adult systemic toxicity. Chicken eggs were injected with varying doses of perfluorooctanoic acid prior to incubation. Observed were defects in hatching, increased incidence of splayed legs, and interference with the appropriate development of yellow plumage. All these defects are potentially related to essential molecular/biochemical and functional development of the chick. Because of the relationship between structural defects and vulnerability of the developing brain, our model points to the need to evaluate neurobehavioral teratogenicity, which may involve even lower doses.

Is post exposure prevention of teratogenic damage possible: Studies on diabetes, valproic acid, alcohol and anti folates in pregnancy: Animal studies with reflection to human.

We discuss the possibilities to prevent the post-exposure teratogenic effects of several teratogens: valproic acid (VPA), diabetes and alcohol. Co-administration of folic acid with VPA reduced the rate of Neural Tube Defects (NTD) and other anomalies in rodents, but apparently not in pregnant women. Antioxidants or the methyl donor S-adenosyl methionine prevented Autism Spectrum Disorder (ASD) like behavior in mice and rats. In vivo and in vitro studies demonstrated that antioxidants, arachidonic acid, myoinositol and nutritional agents may prevent diabetes-embryopathy. Prevention of alcohol-induced embryonic and fetal injuries and neurodevelopmental deficits was achieved by supplementation of zinc, choline, vasoactive intestinal proteins (VIP related peptides), antioxidants and folic acid. While the animal research described in this review is indicative of possible preventions of the different teratogenic effects, this is not yet the focus in human research. Future research should promote further knowledge where our current understanding is the vaguest, human prevention.

Mechanism-based approaches for the reversal of drug neurobehavioral teratogenicity.

Understanding the mechanism of neurobehavioral teratogenicity is the primary prerequisite for reversal of the defect. Progress in such studies can be best achieved if the investigation focuses on behaviors related to a specific brain region and innervation. Our model focused on teratogen-induced deficits in hippocampus-related eight-arm and Morris maze behaviors. Different "cholinergic" teratogens, mainly heroin, induced both pre- and postsynaptic hyperactivity in the hippocampal cholinergic innervation that terminated in desensitization of Protein Kinase C (PKC) isoforms to cholinergic receptor stimulation. Understanding this mechanism enabled its reversal with a pharmacological therapy-nicotine infusion. Studies by others provided similar findings by targeting the deficits respective to the model investigated. Consistently, destruction of the A10-septal dopaminergic pathways that downregulate the septohippocampal cholinergic innervation ameliorated maze performance. Grafting of embryonic differentiated cholinergic cells or neural progenitors similarly reversed the biochemical/molecular alterations and the resulting deficits. Reversal therapies offer a model for the understanding of neurobehavioral teratogenicity and, clinically, offer a model for potential treatment of these deficits. Whereas neural progenitor grafting appears to be the most effective treatment, pharmacological reversal with nicotine infusion seems to possess the most feasible and immediate therapy for neurobehavioral birth defects produced by various teratogens, including drugs. This is true even though the effect of pharmacological therapies is diffuse, affecting multiple areas of the brain. "Everybody is talking about the weather but nobody does anything about it." (Mark Twain).

Disruption of the development of cholinergic-induced translocation/activation of PKC isoforms after prenatal heroin exposure.

Prenatal exposure of mice to heroin resulted in behavioral deficits present at adulthood, and related to septohippocampal cholinergic innervation accompanied by both pre- and postsynaptic cholinergic hyperactivity; including an increase in membrane PKC activity, and a desensitization of PKC to cholinergic input, which correlated highly with the behavioral performance, and was reversed by cholinergic grafting. The effect was shown in the behaviorally relevant PKCgamma and beta whereas the less behaviorally relevant PKCalpha isoform was not affected. The present study was designed to establish the effect of heroin exposure on the expression of the PKC isoforms level and on the more functionally relevant cholinergic translocation/activation of the isoforms throughout postnatal development. The hippocampi of mice pups, exposed to heroin transplacentally, were assayed after incubation with carbachol for PKC isoforms on postnatal days (PN) 1, 7, 14, 21, 30 and 50. Prenatal heroin exposure increased basal PKCgamma, beta and alpha levels. PKCgamma and alpha levels returned to control levels on PN50. While in PKCbeta, this increase lasted until PN50. Translocation/activation of the PKC isoforms gamma and beta by cholinergic receptor stimulation was present from PN1, concurrent with the presence of the isoforms. Prenatal exposure to heroin completely abolished the translocation/activation throughout the entire postnatal development. This defect was shown from the very beginning, PN1, the day when the PKC isoforms appear. The results suggest that the PKCgamma and beta isoforms are functional concurrent with their developmental appearance. Unlike findings on some other teratogens, the prenatal heroin effect on the isoforms function is similar throughout postnatal development.

Nicotine therapy in adulthood reverses the synaptic and behavioral deficits elicited by prenatal exposure to phenobarbital.

A major objective in identifying the mechanisms underlying neurobehavioral teratogenicity is the possibility of designing therapies that reverse or offset drug- or toxicant-induced neural damage. In our previous studies, we identified deficits in hippocampal muscarinic cholinergic receptor-induced membrane translocation of protein kinase C (PKC)gamma as the likely mechanism responsible for adverse behavioral effects of prenatal phenobarbital exposure. We therefore explored whether behavioral and synaptic defects could be reversed in adulthood by nicotine administration. Pregnant mice were given milled food containing phenobarbital to achieve a daily dose of 0.5-0.6 g/kg from gestational days 9-18. In adulthood, offspring showed deficits in the Morris maze, a behavior dependent on the integrity of septohippocampal cholinergic synaptic function, along with the loss of the PKCgamma response. Phenobarbital-exposed and control mice then received nicotine (10 mg/kg/day) for 14 days via osmotic minipumps. Nicotine reversed the behavioral deficits and restored the normal response of hippocampal PKCgamma to cholinergic receptor stimulation. The effects were regionally specific, as PKCgamma in the cerebellum was unaffected by either phenobarbital or nicotine; furthermore, in the hippocampus, PKC isoforms unrelated to the behavioral deficits showed no changes. Nicotine administration thus offers a potential therapy for reversing neurobehavioral deficits originating in septohippocampal cholinergic defects elicited by prenatal drug or toxicant exposures.

A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity.

The chemical warfare blistering agent, sulfur mustard (SM), is a powerful mutagen and carcinogen. Due to its similarity to the related chemotherapy agents nitrogen mustard (mechlorethamine), it is expected to act as a developmental neurotoxicant. The present study was designed to establish a chick model for the mechanisms of SM on neurobehavioral teratogenicity, free of confounds related to mammalian maternal effects. Chicken eggs were injected with SM at a dose range of 0.0017-17.0 microg/kg of egg, which is below the threshold for dysmorphology, on incubation days (ID) 2 and 7, and then tests were conducted posthatching. Exposure to SM elicited significant deficits in the intermedial part of the hyperstriatum ventrale (IMHV)-related imprinting behavior. Parallel decreases were found in the level of membrane PKCgamma in the IMHV, while eliciting no net change in cytosolic PKCgamma. The chick, thus, provides a suitable model for the rapid evaluation of SM behavioral teratogenicity and elucidation of the mechanisms underlying behavioral anomalies. The results obtained, using a model that controls for confounding maternal effects, may be replicated in the mammalian model and provide the groundwork for studies designed to offset or reverse the SM-induced neurobehavioral defects in both avian and mammals.

An avian model for ascertaining the mechanisms of organophosphate neuroteratogenicity and its therapy with mesenchymal stem cell transplantation.

INTRODUCTION: A fast and simple model which uses animals lower on the evolutionary scale is beneficial for progress in neuroteratological research. Here, we established this novel model and applied it in the study of the detrimental effects of pre-hatch exposure to chlorpyrifos on neurogenesis and several neurotransmitter systems in the chick and their reversal, using mesenchymal stem cell (MSC) transplantation. METHODS: Chicken eggs were injected with the organophosphate chlorpyrifos, 10mg/kg eggs - a dose below the threshold for dysmorphology - on incubation days (ID) 0 and 5 and subsequently the embryos were subjected to intravenous transplantation of MSC on ID 13. RESULTS: After hatching (day 1) the expression of the neurogenesis-related genes DCX (also confirmed by immunohistochemistry), BDNF, MAP 2, FGF 2, SOX 2 and VEGF in the lateral striatum area was decreased in the exposed group (p<0.005). Among the studied neurotransmitter systems (serotonergic, dopaminergic and cholinergic), increased gene expression was demonstrated for tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) with a corresponding decrease in serotonin receptor 1A (5HTR1A) (p<0.05); no changes in gene expression of choline transporter, PKC beta and D2 were found following chlorpyrifos exposure. CONCLUSION: Transplantation of MSC reversed all the neurogenic and serotonergic alterations (p<0.01). The study of chick embryo exposure to insults with subsequent MSC therapy provides a fast and simple model for elucidating the mechanisms of both the neuroteratogenicity and the therapy, steps that are critical for progress toward therapeutic applications.

Mesenchymal stem cells can prevent alterations in behavior and neurogenesis induced by Aß25-35 administration.

Mesenchymal stem cells (MSCs) are known to enhance neurogenesis in the dentate gyrus, as well as to modulate immune cell activity and inflammation. Easily obtained and expanded from the bone marrow and other tissues, MSCs have been proposed as candidates for stem cell therapy in various neurodegenerartive diseases. In the present study, we sought to explore these therapeutic properties of MSC on Aß25-35-induced pathology when coadministered together. Apparently, coadministration of MSC prevented mild cognitive deficits observed following Aß administration alone, by promoting microglial activation and rapid clearance of injected Aß aggregates. Surprisingly, increased hippocampal neurogenesis was observed in the Aß-injected animals and was normal in MSC-coadministered animals just as in control animals. The observed increase in neurogenesis can be explained as a compensating mechanism responsible for the mild and temporary cognitive deficits observed in the Morris water maze assay in Aß-injected animals. Interestingly, MSC engrafted not only to the hippocampus but were also detected in the choroid plexus. We thus conclude that MSC may act in multiple pathways to protect the CNS from Aß pathology, while neurogenesis is a possible compensating mechanism; it is not always activated by MSC, which in turn may interact with local immune cells to regulate Aß accumulation.