Alterations in microbiota-metabolism-circRNA crosstalk in autism spectrum disorder-like behaviours caused by maternal exposure to glyphosate-based herbicides in mice.

Epidemiological evidence indicates exposure to glyphosate-based herbicides (GBHs) increases the risk for autism spectrum disorder (ASD). The gut microbiota has been found to influence ASD behaviours through the microbiota-gut-brain axis. However, the underlying links between early life GBH exposure and ASD-like phenotypes through the microbiota-gut-brain axis remain unclear. Therefore, we exposed mice to low-dose GBH (0.10, 0.25, 0.50, and 1.00 %) and determined the effects on ASD-like behaviours. Furthermore, three kinds of omics (gut microbiomics, metabolomics, and transcriptomics) were conducted to investigate the effects of GBH exposure on gut microbiota, gut metabolites, and circular RNAs (circRNAs) in the prefrontal cortex (PFC) using a cross-generational mouse model. Behavioural analyses suggested social impairment and repetitive/stereotypic behaviours in the GBH-exposed offspring. Furthermore, maternal exposure to glyphosate significantly altered the ASD-associated gut microbiota of offspring, and ASD-associated gut metabolites were identified. Specifically, we found that alterations in the gut microenvironment may contribute to changes in gut permeability and the blood-brain barrier, which are related to changes in the levels of circRNAs in the PFC. Our results suggest a potential effect of circRNAs through the disruption of the gut-brain interaction, which is an important factor in the pathogenesis of ASD in offspring induced by maternal exposure to GBH.

Occupational agents-mediated asthma: From the perspective of autophagy.

Occupational asthma (OA) is a common occupational pulmonary disease that is frequently underdiagnosed and underreported. The complexity of diagnosing and treating OA creates a significant social and economic burden, making it an important public health issue. In addition to avoiding allergens, patients with OA require pharmacotherapy; however, new therapeutic targets and strategies need further investigation. Autophagy may be a promising intervention target, but there is a lack of relevant studies summarizing the role of autophagy in OA. In this review consolidates the current understanding of OA, detailing principal and novel agents responsible for its onset. Additionally, we summarize the mechanisms of autophagy in HMW and LMW agents induced OA, revealing that occupational allergens can induce autophagy disorders in lung epithelial cells, smooth muscle cells, and dendritic cells, ultimately leading to OA through involving inflammatory responses, oxidative stress, and cell death. Finally, we discuss the prospects of targeting autophagy as an effective strategy for managing OA and even steroid-resistant asthma, encompassing autophagy interventions focused on organoids, organ-on-a-chip systems, nanomaterials vehicle, and nanobubbles; developing combined exposure models, and the role of non-classical autophagy in occupational asthma. In briefly, this review summarizes the role of autophagy in occupational asthma, offers a theoretical foundation for OA interventions based on autophagy, and identifies directions and challenges for future research.

Developmental exposure to nonylphenol leads to depletion of the neural precursor cell pool in the hippocampal dentate gyrus.

Developmental exposure to nonylphenol (NP) results in irreversible impairments of the central nervous system (CNS). The neural precursor cell (NPC) pool located in the subgranular zone (SGZ), a substructure of the hippocampal dentate gyrus, is critical for the development of hippocampal circuits and some hippocampal functions such as learning and memory. However, the effects of developmental exposure to NP on this pool remain unclear. Thus, our aim was to clarify the impacts of developmental exposure to NP on this pool and to explore the potential mechanisms. Animal models of developmental exposure to NP were created by treating Wistar rats with NP during pregnancy and lactation. Our data showed that developmental exposure to NP decreased Sox2-and Ki67-positive cells in the SGZ of offspring. Inhibited activation of Shh signaling and decreased levels of its downstream mediators, E2F1 and cyclins, were also observed in pups developmentally exposed to NP. Moreover, we established the in vitro model in the NE-4C cells, a neural precursor cell line, to further investigate the effect of NP exposure on NPCs and the underlying mechanisms. Purmorphamine, a small purine-derived hedgehog agonist, was used to specifically modulate the Shh signaling. Consistent with the in vivo results, exposure to NP reduced cell proliferation by inhibiting the Shh signaling in NE-4C cells, and purmorphamine alleviated this reduction in cell proliferation by restoring this signaling. Altogether, our findings support the idea that developmental exposure to NP leads to inhibition of the NPC proliferation and the NPC pool depletion in the SGZ located in the dentate gyrus. Furthermore, we also provided the evidence that suppressed activation of Shh signaling may contribute to the effects of developmental exposure to NP on the NPC pool.

Exposure to nonylphenol in early life causes behavioural deficits related with autism spectrum disorders in rats.

Early-life exposure to environmental endocrine disruptors (EDCs) is a potential risk factor for autism spectrum disorder (ASD). Exposure to nonylphenol (NP), a typical EDC, is known to cause some long-term behavioural abnormalities. Moreover, these abnormal behaviours are the most frequent psychiatric co-morbidities in ASD. However, the direct evidence for the link between NP exposure in early life and ASD-like behavioural phenotypes is still missing. In the present study, typical ASD-like behaviours induced by valproic acid treatment were considered as a positive behavioural control. We investigated impacts on social behaviours following early-life exposure to NP, and explored effects of this exposure on neuronal dendritic spines, mitochondria function, oxidative stress, and endoplasmic reticulum (ER) stress. Furthermore, primary cultured rat neurons were employed as in vitro model to evaluate changes in dendritic spine caused by exposure to NP, and oxidative stress and ER stress were specifically modulated to further explore their roles in these changes. Our results indicated rats exposed to NP in early life showed mild ASD-like behaviours. Moreover, we also found the activation of ER stress triggered by oxidative stress may contribute to dendritic spine decrease and synaptic dysfunction, which may underlie neurobehavioural abnormalities induced by early-life exposure to NP.

Impact of pesticides exposure during neurodevelopmental period on autism spectrum disorders - A focus on gut microbiota.

Accumulating evidence indicates exposure to pesticides during the crucial neurodevelopmental period increases susceptibility to many diseases, including the neurodevelopmental disorder known as autism spectrum disorder (ASD). In the last few years, it has been hypothesized that gut microbiota dysbiosis is strongly implicated in the aetiopathogenesis of ASD. Recently, new studies have suggested that the gut microbiota may be involved in the neurological and behavioural defects caused by pesticides, including ASD symptoms. This review highlights the available evidence from recent animal and human studies on the relationship between pesticides that have the potential to disturb intestinal microbiota homeostasis, and ASD symptoms. The mechanisms through which gut microbiota dysbiosis may trigger ASD-like behaviours induced by pesticides exposure during the neurodevelopmental period via the altered production of bacterial metabolites (short chain fatty acids, lipids, retinol, and amino acid) are also described. According to recent research, gut microbiota dysbiosis may be a major contributor to the symptoms of ASD associated with pesticides exposure. However, to determine the detailed mechanism of action of gut microbiota on pesticide-induced ASD behaviours, actual population exposure scenarios from epidemiological studies should be used as the basis for the appropriate exposure pattern and dosage to be used in animal studies.

Combined exposure to benzo(a)pyrene and dibutyl phthalate aggravates pro-inflammatory macrophage polarization in spleen via pyroptosis involving cathepsin B.

Humans are often simultaneously exposed to benzo(a)pyrene (BaP) and dibutyl phthalate (DBP) through consumption of food and water. Yet, direct evidence of the link between BaP and DBP co-exposure and the risk of splenic injury is lacking. In the present study, we established the rats and primary splenic macrophages models to evaluate the effects of BaP or/and DBP exposure on spleen and underlying mechanisms. Compared to the single exposure or control groups, the co-exposure group showed more severe spleen damage and higher production of pro-inflammatory cytokines. Co-exposure to BaP and DBP resulted in a 1.79-fold, 2.11-fold and 1.9-fold increase in the M1 macrophage markers iNOS, NLRP3 (pyroptosis marker protein) and cathepsin B (CTSB), respectively, and a 0.8-fold decrease in the M2 macrophage marker Arg1 in vivo. The more prominent effects in perturbation of imbalance in M1/M2 polarization (iNOS, 2.25-fold; Arg1, 0.55-fold), pyroptosis (NLRP3, 1.43-fold), and excess CTSB (1.07-fold) in macrophages caused by BaP and DBP co-exposure in vitro were also found. Notably, MCC950 (the NLRP3-specific inhibitor) treatment attenuated the pro-inflammatory macrophage polarization and following pro-inflammatory cytokine production triggered by BaP and DBP co-exposure. Furthermore, CA-074Me (the CTSB-specific inhibitor) suppressed the macrophages pyroptosis, pro-inflammatory macrophage polarization, and secretion of pro-inflammatory cytokine induced by BaP and DBP co-exposure. In conclusion, this study indicates co-exposure to BaP and DBP poses a higher risk of spleen injury. Pro-inflammatory macrophage polarization regulated by pyroptosis involving CTSB underlies the spleen injury caused by BaP and DBP co-exposure.

DBP and BaP co-exposure induces kidney injury via promoting pyroptosis of renal tubular epithelial cells in rats.

Dibutyl phthalate (DBP) and benzo(a)pyrene (BaP) are widespread environmental and foodborne contaminants that have detrimental effects on human health. Although people are often simultaneously exposed to DBP and BaP via the intake of polluted food and water, the combined effects on the kidney and potential mechanisms remain unclear. Hence, we treated rats with DBP and BaP for 90 days to investigate their effects on kidney histopathology and function. We also investigated the levels of paramount proteins and genes involved in pyroptosis and TLR4/NF-κB p65 signaling in the kidney. Our research showed that combined exposure to DBP and BaP triggered more severe histopathological and renal function abnormalities than in those exposed to DBP or BaP alone. Simultaneously, combined exposure to DBP and BaP enhanced the excretion of IL-1ß and IL-18, along with the release of LDH in rat renal tubular epithelial cells (RTECs). Moreover, combined exposure to DBP and BaP increased the expression of pyroptosis marker molecules, including NLRP3, ASC, cleaved-Caspase-1, and GSDMD. Meanwhile, the combination of DBP and BaP activated TLR4/NF-κB signaling in the kidney. Taken together, the combined exposure to DBP and BaP causes more severe kidney injury than that caused by DBP or BaP exposure separately. In addition, pyroptosis of RTECs regulated by TLR4/NF-κB signaling may add to the kidney damage triggered by combined exposure to DBP and BaP.

Developmental exposure to chlorpyrifos causes neuroinflammation via necroptosis in mouse hippocampus and human microglial cell line.

Neurodevelopmental exposure to chlorpyrifos (CPF) could increase risks for neurological disorders, such as autism spectrum disorder, cognitive impairment, or attention deficit hyperactivity disorder. The potential involvement of microglia reactive to inflammatory stimuli in these neurological disorders has been generally reported. However, the concrete effects and potential mechanisms of microglia dysfunction triggered by developmental CPF exposure remain unclear. Therefore, we established mouse and human embryonic microglial cells (HMC3 cell) models of developmental CPF exposure to evaluate the effects of developmental CPF exposure on neuroinflammation and underlying mechanisms. The results showed that developmental exposure to CPF enhanced the expression of Iba1 in hippocampus. CPF treatment increased inflammatory cytokines levels and TSPO expression in hippocampus and HMC3 cells. The levels of necroptosis and necroptosis-related signaling RIPK/MLKL were increased in hippocampus and HMC3 cells following CPF exposure. Furthermore, the expression of TLR4/TRIF signaling was increased in hippocampus and HMC3 cells subjected to CPF exposure. Notably, the increased levels of TLR4/TRIF signaling, RIPK/MLKL signaling, necroptosis and pro-inflammatory cytokines induced by CPF treatment were remarkably inhibited by TAK-242 (a specific TLR4 inhibitor). Additionally, the necroptosis and pro-inflammatory cytokines production induced by CPF treatment were significantly relieved by Nec-1 (a specific RIPK1 inhibitor). In general, the above results suggested that activated microglia in hippocampus subjected to developmental CPF exposure underwent RIPK1/MLKL-mediated necroptosis regulated by TLR4/TRIF signaling.

Long-term co-exposure DBP and BaP causes imbalance in liver macrophages polarization via activation of Notch signaling regulated by miR-34a-5p in rats.

Humans are often exposed to complex mixtures of environmental pollutants over long periods of time. It is reported that Dibutyl phthalate (DBP) and benzo[a]pyrene (BaP) are typical environmental pollutants, which are associated with liver injury. Nevertheless, little is known about the effects of DBP and BaP combined exposure on liver. In the current study, rats were exposed to DBP alone (50, or 250 mg/kg), BaP alone (1, or 5 mg/kg), or DBP and BaP (50 + 1, or 250 + 5 mg/kg) for ninety days. More serious liver damage, including abnormal liver function, infiltration of inflammatory cells and disturbed secretion of inflammatory factors, were observed in long-term co-exposure to DBP and BaP group relative to those in single exposure group. Our data showed that long-term co-exposure to DBP and BaP induces macrophages to polarize toward M1 and inhibits polarization of M2 macrophages. Long-term co-exposure to DBP and BaP downregulated miR-34a-5p level and upregulated Notch signaling. These results indicated that imbalance in macrophages M1/M2 polarization mediated by activation of Notch signaling due to reduced miR-34a-5p level may contribute to additive effects on disorder of inflammatory factors secretion and subsequent liver injury following long-term DBP and BaP co-exposure.

Arsenic exposure via drinking water during pregnancy and lactation induces autism-like behaviors in male offspring mice.

Exposure to arsenic (As), an environmental toxicant, causes damages to the central nervous system (CNS) structure and function. Emerging epidemiological studies support that exposure to As, especially during the critical periods of the CNS development, may act as an environmental risk factor of autism spectrum disorders (ASD), which is characterized by behavioral changes, including abnormal social behaviors, restricted interests and repetitive behaviors. However, direct evidence supporting the cause-effect relationship between As exposure and the risk of ASD is still missing. Thus, we aimed to investigate whether As exposure during pregnancy and lactation led to autism-like behaviors in offspring mice in the present study. We established a mice model of exposure to As via drinking water during pregnancy and lactation and conducted a battery of behavioral tests to evaluate social behaviors, repetitive behaviors, anxiety behaviors and learning and memory ability in offspring mice. We found that perinatal exposure to As caused autism-like behaviors in male offspring, which demonstrated by abnormal social behaviors and repetitive behaviors. Anxiety-like behaviors, and learning and memory impairments, known as concomitant behavioral phenotypes in mice with autism-like behaviors, were also observed. Decreases of synaptic density, especially in cortex, hippocampus and cerebellum, are extensively observed in both ASD patients and animal models of ASD. Thus, immunofluorescence staining and western blotting were used to observe the expression of PSD-95 and SYP, well-known markers for presynaptic and postsynaptic membranes, to assess the synaptic density in offspring cortex, hippocampus and cerebellum. We found perinatal exposure to As decreased the expression of PSD-95 and SYP in these brain regions. This indicated that perinatal exposure to As caused decreases of synaptic density, a typical autism-like cellular alteration in brains, which may contribute to autism-like behaviors in offspring.

The relationship between pesticide exposure during critical neurodevelopment and autism spectrum disorder: A narrative review.

Agricultural pesticides have been one of the most extensively used compounds throughout the world. The main sources of contamination for humans are dietary intake and occupational exposure. The impairments caused by agricultural pesticide exposure have been a significant global public health problem. Recent studies have shown that low-level agricultural pesticide exposure during the critical period of neurodevelopment (pregnancy and lactation) is closely related to autism spectrum disorder (ASD). Inhibition of acetylcholinesterase, gut microbiota, neural dendrite morphology, synaptic function, and glial cells are targets for the effects of pesticides during nervous system development. In the present review, we summarize the associations between several highly used and frequently studied pesticides (e.g., glyphosate, chlorpyrifos, pyrethroids, and avermectins) and ASD. We also discusse future epidemiological and toxicological research directions on the relationship between pesticides and ASD.

The Notch signaling pathway regulates macrophage polarization in liver diseases.

The liver is not only the main metabolic site of exogenous compounds and drugs, but also an important immune organ in the human body. When a large number of nonself substances (such as drugs, alcohol, pathogens, microorganisms and their metabolites) enter the liver, they will cause serious liver diseases, including liver fibrosis, liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Macrophages are the first line of defense against the invasion of exogenous pathogens and significant cellular components of the innate immune system. Macrophages have strong heterogeneity and plasticity. When different pathogens invade the body, they cause different types of polarization of macrophages through different molecular mechanisms. Notch signaling is considered to be the key regulator of the biological function of macrophages. Activating Notch signaling can regulate the differentiation of macrophages into M1 and play a role in promoting inflammation and antitumor activity, while blocking Notch signaling can polarize macrophages to M2, suppressing inflammation and promoting tumor growth. However, there are few studies on regulation of macrophage polarization by the Notch signaling pathway in liver diseases. Therefore, in this review, we will introduce the role of the Notch signaling pathway in regulating macrophage polarization in liver diseases.

miR-122-5p regulates hepatocytes damage caused by BaP and DBP co-exposure through SOCS1/STAT3 signaling in vitro.

BaP and DBP are ubiquitously and contemporaneously present in the environment. However, Current studies largely concentrate on the effects of a single pollutant (BaP or DBP). The liver is vital for biogenic activities. The effects of BaP and DBP co-exposure on liver remain unclear. Thus, we treated human normal liver cell (L02 cell) with BaP or/and DBP. We found that compared to individual exposure, co-exposure to BaP and DBP induced further increased levels of AST and ALT. BaP and DBP co-exposure caused further increased levels of IL-2, IL-6, and TNF-α, decreased IL-10 level, and a higher percentage of apoptotic cells and S-phase arrest cells. BaP and DBP co-exposure worsen the decrease of miR-122-5p level and chaos of SOCS1/STAT3 signaling. Dual-luciferase reporter gene assays showed that SOCS1 was a validated target of miR-122-5p. miR-122-5p overexpression alleviated the increased SOCS1 expression, decreased phospho-STAT3 expression, decreased IL-10 level, increased TNF-α levels, increased percentage of apoptosis and S-phase arrest, and cytotoxicity induced by BaP and DBP co-exposure in hepatocytes. These results suggested that miR-122-5p negatively regulated the synergistic effects on apoptosis and disorder of inflammatory factor secretion involved in hepatocyte injury caused by BaP and DBP co-exposure through targeting SOCS1/STAT3 signaling.

Perinatal exposure to BDE-47 exacerbated autistic-like behaviors and impairments of dendritic development in a valproic acid-induced rat model of autism.

Perinatal exposure to polybrominated diphenyl ethers (PBDEs) may be a potential risk factor for autism spectrum disorders (ASD). BDE-47 is one of the most common PBDEs and poses serious health hazards on the central nervous system (CNS). However, effects of perinatal exposure to BDE-47 on social behaviors and the potential mechanisms are largely unexplored. Thus, we aimed to investigate whether BDE-47 exposure during gestation and lactation led to autistic-like behaviors in offspring rats in the present study. Valproic acid (VPA), which is widely used to establish animal model of ASD, was also adopted to induce autistic-like behaviors. A battery of tests was conducted to evaluate social and repetitive behaviors in offspring rats. We found that perinatal exposure to BDE-47 caused mild autistic-like behaviors in offspring, which were similar but less severe to those observed in pups maternally exposed to VPA. Moreover, perinatal exposure to BDE-47 aggravated the autistic-like behaviors in pups maternally exposed to VPA. Abnormal dendritic development is known to be deeply associated with autistic-like behaviors. Golgi-Cox staining was used to observe the morphological characteristics of dendrites in the prefrontal cortex of pups. We found perinatal exposure to BDE-47 reduced dendritic length and complexity of branching pattern, and spine density in the offspring prefrontal cortex, which may contribute to autistic-like behaviors observed in the present study. Perinatal exposure to BDE-47 also exacerbated the impairments of dendritic development in pups maternally exposed to VPA. Besides, our study also provided the evidence that the inhibition of BDNF-CREB signaling, a key regulator of dendritic development, may be involved in the dendritic impairments induced by perinatal exposure to BDE-47 and/or VPA, and the consequent autistic-like behaviors.

Maternal Exposure to Di-(2-ethylhexyl) Phthalate Impairs Hippocampal Synaptic Plasticity in Male Offspring: Involvement of Damage to Dendritic Spine Development.

Exposure to di-(2-ethylhexyl) phthalate (DEHP), a widely used kind of plasticizer, can result in neurodevelopment impairments and learning and memory disorders. We studied the effects and possible mechanisms of maternal DEHP treatment on hippocampal synaptic plasticity in offspring. Pregnant Wistar rats were randomly divided into four groups and received 0, 30, 300, 750 (mg/kg)/d DEHP by gavage from gestational day (GD) 0 to postnatal day (PN) 21. Our data showed that DEHP exposure impaired hippocampal synaptic plasticity, damaged synaptic ultrastructure, and decreased synaptic protein levels in male pups. Furthermore, DEHP decreased the density of dendritic spines, affected F-actin polymerization, and downregulated the Rac1/PAK/LIMK1/cofilin signaling pathway in male offspring. However, the alterations in the hippocampi of female offspring were not observed. These results illustrate that maternal DEHP exposure could impair hippocampal synaptic plasticity by affecting synaptic structure and dendritic spine development in male offspring, which may be attributed to altered cytoskeleton construction induced by downregulation of the Rac1/PAK/LIMK1/cofilin signaling pathway.

Perinatal exposure to nonylphenol promotes proliferation of granule cell precursors in offspring cerebellum: Involvement of the activation of Notch2 signaling.

Nonylphenol (NP), a widely diffused persistent organic pollutant (POP), has been shown to impair cerebellar development and cause cerebellum-dependent behavioral and motor deficits. The precise proliferation of granule cell precursors (GCPs), the source of granular cells (GCs), is required for normal development of cerebellum. Thus, we established an animal model of perinatal exposure to NP, investigated the effect of NP exposure on the cerebellar GCPs proliferation, and explored the potential mechanism involved. Our results showed that perinatal exposure to NP increased cerebellar weight, area, and internal granular cell layer (IGL) thickness in offspring rats. Perinatal exposure to NP also resulted in the GCPs hyperproliferation in the external granular layer (EGL) of the developing cerebellum, which may underlie the above-mentioned cerebellar alterations. However, our results suggested that perinatal exposure to NP had no effects on the length of GCPs proliferation. Meanwhile, perinatal exposure to NP also increased the activation of Notch2 signaling, the regulator of GCPs proliferation. In conclusion, our results supported the idea that exposure to NP caused the hyperproliferation of GCPs in the developing cerebellum. Furthermore, our study also provided the evidence that the activation of Notch2 signaling may be involved in the GCPs hyperproliferation.

Perinatal exposure to nonylphenol delayed myelination in offspring cerebellum.

As a stable environmental contaminant, nonylphenol (NP) has been shown to induce some neurological deficits in the cerebellum, although the underlying mechanism is still unknown. In the present study, we aimed to investigate the effects of perinatal exposure to NP on myelination, an important process essential for the intact cerebellar function, in the offspring cerebellum. Exposure to NP delayed the myelination in the offspring cerebellum during perinatal period. The myelination recovered in the cerebellum of offspring exposed to NP over time, and returned to normal in adulthood. In addition, perinatal exposure to NP reduced mature oligodendrocytes (myelin-forming glial cells) and increased astrocytes in the offspring cerebellum. BMP signaling is believed to negatively regulate oligodendrogliogenesis and myelination. In the present study, BMP4, p-Smad1/5, and ID4, key members of BMP signaling, were increased in the cerebellum of offspring exposed to NP. Taken together, these lines of evidence suggest that the activation of BMP signaling may underlie the decreased oligodendrogliogenesis and increased astrogliogenesis, and the consequent delay of myelination in the cerebellum of offspring perinatally exposed to NP.

Exposure to nonylphenol in early life increases pro-inflammatory cytokines in the prefrontal cortex: Involvement of gut-brain communication.

A growing body of evidence indicates that exposure to nonylphenol (NP), a typical persistent organic pollutant (POP), in early life results in the impairment of the central nervous system (CNS), but the underlying mechanism still remains to be elucidated. High levels of pro-inflammatory cytokines in the brain have been implicated in the CNS damages. The animal model of exposure to NP in early life was established by maternal gavage during the pregnancy and lactation in the present study. We found that exposure to NP in early life increased the levels of pro-inflammatory cytokines in the rat prefrontal cortex. Interestingly, the levels of pro-inflammatory cytokines in the intestine as well as in the serum were also increased by NP exposure. Furthermore, the increased permeability of intestinal barrier and blood-brain barrier (BBB), two critical barriers in the gut to brain communication, was observed in the rats exposed to NP in early lives. The decreased expression of zonula occludens-1 (ZO-1) and claudin-1 (CLDN-1), tight junction proteins (TJs) that responsible for maintaining the permeability of intestinal barrier and BBB, was found, which may underlie these increases in permeability. Taken together, these results suggested that the disturbed gut-brain communication may contribute to the increased levels of pro-inflammatory cytokines in the prefrontal cortex caused by NP exposure in early life.

Developmental exposure to nonylphenol induced rat axonal injury in vivo and in vitro.

Increasing evidence indicates that developmental exposure to nonylphenol (NP) causes damage to the central nervous system (CNS). As the most unique and primary component of neuron, axon is an essential structure for the CNS function. Here, we investigated whether developmental exposure to NP affected rat axonal development in vivo and in vitro. Our results showed that developmental exposure to NP 10, 50, and 100 mg/(kg day) caused an obvious decrease in axonal length and density in the hippocampus. Developmental exposure to NP also altered the expression of CRMP-2 and p-CRMP-2, and activated Wnt-Dvl-GSK-3ß cascade in the hippocampus, the crucial signaling that regulates axonal development. Even months after the exposure, impairment of axonal growth and alteration of this cascade were not fully restored. In the primary cultured neurons, 30, 50, and 70 µM NP treatment decreased axonal length and impaired axonal function. Similar to in vivo results, it also activated Wnt-Dvl-GSK-3ß cascade in cultured neurons. SB-216763, a specific GSK-3ß inhibitor, recovered the shortening of axon and the impairment of axonal function induced by NP. Taken together, our results support the idea that exposure to NP induces axonal injury in the developing neurons. Furthermore, the activation of Wnt-Dvl-GSK-3ß cascade contributes to the axonal injury induced by NP.

Effects of perinatal di (2-ethylhexyl) phthalate exposure on thyroid function in rat offspring.

Di (2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer in industry and displays the characteristics of an endocrine disruptor. Disorders of the maternal thyroid hormone (TH) during pregnancy can cause adverse effects on the fetus. We investigated the effects and possible mechanism of perinatal DEHP exposure on the thyroid function of pups. Pregnant female Wistar rats were randomly divided into four groups and received doses of DEHP of 0, 30, 300, 750 mg/kg/day by gavage at from gestational day (GD) 0 to postnatal day (PN) 21. The concentration of serum THs and the ultrastructure of thyroid follicular cells in the offspring were examined. Related protein level and gene expression of thyroid proteins in pups were analyzed by western blotting and real-time PCR. We found that DEHP significantly reduced total thyroxine (TT4) and increased thyroid stimulating hormone (TSH) in pups, while total triiodothyronine (TT3) showed no change. Thyroid follicular cells ultrastructure was damaged in DEHP exposed pups as viewed by electron microscopy. Furthermore, exposure to DEHP significantly increased protein and mRNA levels of thyroid transcription factor 1 (TTF-1), paired box 8 (PAX8), sodium iodide symporter (NIS) and thyroid peroxidase (TPO) in pups. In addition, levels of deiodinases of pups were also affected. These findings indicated that DEHP can disrupt thyroid function by damaging thyroid follicles and affecting TTF-1, PAX8, NIS, TPO and the deiodinase protein family.