Exploring microbiota-gut-brain axis biomarkers linked to autism spectrum disorder in prenatally chlorpyrifos-exposed Fmr1 knock-out and wild-type male rats.

Fmr1 (fragile X messenger ribonucleoprotein 1)-knockout (KO) rats, modeling the human Fragile X Syndrome (FXS), are of particular interest for exploring the ASD-like phenotype in preclinical studies. Gestational exposure to chlorpyrifos (CPF) has been associated with ASD diagnosis in humans and ASD-like behaviors in rodents and linked to the microbiota-gut-brain axis. In this study, we have used both Fmr1-KO and wild-type male rats (F2 generation) at postnatal days (PND) 7 and 40 obtained after F1 pregnant females were randomly exposed to 1 mg/kg/mL/day of CPF or vehicle. A nuclear magnetic resonance (NMR) metabolomics approach together with gene expression profiles of these F2 generation rats were employed to analyze different brain regions (such as prefrontal cortex, hippocampus, and cerebellum), whole large intestine (at PND7) and gut content (PND40). The statistical comparison of each matrix spectral profile unveiled tissue-specific metabolic fingerprints. Significant variations in some biomarker levels were detected among brain tissues of different genotypes, including taurine, myo-inositol, and 3-hydroxybutyric acid, and exposure to CPF induced distinct metabolic alterations, particularly in serine and myo-inositol. Additionally, this study provides a set of metabolites associated with gastrointestinal dysfunction in ASD, encompassing several amino acids, choline-derived compounds, bile acids, and sterol molecules. In terms of gene expression, genotype and gestational exposure to CPF had only minimal effects on decarboxylase 2 (gad2) and cholinergic receptor muscarinic 2 (chrm2) genes.

Sociability: Comparing the Effect of Chlorpyrifos with Valproic Acid.

In recent years, exposures to organophosphate pesticide have been highlighted as a possible cause or aggravating factor of autism spectrum disorder (ASD). The present study examined if Wistar rats prenatally exposed to chlorpyrifos (CPF) at a dose of 1 mg/kg in GD 12.5-15.5 could express similar behaviors to those exposed to valproic acid (VPA, 400 mg/kg) during the same administration window, which is an accepted animal model of autism. The 3-chambered test was employed to evaluate sociability and reaction to social novelty in two experiments, the first in adolescence and the second in adulthood. The results obtained in this study show that animals prenatally treated with CPF or VPA show a similar behavioral phenotype compared to the control group (CNT). In adolescence, the CPF animals showed a negative index in the reaction to social novelty, followed closely by the VPA, while both experimental groups showed a recovery in this aspect during adulthood. This study therefore provides evidence to suggest that prenatal exposure to CPF in rats could have similar effects on certain components of sociability to those seen in autistic models.

Environmental exposure to chlorpyrifos during gestation, APOE polymorphism and the risk on autistic-like behaviors.

Autism spectrum disorder (ASD) encompasses several neurodevelopmental conditions characterized by communication and social impairment, as well as repetitive patterns of behavior. However, it can co-occur with other mental conditions such as anxiety. The massive use of chlorpyrifos (CPF) has been linked to the increased prevalence of developmental disorders. Likewise, ASD has also been closely linked to a wide variety of genetic factors. The aims of the present investigation are to study how gestational CPF exposure and APOE polymorphism affects communication skills, early development and mid-term anxiety-like behaviors, as well as, changes in gene expression related to the cholinergic system. C57BL/6J and humanized apoE3 and apoE4 homozygous mice were exposed to 0 or 1 mg/kg/day of CPF through the diet, from gestational day (GD) 12-18. In addition, a group of C57BL/6J females were injected subcutaneously with 300 mg/kg/day of valproic acid (VPA) on GD 12 and 13. This group was used as a positive control for studying some core and associated autism-like behaviors. Communication skills by means of ultrasonic vocalizations and physical/motor development were assessed during the preweaning period, whereas locomotor activity, anxiety-like behaviors and the gene expression of cholinergic elements were evaluated during adolescence. Our results showed that C57BL/6J mice prenatally exposed to CPF or VPA showed a decrease in body weight and a delay in eye opening. Communication and anxiety behavior were affected differently depending on treatment, while gene expression was altered by sex and treatment. In addition, none of the parameters evaluated in apoE transgenic mice exposed to CPF were affected, but there were differences between genotypes. Therefore, we suggest that prenatal CPF exposure and VPA produce divergent effects on communication and anxiety.

The influence of environmental particulate matter exposure during late gestation and early life on the risk of neurodevelopmental disorders: A systematic review of experimental evidences.

Particulate matter (PM) is a major component of ambient air pollution (AAP), being widely associated with adverse health effects. Epidemiological and experimental studies point towards a clear implication of AAP on the development of central nervous system (CNS) diseases. In this sense, the period of most CNS susceptibility is early life, when the CNS is maturing. In humans the last trimester of gestation is crucial for brain maturation while in rodents, due to the shorter gestational period, the brain is still immature at birth, and early postnatal development plays a significant role. The present systematic review provides an updated overview and discusses the existing literature on the relationship between early exposure to PM and neurodevelopmental outcomes in experimental studies. We included 11 studies with postnatal exposure and 9 studies with both prenatal and postnatal exposure. Consistent results between studies suggest that PM exposure could alter normal development, triggering impairments in short-term memory, sociability, and impulsive-like behavior. This is also associated with alterations in synaptic plasticity and in the immune system. Interestingly, differences have been observed between sexes, although not all studies included females. Furthermore, the developmental window of exposure seems to be crucial for effects to be observed in the future. In summary, air pollution exposure during development affects subjects in a time- and sex-dependent manner, the postnatal period being more important and being males apparently more sensitive to exposure than females. Nevertheless, additional experimental investigations should prioritize the examination of learning, impulsivity, and biochemical parameters, with particular attention provided to disparities between sexes.

Reduced Expression of the Htr2a, Grin1, and Bdnf Genes and Cognitive Inflexibility in a Model of High Compulsive Rats.

Compulsivity is a core symptom in different psychopathological disorders, characterized by excessive behaviors and behavioral inflexibility. The selection of high drinker (HD) versus low drinker (LD) rats by schedule-induced polydipsia (SIP) is a valid model for studying the compulsive phenotype. The compulsive HD rats showed cognitive inflexibility and reduced serotonin 2A (5-HT2A) receptor binding levels in the frontal cortex (FC). According to that, we hypothesize that compulsive HD rats might have an alteration in the cognitive control domain regarding inflexibility, assessed by spatial memory on the Morris Water Maze (MWM), working and reference memory by the Radial Arm Maze, and behavioral deficits in stimulus processing by the Novel Object Recognition test. The possible underlying mechanisms might be linked to the brain gene expression of 5HT2A, 5HT2C, glutamate NMDA receptors, and brain-derived neurotrophic factor (BDNF) in FC, hippocampus, and amygdala. HD rats confirmed a cognitive inflexibility profile on the reversal condition in the MWM compared to LD rats, while no differences were observed on stimulus processing, spatial, and working memory. Moreover, HD rats showed a reduced expression of the Htr2a, Grin1, and Bdnf genes in FC. Furthermore, there was a negative correlation between the relative expression of the Htr2a, Grin1, and Bdnf genes in FC and the level of compulsive water intake in HD rats on SIP. These data reveal that cognitive inflexibility may not be associated with a memory or stimulus processing deficit in compulsive individuals but may result by a region-specific alteration of the Htr2a, Grin1, and Bdnf gene expression in FC.

Uncovering the link between air pollution and neurodevelopmental alterations during pregnancy and early life exposure: A systematic review.

Air pollution plays, nowadays, a huge role in human's health and in the personal economy. Moreover, there has been a rise in the prevalence of neurodevelopmental disorders like the Autism Spectrum Disorder (ASD) in recent years. Current scientific studies have established a link between prenatal or perinatal exposure to environmental pollutants and ASD. This systematic review summarizes the current literature available about the relationship between exposure to air pollutants (particulate matter [PM], Second Organic Aerosols [SOA], Diesel Exhaust [DE], and Traffic Related Air Pollution [TRAP]) and neurodevelopmental disorders in preclinical models using rats and mice. The articles were selected and filtered using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, and bias-evaluated using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool. Overall, our findings suggest that air pollutants are associated with negative developmental outcomes characterized by ASD-like behaviors, abnormal biochemical patterns, and impaired achievement of developmental milestones in rodents. However, there is not sufficient information in certain domains to establish a clear relationship. Short phrases for indexing terms: Air pollution affects neurodevelopment; PM exposure modifies glutamate system; Prenatal exposure combined with postnatal affect more to behavioral / cognitive domain; Air pollution modifies social behavior in rodents; Cognitive deficits can be detected after gestational exposure to air pollution.

Developmental brain lipidomics is influenced by postnatal chlorpyrifos exposure and APOE genetic background in mice.

Lipids are a major component of the brain, and are involved in structural and neurodevelopmental processes such as neurogenesis, synaptogenesis and signaling. Apolipoprotein E (apoE) is the main lipoprotein involved in lipid transport in the brain. The apoE isoforms can determine vulnerability to the toxic effects of the pesticide chlorpyrifos (CPF), which can interfere with normal neurodevelopment. We aimed to study the effects of postnatal exposure to CPF and of the APOE genotype on the lipid composition of the brain at early ages. For it, we used apoE3 and apoE4 targeted-replacement (TR) male mice, as well as wild-type C57BL/6. The mice were orally exposed to 1 mg/kg/day of CPF on postnatal days 10-15 and, four hours after the treatment, we obtained samples to assess the cerebral lipid composition. Differences between APOE genotypes were found in the cerebral lipid profile in the postnatal period. ApoE4-TR mice exhibited higher lipid concentrations compared to the other groups in most of the cases. CPF exposure led to a decrease in cholesteryl ester and triglyceride concentrations, while modulating the levels of phosphatidylcholine species based on the apoE isoform. Specifically, CPF treatment decreased the concentration of some species of this lipid (PC30:0, PC31:0, PC32:2, PC36:5, PC40:4 and PC40:5) in C57BL/6 mice exposed to CPF, increased (PC31:0 and PC37:6) in apoE3-TR exposed mice while exposed apoE4-TR mice remained unaltered. These results provide further insights into the lipid composition of the brain at early ages, and how it can be modulated by environmental and genetic factors.

Exposure to chlorpyrifos during pregnancy differentially affects social behavior and GABA signaling elements in an APOE- and sex-dependent manner in a transgenic mouse model.

The massive use of chlorpyrifos (CPF) has been associated with an increased prevalence of neurodevelopmental disorders. Some previous studies have shown that prenatal, but not postnatal, CPF exposure causes social behavior deficits in mice depending on sex while others have found that in transgenic mice models carrying the human apolipoprotein E (APOE) ε3 and ε4 allele confer different vulnerabilities to either behavioral or metabolic disorders after CPF exposure. This study aims to evaluate, in both sexes, how prenatal CPF exposure and APOE genotype impact on social behavior and its relation to changes in GABAergic and glutamatergic systems. For this purpose, apoE3 and apoE4 transgenic mice were exposed through the diet to 0 or 1 mg/kg/day of CPF, between gestational day 12 and 18. A three-chamber test was used to assess social behavior on postnatal day (PND) 45. Then, mice were sacrificed, and hippocampal samples were analyzed to study the gene expression of GABAergic and glutamatergic elements. Results showed that prenatal exposure to CPF impaired social novelty preference and increased the expression of GABA-A α1 subunit in females of both genotypes. In addition, the expression of GAD1, the ionic cotransporter KCC2 and the GABA-A α2 and α5 subunits were increased in apoE3 mice, whereas CPF treatment only accentuated the expression of GAD1 and KCC2. Nevertheless, future research is needed to evaluate whether the influences detected in the GABAergic system are present and functionally relevant in adults and old mice.

Prenatal, but not postnatal exposure to chlorpyrifos affects social behavior of mice and the excitatory-inhibitory balance in a sex-dependent manner.

The balance between excitatory and inhibitory neurotransmitters is essential for proper brain development. An imbalance between these two systems has been associated with neurodevelopmental disorders. On the other hand, literature also associates the massive use of pesticides with the increase of these disorders, with a particular focus on chlorpyrifos (CPF) a world-wide used organophosphate pesticide. This study was aimed at assessing social autistic-like behaviors on mice pre or postnatally exposed to CPF (0 or 1 mg/kg/day), in both sexes. In prenatal exposure, C57BL/6J pregnant mice were exposed to CPF through the diet, between gestational days (GD) 12 and 18, while a positive control group for some autistic behaviors was exposed to valproic acid (VPA) on GD 12 and 13. To assess postnatal exposure, C57BL/6J mice were orally exposed to the vehicle (corn oil) or CPF, from postnatal days (PND) 10-15. Social behavior and gene expression analysis were assessed on PND 45. Results showed social alterations only in males prenatally treated. GABA system was upregulated in CPF-treated females, whereas an increase in both systems was observed in both treated males. These findings suggest that males are more sensitive to prenatal CPF exposure, favoring the sex bias observed in ASD.

Influence of Gestational Chlorpyrifos Exposure on ASD-like Behaviors in an fmr1-KO Rat Model.

Based on previous reports, exposure to pesticides could be linked to the prevalence increase of autism spectrum disorders (ASD). Gestational exposure to chlorpyrifos (CPF) has been associated with ASD diagnosis in humans and ASD-like behaviors in rodents. However, ASD severity degree results from the complex relationship between genetic background and environmental factors. Thus, animals with a genetic vulnerability and prenatally exposed to CPF could have a more severe ASD-like phenotype. Fragile X syndrome is one of the most common monogenic causes of ASD, characterized by a mutation in the X chromosome which alters the expression of the fragile X mental retardation protein (FMRP). Based on this, some fmr1 knockout (KO) rodent models have been developed to study the physiological and genetic basis of ASD. Both fmr1-KO and wild-type male rats (F2 generation) were used in the present study. F1 pregnant females were randomly exposed to 1 mg/kg/mL/day of CPF (s.c.) from GD12.5-15.5 or vehicle. Different behavioral, developmental, and molecular variables were analyzed in F2 males. KO rats were heavier, emitted altered USVs, were socially inefficient, reacted more to a novel stimulus, were hyperactive when exploring a new context, but hypoactive when exploring anxiety-inducing environments, and had an upregulated hippocampal expression of the grin2c gene. When exposed to low doses of CPF during gestation, these KO rats showed decreased climbing capacity, dysfunctional social interaction, and increased hippocampal expression for kcc1 and 5ht2c genes. Gestational CPF exposure increased the ASD-like phenotype in those animals with a genetic vulnerability, although its effect was less generalized than expected. It is the first time that this additive effect of CPF exposure and the fmr1-KO genetic vulnerability model is explored concerning social traits or any other behavior.

Relationship between Prenatal or Postnatal Exposure to Pesticides and Obesity: A Systematic Review.

In recent years, the worldwide prevalence of overweight and obesity among adults and children has dramatically increased. The conventional model regarding the onset of obesity is based on an imbalance between energy intake and expenditure. However, other possible environmental factors involved, such as the exposure to chemicals like pesticides, cannot be discarded. These compounds could act as endocrine-disrupting chemicals (EDC) that may interfere with hormone activity related to several mechanisms involved in body weight control. The main objective of this study was to systematically review the data provided in the scientific literature for a possible association between prenatal and postnatal exposure to pesticides and obesity in offspring. A total of 25 human and 9 animal studies were analyzed. The prenatal, perinatal, and postnatal exposure to organophosphate, organochlorine, pyrethroid, neonicotinoid, and carbamate, as well as a combined pesticide exposure was reviewed. This systematic review reveals that the effects of pesticide exposure on body weight are mostly inconclusive, finding conflicting results in both humans and experimental animals. The outcomes reviewed are dependent on many factors, including dosage and route of administration, species, sex, and treatment duration. More research is needed to effectively evaluate the impact of the combined effects of different pesticides on human health.

Pesticides and aging: Preweaning exposure to Chlorpyrifos induces a general hypomotricity state in late-adult rats.

The molecular and behavioral effects of the developmental exposure to low doses of Chlorpyrifos (CPF) have been intensively studied in young (neonates and adolescents), and adult animals. However, no study examined influences of developmental CPF exposure in older adult or geriatric rats. This is relevant as such ages are generally linked to cognitive decline and the onset of specific neurodegenerative disorders, some of them previously associated with CPF exposure in both preclinical and human studies. 1 mg/kg/mL of CPF was orally administered to both male and female Wistar rats from Postnatal day 10 to 15. Animals' spatial memory, learning, compulsivity, motricity, and anxiety were analyzed with Morris Water Maze (15-16 months of age) and the Plus-maze (at 18 months of age). Results showed that postnatal CPF exposure did not alter either spatial memory, compulsive-like behaviors, or anxiety levels in late-adult rats. However, CPF exposed rats were hyposensitive to brief disruptions (Probe stage) following the learning phase and showed a general decrease in locomotor activity in both paradigms. These data are relevant as it is the first time that developmental exposure to CPF has been studied at such a late age, observing important effects in locomotor activity that could be linked to specific pathologies previously associated with CPF effects in people. Future studies should extend these findings to other behaviors and molecular outcomes.

Relationship between Autism Spectrum Disorder and Pesticides: A Systematic Review of Human and Preclinical Models.

Autism spectrum disorder (ASD) is a complex set of neurodevelopmental pathologies characterized by impoverished social and communicative abilities and stereotyped behaviors. Although its genetic basis is unquestionable, the involvement of environmental factors such as exposure to pesticides has also been proposed. Despite the systematic analyses of this relationship in humans, there are no specific reviews including both human and preclinical models. The present systematic review summarizes, analyzes, and discusses recent advances in preclinical and epidemiological studies. We included 45 human and 16 preclinical studies. These studies focused on Organophosphates (OP), Organochlorine (OC), Pyrethroid (PT), Neonicotinoid (NN), Carbamate (CM), and mixed exposures. Preclinical studies, where the OP Chlorpyrifos (CPF) compound is the one most studied, pointed to an association between gestational exposure and increased ASD-like behaviors, although the data are inconclusive with regard to other ages or pesticides. Studies in humans focused on prenatal exposure to OP and OC agents, and report cognitive and behavioral alterations related to ASD symptomatology. The results of both suggest that gestational exposure to certain OP agents could be linked to the clinical signs of ASD. Future experimental studies should focus on extending the analysis of ASD-like behaviors in preclinical models and include exposure patterns similar to those observed in human studies.

NMR-Based Metabolomics Approach to Explore Brain Metabolic Changes Induced by Prenatal Exposure to Autism-Inducing Chemicals.

NMR offers the unique potential to holistically screen hundreds of metabolites and has already proved to be a powerful technique able to provide a global picture of a wide range of metabolic processes underlying complex and multifactorial diseases, such as neurodegenerative and neurodevelopmental diseases. The aim of this study was to apply an NMR-based metabolomics approach to explore brain metabolic changes in both male and female rats induced by prenatal exposure to two chemicals associated with autism disorders-the organophosphorus pesticide chlorpyrifos (CPF) and the antiepileptic drug valproic acid (VPA)-at different postnatal ages. Depending on the age and on the brain region (hippocampus and cerebellum), several metabolites were shown to be significantly affected by exposure to both compounds. The evaluation of the spectral profiles revealed that the nervous-system-specific metabolite N-acetylaspartate (NAA), amino acid neurotransmitters (e.g., glutamate, glutamine, GABA, glycine), pyroglutamic acid, unsaturated fatty acids, and choline-based compounds are discriminant biomarkers. Additionally, metabolic changes varied as a function of age, but importantly not of sex.

Similarities between the Effects of Prenatal Chlorpyrifos and Valproic Acid on Ultrasonic Vocalization in Infant Wistar Rats.

BACKGROUND: In recent years, ultrasonic vocalizations (USV) in pups has become established as a good tool for evaluating behaviors related to communication deficits and emotional states observed in autism spectrum disorder (ASD). Prenatal valproic acid (VPA) exposure leads to impairments and social behavior deficits associated with autism, with the effects of VPA being considered as a reliable animal model of ASD. Some studies also suggest that prenatal exposure to chlorpyrifos (CPF) could enhance autistic-like behaviors. METHODS: In order to explore these similarities, in the present study we tested whether prenatal exposure to CPF at GD12.5-14.5 produces effects that are comparable to those produced by prenatal VPA exposure at GD12.5 in infant Wistar rats. Using Deep Squeek software, we evaluated total number of USVs, latency to the first call, mean call duration, principal frequency peak, high frequency peak, and type of calls. RESULTS: Consistent with our hypothesis, we found that exposure to both CPF and VPA leads to a significantly smaller number of calls along with a longer latency to produce the first call. No significant effects were found for the remaining dependent variables. CONCLUSIONS: These results suggest that prenatal exposure to CPF could produce certain behaviors that are reminiscent of those observed in ASD patients.

Postnatal exposure to low doses of Chlorpyrifos induces long-term effects on 5C-SRTT learning and performance, cholinergic and GABAergic systems and BDNF expression.

Alterations in attention and inhibitory control are common features in several neurological disorders. Environmental factors such as exposure to pesticides have been linked to their appearance. Chlorpyrifos (CPF) is one of the most widely used organophosphate compounds in the world. CPF exposure during development seems to be critical for later behavioral and molecular disruptions during adult ages, although this depends on the specific period of development, where the preweaning period is one of the least studied. Despite the abundant empirical work made in the last decades on developmental CPF exposure, the systematic study of this on attention is sparse, and nonexistent concerning inhibitory control, without a single study on preweaning developmental stages. The present research explored the effects of the exposure to low doses of CPF that do not elicit a significant inhibition of the Cholinesterases during this developmental period on rats' behavior in the five-choice serial reaction time task. Behavioral manipulations (inter-trial interval and stimulus duration), pharmacological manipulations (cholinergic and GABAergic drugs) and brain gene expression analyses were also conducted. Exposure to CPF decreased the locomotor activity and enhanced the learning profile of the female rats, increased the impulsive rates, unmasked by a longer inter-trial interval, hypo-sensitized the cholinergic system and down-regulated the mRNA expression levels of the brain-derived neurotrophic factor in the dorsal striatum of the male rats. This happened without significant inhibition of the brain Acetylcholinesterase. All this new information corroborates that the exposure to a common pesticide at low doses during a key, but under-explored developmental period importantly affects different behaviors, neurotransmitter systems, and molecules that are altered in the main neurological disorders observed nowadays.

Medium and long-term effects of low doses of Chlorpyrifos during the postnatal, preweaning developmental stage on sociability, dominance, gut microbiota and plasma metabolites.

Autism spectrum disorder (ASD) is a complex neurodevelopmental pathology characterized by altered verbalizations, reduced social interaction behavior, and stereotypies. Environmental factors have been associated with its development. Some researchers have focused on pesticide exposure. Chlorpyrifos (CPF) is the most used Organophosphate. Previous developmental studies with CPF showed decreased, enhanced or no effect on social outcomes eminently in mice. The study of CPF exposure during preweaning stages on social behavior is sparse in mice and non-existent in rats. d stressors could be at the basis of ASD development, and around postnatal day 10 in the rat is equivalent to the human birthday in neurodevelopmental terms. We explored the effects of exposure to low doses (1mg/kg/mL/day) of CPF during this stage regarding: sociability, dominance gut microbiome and plasma metabolomic profile, since alterations in these systems have also been linked to ASD. There was a modest influence of CPF on social behavior in adulthood, with null effects during adolescence. Dominance and hierarchical status were not affected by exposure. Dominance status explained the significant reduction in reaction to social novelty observed on the sociability test. CPF induced a significant gut microbiome dysbiosis and triggered a hyperlipidemic, hypoglycemic/hypogluconeogenesis and a general altered cell energy production in females. These behavioral results in rats extend and complement previous studies with mice and show novel influences on gut metagenomics and plasma lipid profile and metabolomics, but do not stablish a relation between the exposure to CPF and the ASD phenotype. The effects of dominance status on reaction to social novelty have an important methodological meaning for future research on sociability.

Age-dependent effects of repeated methamphetamine exposure on locomotor activity and attentional function in rats.

Many adolescents use amphetamines which are the second most common abused illegal drugs. Methamphetamine (Meth), as a potent amphetamine affects attentional functions. However, the most significant factor for susceptibility to Meth is the age of exposure, most studies have examined the effects of Meth after early adolescence stage. The present experiment was aimed to investigate some possible short- and long-term effects of Meth at two distinct points of adolescence stage (early versus late) on 1) locomotor activity in adolescent rats and 2) attentional functions in their adulthood. Rats received Meth (5 mg/kg, i.p., for consecutive 10 days) during early adolescence (postnatal days (PND) 30-39) or late adolescence (PND 50-59). Locomotor activity was assessed after the first and tenth injections. Then, in adulthood, rats were trained and tested on the Five-choice serial reaction time task (5-CSRTT) to display possible attentional impairments. The first Meth administration in early exposed adolescent (EEA) group produced the highest level of activity, compared with the first exposure in late exposed adolescent (LEA) group and tenth administrations in both groups. In adulthood, LEA group significantly delayed learning the 5-CSRTT and exhibited attentional impairments, as demonstrated by significant reduced response accuracy and increased omission errors under pharmacological challenge, compared with control group. The susceptibility to Meth depends on the age of exposure and Meth administration during late adolescence stage may cause prolonged attentional deficits in adulthood.

Sex and Exposure to Postnatal Chlorpyrifos Influence the Epigenetics of Feeding-Related Genes in a Transgenic APOE Mouse Model: Long-Term Implications on Body Weight after a High-Fat Diet.

Developmental exposure to toxicants and diet can interact with an individual's genetics and produce long-lasting metabolic adaptations. The different isoforms of the apolipoprotein E (APOE) are an important source of variability in metabolic disorders and influence the response to the pesticide chlorpyrifos (CPF). We aimed to study the epigenetic regulation on feeding control genes and the influence of postnatal CPF exposure, APOE genotype, and sex, and how these modifications impact on the metabolic response to a high-fat diet (HFD). Both male and female apoE3- and apoE4-TR mice were exposed to CPF on postnatal days 10-15. The DNA methylation pattern of proopiomelanocortin, neuropeptide Y, leptin receptor, and insulin-like growth factor 2 was studied in the hypothalamus. At adulthood, the mice were given a HFD for eight weeks. The results highlight the importance of sex in the epigenetic regulation and the implication of CPF treatment and APOE genotype. The body weight progression exhibited sex-dimorphic differences, apoE4-TR males being the most susceptible to the effects induced by CPF and HFD. Overall, these results underscore the pivotal role of sex, APOE genotype, and developmental exposure to CPF on subsequent metabolic disturbances later in life and show that sex is a key variable in epigenetic regulation.

APOE genotype and postnatal chlorpyrifos exposure modulate gut microbiota and cerebral short-chain fatty acids in preweaning mice.

The gut microbiota comprises a large number of microorganisms, whose composition can be modified by genetic and environmental factors. The host's genetic background, including the different isoforms of the apolipoprotein E (APOE) gene, can exert an influence over microbiota composition. Exposure to the widely-used pesticide chlorpyrifos (CPF), can lead to dysbiosis and alter the levels of metabolites produced by the microbiota, such as short-chain fatty acids (SCFAs). This study was aimed at assessing the contribution of the APOE genotype and early exposure to CPF on gut microbiota and SCFA in brain. For it, C57BL/6, apoE3-and apoE4-TR mice were orally exposed to CPF from postnatal day (PND) 10 to PND 15. Microbiota in the gut and SCFA in the brain were assessed at PND 15 after CPF exposure. Differences between genotypes at different taxonomic levels were found, A. muciniphila presented greater abundance in APOE4 genotype, but was reduced by CPF exposure. APOE and CPF influenced cerebral SCFAs, with APOE3 genotype showing the highest levels of acetic, propionic and butyric acids and CPF exposure inducing the highest levels of isovaleric and 4-methylvaleric acids. These results provide further knowledge about gut microbiota and cerebral SCFAs composition at early ages and their modulation by APOE and postnatal CPF exposure.