Triggering Receptor Expressed on Myeloid Cells 2 Alleviated Sevoflurane-Induced Developmental Neurotoxicity via Microglial Pruning of Dendritic Spines in the CA1 Region of the Hippocampus

Sevoflurane induces developmental neurotoxicity in mice;however,the underlying mechanisms remain unclear.Triggering receptor expressed on myeloid cells 2(TREM2)is essential for microglia-mediated synaptic refinement during the early stages of brain development.We explored the effects of TREM2 on dendritic spine pruning during sevoflurane-induced developmental neurotoxicity in mice.Mice were anaesthetized with sevoflurane on postnatal days 6,8,and 10.Behavioral performance was assessed using the open field test and Morris water maze test.Genetic knockdown of TREM2 and overexpression of TREM2 by stereotaxic injection were used for mechanistic experiments.Western blotting,immunofluorescence,electron microscopy,three-dimensional reconstruction,Golgi staining,and whole-cell patch-clamp recordings were performed.Sevoflurane exposures upregulated the protein expression of TREM2,increased microglia-mediated pruning of dendritic spines,and reduced synaptic multiplicity and excitability of CA1 neurons.TREM2 genetic knockdown significantly decreased dendritic spine pruning,and partially aggravated neuronal morphological abnormalities and cognitive impairments in sevoflurane-treated mice.In contrast,TREM2 overexpression enhanced microglia-mediated pruning of dendritic spines and rescued neuronal morphological abnormalities and cognitive dysfunction.TREM2 exerts a protective role against neurocognitive impairments in mice after neonatal exposures to sevoflurane by enhancing microglia-mediated pruning of dendritic spines in CA1 neurons.This provides a potential therapeutic target in the prevention of sevoflurane-induced developmental neurotoxicity.

Developmental effects of Malathion exposure on locomotor activity and anxiety-like behavior in Wistar rat

Developmental exposure to organophosphate insecticide is well known to induce neurobeha-vioral impairments, at late period. The present study aims to investigate the effects of chronic exposure to Malathion, from in utero to young adult stage, on locomotor skills and anxiety like- behavior among wistar rat. Four groups of female rats, bred with one non-pesticide exposed male, are used. On gestational day 6, three groups receive daily, by intragastric gavage, 3 different doses of Malathion dissolved in corn oil (100, 200 and 300 mg/kg body weight). The control group receives the corn oil only. On postnatal day 21, weaned offsprings are submitted to the similar treatment until adult age. Spontaneous locomotor activity is evaluated using the Open-Field test (OF) and anxiety-like behavior is measured using both Open-Field (OF) test and Elevate Plus-Maze (EPM). Malathion at 300 mg/kg is toxic to pregnant dams, and pups are stillborns. In males, Malathionlevelat 100 and 200 mg/kg induced significant impairment of spontaneous locomotor activities, which is reflected by high decrease of number of squares crossed in OF. In contrast, no discernible changes are observed within females Malathion-treated-group. However, females exposed to both malathion levels develop further anxiety-like response, expressed by significant reductions of exploratory activities in OF and time spent in open arm of EPM. Neurochemistry assay shows that cerebellum and neocortex acetylcholinesterase (AChE) activity inhibition are significantly increased with neurobehavioral deficits in males, relative to females. Overall, neurobehavioral outcomes of current study reveal that developmental exposure to Malathion induces sex-selective effects with greater changes in females.

Developmental Effects of Malathion Exposure on Recognition Memory and Spatial Learning in Males Wistar Rats

Most cognitive effects of Organophosphate Pesticides (OP) are induced after exposure to parathion, chlorpyrifos and diazinon, which the usage has been restricted because of overt signs of their toxicities. In this study, we investigate whether developmental exposure to Malathion could impair spatial learning and recognition memory in male rats. Animals exposed by intragastric route, from in utero to young adult stage, to incremental doses of Malathion dissolved in corn oil;100, 200 and 300 mg/kg of body weight, and one control group are given corn oil. Then, cognitive and behaveioral abilities are assessed using Barnes maze and object recognition memory task. Malathion administration at 300 mg/kg is toxic to pregnant dams, and pups are stillborns. Rats exposed to 200 mg/kg make a significant working memory error, and require more time to find an escape box during the initial training phase of Barnes maze. However, fewer errors are made in rats exposed to 100 mg/kg. For reversal learning task, the high dose group shows great deficits in spatial strategy to locate the new position of the box. With respect to recognition task, both dose 100 and 200 mg/kg impair significant short-term (2 h after habituation phase) object recognition memory, but long-term (24 h after habituation phase) recognition memory is intact in high dose group. The current study also reveals that all treatments induce high significant neocortex acetylcholinesterase (AChE) activity inhibition, but 100 mg/kg dose is not sufficient to disrupt great hippocampal activity alteration. These results suggest that developmental exposure to Malathion, despite low toxicity described, may induce late-emerging spatial learning and recognition memorialterations. Moreover, Cortical and hippocampal area that support strongly these behaviors remain sensitive to incremental doses of Malathion.

Neurobehavioral Assessment of Rats Exposed to Yttrium Nitrate during Development

Objective The aim of this study was to assess the effects of yttrium nitrate on neurobehaviora development in Sprague-Dawley rats. Methods Dams were orally exposed to 0, 5, 15, or 45 mg/kg daily of yttrium nitrate from gestation day （GD） 6 to postnatal day （PND） 21. Body weight and food consumption were monitored weekly. Neurobehavior was assessed by developmental landmarks and reflexes, motor activity, hot plate, Rota-rod and cognitive tests. Additionally, brain weights were measured on PND 21 and 70. Results No significant difference was noted among all groups for maternal body weight and food consumption. All yttrium-exposed offspring showed an increase in body weight on PND 21; however, no significant difference in body weight for exposed pups versus controls was observed 2 weeks or more after the yttrium solution was discontinued. The groups given 5 mg/kg daily decreased significantly in the duration of female forelime grip strength and ambulation on PND 13. There was no significant difference between yttrium-exposed offspring and controls with respect to other behavioral ontogeny parameters and postnatal behavioral test results. Conclusion Exposure of rats to yttrium nitrate in concentrations up to 45 mg/kg daily had no adverse effects on their neurobehavioral development.

An In Vitro and In Vivo Study of Thyroid Disruption of 1,2-Bis(2,4,6-tribromophenoxy)ethane(BTBPE)�A Novel Brominated Flame Retardant

The novel brominated flame retardant,1,2-bis-(2,4,6-tribromophenoxy)ethane(BTBPE),is an emerging environ-mental pollutant with undetermined toxicity.We investigated how BTBPE causes thyroid endocrine disruption with integrated in silico,in vitro,and in vivo assays.In yeast two-hybrid and T-Screen assays,BTBPE interacted with zebrafish thyroid hormone receptors with binding energies weaker than the TR agonist-3,3′,5-Triiodo-L-thyronine(T3),and disrupted thyroid function as a thyroid receptor(TR)agonist.We examined the bioconcentra-tion,developmental toxicity,and thyroid endocrine disruption in zebrafish after a 14-day exposure to BTBPE(1,3,10μg/L).Thyroxine(T4)was lower in BTBPE-treated larvae,whereas corticotropin-releasing hormone(CRH)and thyroid-stimulating hormone(TSH)were higher.The gene transcription alterations along the hypothalamic-pituitary-thyroid(HPT)axis were observed.Furthermore,reduced locomotion suggested that BTBPE imparts developmental neurotoxicity at zebrafish early developmental stage.Establishing that BTBPE has thyroid endocrine-disrupting effects is an important step for understanding and managing BTBPE toxicity.

Assessment of Bisphenol A(BPA) neurotoxicity in vitro with mouse embryonic stem cells

The adverse effects of environmental pollution on our well-being have been intensively studied with many in vitro and in vivo systems. In our group, we focus on stem cell toxicology due to the multitude of embryonic stem cell（ESC） properties which can be exerted in toxicity assays. In fact, ESCs can differentiate in culture to mimic embryonic development in vivo, or specifically to virtually any kind of somatic cells. Here, we used the toxicant Bisphenol A（BPA）, a chemical known as a hazard to infants and children, and showed that our stem cell toxicology system was able to efficiently recapitulate most of the toxic effects of BPA previously detected by in vitro system or animal tests. More precisely, we demonstrated that BPA affected the proper specification of germ layers during our in vitro mimicking of the embryonic development, as well as the establishment of neural ectoderm and neural progenitor cells.

Studying developmental neurotoxic effects of bisphenol A(BPA) using embryonic stem cells

There is little to no toxicity information regarding thousands of chemicals to which people are exposed daily.In fact,of the84,000 chemicals listed in the United States Toxic Substances Control Act Inventory,there is limited information available on their effects on neural development（Betts,2010;US EPA,2015）.