Stress resilience evidenced by grooming behaviour and dopamine levels in male mice selected for high and low immobility using the tail suspension test.

Grooming behaviour has different functions on many species during development and can be observed and affected during periods of stress. By selecting male mice with high (HI) and low (LI) immobility traits in the tail suspension test, a screening for antidepressant drugs, we investigate how these phenotypes associated with grooming behaviour may be influenced by the effects of repeated restraint stress. For this we used the sucrose preference test and the splash test in a novel and a familiar cage performed before and after exposure to 2 days of restraint stress. Animals were submitted to an additional day of restraint stress before the hypothalamus, prefrontal cortex and midbrain extraction for dopamine activity analysis. Corticosterone analysis was made in three distinct moments: without stress (prior first restraint session), immediately after the last restrain, and 1 hr after the last restrain episode. Compared to LI group, HI animals exhibited an increased frequency and decreased time of grooming in the familiar cage. In the novel cage, stress increased frequency and time of grooming of HI animals compared to LI. Corticosterone levels were increased in HI animals after 3 days of stress. Lower hypothalamic dopaminergic activity without stress and decreased hypothalamic dopaminergic activity immediately after stress in HI group were observed. The HI group displayed decreased prefrontal cortex dopaminergic activity and increased activity in the mesolimbic area. We proposed that through the influence of stress the two phenotypes manifested as a resilient (LI) and a not resilient (HI) trait in response to restraint stress.

Conditional Deletion of Ric-8b in Olfactory Sensory Neurons Leads to Olfactory Impairment.

The olfactory system can discriminate a vast number of odorants. This ability derives from the existence of a large family of odorant receptors expressed in the cilia of the olfactory sensory neurons. Odorant receptors signal through the olfactory-specific G-protein subunit, Gαolf. Ric-8b, a guanine nucleotide exchange factor, interacts with Gαolf and can amplify odorant receptor signal transduction in vitro To explore the function of Ric-8b in vivo, we generated a tissue specific knock-out mouse by crossing OMP-Cre transgenic mice to Ric-8b floxed mice. We found that olfactory-specific Ric-8b knock-out mice of mixed sex do not express the Gαolf protein in the olfactory epithelium. We also found that in these mice, the mature olfactory sensory neuron layer is reduced, and that olfactory sensory neurons show increased rate of cell death compared with wild-type mice. Finally, behavioral tests showed that the olfactory-specific Ric-8b knock-out mice show an impaired sense of smell, even though their motivation and mobility behaviors remain normal.SIGNIFICANCE STATEMENT Ric-8b is a guanine nucleotide exchange factor (GEF) expressed in the olfactory epithelium and in the striatum. Ric-8b interacts with the olfactory Gαolf subunit, and can amplify odorant signaling through odorant receptors in vitro However, the functional significance of this GEF in the olfactory neurons in vivo remains unknown. We report that deletion of Ric-8b in olfactory sensory neurons prevents stable expression of Gαolf. In addition, we demonstrate that olfactory neurons lacking Ric-8b (and consequently Gαolf) are more susceptible to cell death. Ric-8b conditional knock-out mice display impaired olfactory guided behavior. Our results reveal that Ric-8b is essential for olfactory function, and suggest that it may also be essential for Gαolf-dependent functions in the brain.

Origin and dynamics of admixture in Brazilians and its effect on the pattern of deleterious mutations.

While South Americans are underrepresented in human genomic diversity studies, Brazil has been a classical model for population genetics studies on admixture. We present the results of the EPIGEN Brazil Initiative, the most comprehensive up-to-date genomic analysis of any Latin-American population. A population-based genome-wide analysis of 6,487 individuals was performed in the context of worldwide genomic diversity to elucidate how ancestry, kinship, and inbreeding interact in three populations with different histories from the Northeast (African ancestry: 50%), Southeast, and South (both with European ancestry >70%) of Brazil. We showed that ancestry-positive assortative mating permeated Brazilian history. We traced European ancestry in the Southeast/South to a wider European/Middle Eastern region with respect to the Northeast, where ancestry seems restricted to Iberia. By developing an approximate Bayesian computation framework, we infer more recent European immigration to the Southeast/South than to the Northeast. Also, the observed low Native-American ancestry (6-8%) was mostly introduced in different regions of Brazil soon after the European Conquest. We broadened our understanding of the African diaspora, the major destination of which was Brazil, by revealing that Brazilians display two within-Africa ancestry components: one associated with non-Bantu/western Africans (more evident in the Northeast and African Americans) and one associated with Bantu/eastern Africans (more present in the Southeast/South). Furthermore, the whole-genome analysis of 30 individuals (42-fold deep coverage) shows that continental admixture rather than local post-Columbian history is the main and complex determinant of the individual amount of deleterious genotypes.

A genome-wide association study of asthma symptoms in Latin American children.

BACKGROUND: Asthma is a chronic disease of the airways and, despite the advances in the knowledge of associated genetic regions in recent years, their mechanisms have yet to be explored. Several genome-wide association studies have been carried out in recent years, but none of these have involved Latin American populations with a high level of miscegenation, as is seen in the Brazilian population. METHODS: 1246 children were recruited from a longitudinal cohort study in Salvador, Brazil. Asthma symptoms were identified in accordance with an International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Following quality control, 1,877,526 autosomal SNPs were tested for association with childhood asthma symptoms by logistic regression using an additive genetic model. We complemented the analysis with an estimate of the phenotypic variance explained by common genetic variants. Replications were investigated in independent Mexican and US Latino samples. RESULTS: Two chromosomal regions reached genome-wide significance level for childhood asthma symptoms: the 14q11 region flanking the DAD1 and OXA1L genes (rs1999071, MAF 0.32, OR 1.78, 95% CI 1.45-2.18, p-value 2.83 × 10(-8)) and 15q22 region flanking the FOXB1 gene (rs10519031, MAF 0.04, OR 3.0, 95% CI 2.02-4.49, p-value 6.68 × 10(-8) and rs8029377, MAF 0.03, OR 2.49, 95% CI 1.76-3.53, p-value 2.45 × 10(-7)). eQTL analysis suggests that rs1999071 regulates the expression of OXA1L gene. However, the original findings were not replicated in the Mexican or US Latino samples. CONCLUSIONS: We conclude that the 14q11 and 15q22 regions may be associated with asthma symptoms in childhood.

Anti-inflammatory effects in muscle injury by transdermal application of gel with Lychnophora pinaster aerial parts using phonophoresis in rats.

BACKGROUND: Lycnophora pinaster is used by the traditional Brazilian medicine for the treatment of inflammations. Anti-inflammatory activity of Lycnophora pinaster was investigated for extracts, fractions, and isolated compounds of their aerial parts. The hexane extract (HE) provided α-amyrin, lupeol, mixture of α-amyrin and lupeol, mixture of 3-O-acetyl-lupeol and 3-O-acetyl-pseudotaraxasterol, and mixture of the steroids stigmasterol and sitosterol. The aqueous extract (WE) provided a fraction containing alkaloids (AF) and another one containing phenolic compounds (PF). METHODS: The crude hexane extract obtained from aerial parts of L. pinaster was submitted to chromatographic fractionation. The fractionation of PF was performed by preparative HPLC analysis, providing the flavonoid quercetin. The extracts, fractions, and compounds isolated from L. pinaster were tested to evaluate the anti-inflammatory activity by experimental model of impact injury, followed by transdermal application of gels with these samples. The application of the gels was performed using phonophoresis in rat paws after induction of muscle injury. Histological analysis was based on scores assigned by the capacity of decreasing the lesion. RESULTS: HE and WE exhibited anti-inflammatory activity. Some fractions, triterpenes, and steroids also reduced the inflammatory infiltrates caused by muscle injury. Lupeol promoted a significant reduction of inflammation. Quercetin also provided significant results, promoting the greatest decreases in muscle injury. CONCLUSION: The results of this work suggest that topical application of triterpenes, steroids and flavonoid significantly decreases the inflammatory process generated by muscle injury. The transdermal application using phonophoresis in rat paws of gel with lupeol and quercetin attenuates the inflammation.

Tryparedoxin peroxidases and superoxide dismutases expression as well as ROS release are related to Trypanosoma cruzi epimastigotes growth phases.

Trypanosoma cruzi's antioxidant system is unique and relevant to the parasite. In this study, quantitative assays were performed to determine cytosolic and mitochondrial tryparedoxin peroxidases and superoxide dismutases expression (TcCPx, TcMPx, SODB and SODA) in correlation to H(2)O(2) release and O(2)(-) production. Differences were observed regarding H(2)O(2) release and O(2)(-) production between strains and along the growth curve. All of the enzymes studied exhibited varied expression as a function of time in culture. Although at lower levels, the Y strain exhibited the same pattern of Tulahuen 2 enzyme expression for all of the proteins studied, except SODA. In the stationary phase, the degree of expression of all of the enzymes in the Y strain returned to similar levels as those detected in the log phase with the exception of TcCPx and SODA. In Tulahuen 2, a higher expression of TcMPx, SODA and SODB was detected in the early stationary phase, and a slight decrease was observed in the late stationary phase for each enzyme, excluding TcMPx, which exhibited a marked decrease, and TcCPx, which increased its level. Because of the significance of ROS in redox signaling, these differences in enzyme expression underscore the importance of these parameters for epimastigote proliferation.

O2 consumption rates along the growth curve: new insights into Trypanosoma cruzi mitochondrial respiratory chain.

Understanding the energy-transduction pathways employed by Trypanosoma cruzi, the etiological agent of Chagas disease, may lead to the identification of new targets for development of a more effective therapy. Herein, the contribution of different substrates for O(2) consumption rates along T. cruzi epimastigotes (Tulahuen 2 and Y strains) growth curve was evaluated. O(2) consumption rates were higher at the late stationary phase not due to an increase on succinate-dehydrogenase activity. Antimycin A and cyanide did not totally inhibit the mitochondrial respiratory chain (MRC). Malonate at 10 or 25 mM was not a potent inhibitor of complex II. Comparing complex II and III, the former appears to be the primary site of H(2)O(2) release. An update on T. cruzi MRC is presented that together with our results bring important data towards the understanding of the parasite's MRC. The findings mainly at the stationary phase could be relevant for epimastigotes transformation into the metacyclic form, and in this sense deserves further attention.

Brazilian red propolis exhibits antiparasitic properties in vitro and reduces worm burden and egg production in an mouse model harboring either early or chronic Schistosoma mansoni infection.

ETHNOPHARMACOLOGICAL RELEVANCE: Propolis has been used in folk medicine for thousands of years and, in the past few decades, it has attracted renewed interest. Although propolis has been traditionally used in many communities worldwide against parasitic diseases, its effect against Schistosoma mansoni infection remains unclear. AIM OF THE STUDY: To demonstrate the effects of Brazilian red propolis on Schistosoma mansoni ex vivo and in an animal model of schistosomiasis. MATERIALS AND METHODS: In vitro, we monitored phenotypic and tegumental changes as well as the effects of the crude extract of propolis on pairing and egg production. In a mouse infected with either immature (early infection) or adult (chronic infection) worms, propolis was administered by oral gavage and we studied the influence of this natural product on worm burden and egg production. RESULTS: Propolis 25 µg/mL reduced motility and caused 100% mortality of adult parasites ex vivo. Further analysis revealed a pronounced reduction in oviposition after exposure to propolis at sub-lethal concentrations. In addition, scanning electron microscopy showed morphological alterations in the tegument of schistosomes. In the animal model, propolis markedly reduced worm burden and egg production in both early and chronic S. mansoni infection when compared to untreated control animals. CONCLUSIONS: The efficacy of Brazilian red propolis in both in vitro and in vivo studies suggests its potential anthelmintic properties against S. mansoni infection.

New variants in NLRP3 inflammasome genes increase risk for asthma and Blomia tropicalis-induced allergy in a Brazilian population.

Atopic asthma is a chronic lung disease of lower airways caused mainly due to action of T-helper (Th) 2 type cytokines, eosinophilic inflammation, mucus hypersecretion and airway remodelling. Interleukin (IL)-33 increases type 2 immunity polarization in airway playing critical role in eosinophilic asthma. On the other hand, NLRP3 inflammasome activation results in the release of caspase-1 (Casp-1) which, in its turn, promotes IL-33 inactivation. Recent studies have shown associations between NLRP3 variants and inflammatory diseases. However, no study with genes in NLRP3 inflammassome route has been conducted so far with asthma and atopy in any population to date. Blood samples were collected from 1246 asthmatic and non-asthmatic children. Associations were tested for single nucleotide polymorphism (SNP)s in NLRP3 and CASP1 with asthma and markers of atopy and in cultures stimulated with Blomia tropicalis (Bt) mite crude extract. The T allele of rs4925648 (NLRP3) was associated with increased asthma risk (OR 1.50, P = 0.005). In addition, the T allele of rs12130711 polymorphism, whithin the same gene, acted as a protector factor for asthma (OR 0.78, P = 0.038). On the other hand, the C allele of rs4378247 NLRP3 variant was associated with lower levels of IL-13 production when peripheral blood cells were stimulated with Bt (OR 0.39, P = 4E-04). In addition, the greater the number of risk alleles in IL33/NLRP3/CASP1 route the greater was the risk for asthma. The T allele of rs7925706 CASP1 variant was also associated with increased risk for asthma (OR 1.47, P = 0.008). In addition, this same allele increased the eosinophil counts in blood (mm3) in asthmatic individuals compared with non-asthmatic (P = 0.0004). These results suggest that NLRP3 and CASP1 polymorphisms may be associated with susceptibility for asthma and markers of atopy in our population.

Genomic Regions 10q22.2, 17q21.31, and 2p23.1 Can Contribute to a Lower Lung Function in African Descent Populations.

Accumulated evidence supports the contribution of genetic factors in modulating airway function, especially ancestry. We investigated whether genetic polymorphisms can affect lung function in a mixed Brazilian child population using the admixture mapping strategy through RFMix software version 1.5.4 (Stanford University, Stanford, CA, USA), followed by fine mapping, to identify regions whereby local African or European ancestry is associated with lung function measured by the forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio, an indicator of airway obstruction. The research cohort included 958 individuals aged 4 to 11 years enrolled in the SCAALA (Social Change, Asthma, Allergy in Latin America) Program. We identified that African ancestry at 17q21.31, 10q22.2, and 2p23.1 regions was associated with lower lung function measured by FEV1/FVC p < 1.9 × 10-4. In contrast, European ancestry at 17q21.31 showed an opposite effect. Fine mapping pointed out 5 single nucleotide polymorphisms (SNPs) also associated in our replication cohort (rs10999948, rs373831475, rs8068257, rs6744555, and rs1520322). Our results suggest that genomic regions associated with ancestry may contribute to differences in lung function measurements in African American children in Brazil replicated in a cohort of Brazilian adults. The analysis strategy used in this work is especially important for phenotypes, such as lung function, which has considerable disparities in terms of measurements across different populations.

African biogeographical ancestry, atopic and non-atopic asthma and atopy: A study in Latin American children.

BACKGROUND: Genetic variants underlying African ancestry have been suggested be implicated in the ethnic-racial inequalities reported for asthma and allergies. OBJECTIVES: To investigate the association between individual African ancestry and asthma symptoms, atopic and non-atopic asthma, and atopy in children. METHODS: A cross-sectional study encompassing 1190 individuals was conducted. African biogeographic ancestry was estimated using 370 539 genome-wide SNPs. Serum levels of specific IgE were measured, and skin prick test (SPT) performed for the most common local aeroallergens. Information on asthma symptoms was obtained by applying the International Study of Allergy and Asthma in Childhood questionnaire. The associations between the proportion of individual African ancestry and the outcomes investigated were analyzed through multivariate models adjusted for socio-environmental variables, infections markers, and psychosocial factors. RESULTS: Each 20% increase in the proportion of African ancestry was negatively associated with SPT reactivity (OR: 0.79, 95%CI: 0.66-0.96) and positively associated with asthma symptoms in non-atopic individuals (OR: 1.40, 95%CI: 1.03-1.89). We estimated that socioeconomic status and number of infections mediated 28.4% of the effect of African ancestry on SPT reactivity, while 20.2% of the effect on non-atopic asthma was explained by socioeconomic status and behavioral problems in children. CONCLUSIONS: The negative association observed between African ancestry and atopy is most probably explained by unobserved environmental or social factors that covariate with ancestry. For non-atopic asthma, in turn, putative genetic variants of risk underlying African ancestry may play some role.

Buried Food-seeking Test for the Assessment of Olfactory Detection in Mice.

The sense of smell allows animals to discriminate a large number of volatile environmental chemicals. Such chemical signaling modulates the behavior of several species that depend on odorant compounds to locate food, recognize territory, predators, and toxic compounds. Olfaction also plays a role in mate choice, mother-infant recognition, and social interaction among members of a group. A key assay to assess the ability to smell odorants is the buried food-seeking test, which checks whether the food-deprived mice can find the food pellet hidden beneath the bedding in the animal's cage. The main parameter observed in this test is the latency to uncover a small piece of chow, cookie, or other pleasant food, hidden beneath a layer of cage bedding, within a limited amount of time. It is understood that food-restricted mice which fail to use odor cues to locate food within a given time period are likely to have deficits in olfactory abilities. Investigators who used the buried food test, or versions of the buried food test, demonstrated that it is possible to evaluate olfactory deficits in different models of murine studies (Alberts and Galef, 1971; Belluscio et al., 1998 ; Luo et al., 2002 ; Li et al., 2013 ). We have recently used this assay to demonstrate that olfactory-specific Ric-8B knock-out mice (a guanine nucleotide exchange factor that interacts with olfactory-specific G-protein) show an impaired sense of smell ( Machado et al., 2017 ). Here we describe the protocol of the buried food-seeking test, as adopted in our assays.

Prenatal lipopolysaccharide exposure affects sexual dimorphism in different germlines of mice with a depressive phenotype.

The objective of the present study was to investigate whether prenatal lipopolysaccharide (LPS) administration modifies the expression of depressive and non-depressive-like behavior in male and female mice across two generations. The sexual dimorphism of these mice was also examined in the open-field test. Male and female mice of the parental (F0) generation were selected for depressive- or non-depressive-like behavioral profiles using the tail suspension test (TST). Animals with similar profiles were matched for further mating. On gestation day (GD) 15, pregnant F0 mice received LPS (100µg/kg, i.p.) and were allowed to nurture their offspring freely. Adult male and female of the F1 generation were then selected according to behavioral profiles and observed in the open field. Male and female mice of the two behavioral profiles were then mated to obtain the F2 generation. Adults from the F2 generation were also behaviorally phenotyped, and open field behavior was assessed. Male mice that were selected for depressive- and non-depressive-like behaviors and treated or not with LPS in the parental generation exhibited similar proportions of behavioral profiles in both filial lines, but LPS exposure increased the number of depressive-like behavior. An effect of gender was observed in the F1 and F2 generations, in which male mice were more sensitive to the intergenerational effects of LPS in the TST. These data indicate that prenatal LPS exposure on GD15 in the F0 generation influenced the transmission of depressive- and non-depressive-like behavior across filial lines, with sexual dimorphism between phenotypes.

A minimum set of ancestry informative markers for determining admixture proportions in a mixed American population: the Brazilian set.

The Brazilian population is considered to be highly admixed. The main contributing ancestral populations were European and African, with Amerindians contributing to a lesser extent. The aims of this study were to provide a resource for determining and quantifying individual continental ancestry using the smallest number of SNPs possible, thus allowing for a cost- and time-efficient strategy for genomic ancestry determination. We identified and validated a minimum set of 192 ancestry informative markers (AIMs) for the genetic ancestry determination of Brazilian populations. These markers were selected on the basis of their distribution throughout the human genome, and their capacity of being genotyped on widely available commercial platforms. We analyzed genotyping data from 6487 individuals belonging to three Brazilian cohorts. Estimates of individual admixture using this 192 AIM panels were highly correlated with estimates using ~370 000 genome-wide SNPs: 91%, 92%, and 74% of, respectively, African, European, and Native American ancestry components. Besides that, 192 AIMs are well distributed among populations from these ancestral continents, allowing greater freedom in future studies with this panel regarding the choice of reference populations. We also observed that genetic ancestry inferred by AIMs provides similar association results to the one obtained using ancestry inferred by genomic data (370 K SNPs) in a simple regression model with rs1426654, related to skin pigmentation, genotypes as dependent variable. In conclusion, these markers can be used to identify and accurately quantify ancestry of Latin Americans or US Hispanics/Latino individuals, in particular in the context of fine-mapping strategies that require the quantification of continental ancestry in thousands of individuals.

Draft genome sequence of Kocuria sp. SM24M-10 isolated from coral mucus.

Here, we describe the genomic features of the Actinobacteria Kocuria sp. SM24M-10 isolated from mucus of the Brazilian endemic coral Mussismilia hispida. The sequences are available under accession number LDNX01000000 (http://www.ncbi.nlm.nih.gov/nuccore/LDNX00000000). The genomic analysis revealed interesting information about the adaptation of bacteria to the marine environment (such as genes involved in osmotic and oxidative stress) and to the nutrient-rich environment provided by the coral mucus.

Zinc prevents sickness behavior induced by lipopolysaccharides after a stress challenge in rats.

Sickness behavior is considered part of the specific beneficial adaptive behavioral and neuroimmune changes that occur in individuals in response to infectious/inflammatory processes. However, in dangerous and stressful situations, sickness behavior should be momentarily abrogated to prioritize survival behaviors, such as fight or flight. Taking this assumption into account, we experimentally induced sickness behavior in rats using lipopolysaccharides (LPS), an endotoxin that mimics infection by gram-negative bacteria, and then exposed these rats to a restraint stress challenge. Zinc has been shown to play a regulatory role in the immune and nervous systems. Therefore, the objective of this study was to examine the effects of zinc treatment on the sickness response of stress-challenged rats. We evaluated 22-kHz ultrasonic vocalizations, open-field behavior, tumor necrosis factor α (TNF-α), corticosterone, and brain-derived neurotrophic factor (BDNF) plasma levels. LPS administration induced sickness behavior in rats compared to controls, i.e., decreases in the distance traveled, average velocity, rearing frequency, self-grooming, and number of vocalizations, as well as an increase in the plasma levels of TNF-α, compared with controls after a stressor challenge. LPS also decreased BDNF expression but did not influence anxiety parameters. Zinc treatment was able to prevent sickness behavior in LPS-exposed rats after the stress challenge, restoring exploratory/motor behaviors, communication, and TNF-α levels similar to those of the control group. Thus, zinc treatment appears to be beneficial for sick animals when they are facing risky/stressful situations.

Prenatal exposure to integerrimine N-oxide enriched butanolic residue from Senecio brasiliensis affects behavior and striatal neurotransmitter levels of rats in adulthood.

Pyrrolizidine alkaloids (PAs) are toxins that are exclusively biosynthesized by plants and are commonly present in foods and herbs. PAs are usually associated with poisoning events in livestock and human beings. The aim of the present study was to evaluate the behavioral and neurochemical effects of prenatal exposure to PA integerrimine N-oxide of rats in adulthood. Pregnant Wistar rats received integerrimine N-oxide from the butanolic residue of Senecio brasiliensis by gavage on gestational days 6-20 at doses of 3, 6 and 9 mg/kg. During adulthood of the offspring, the following behavioral tests were performed: open-field, plus-maze, forced swimming, catalepsy and stereotypy. Histological analyses and monoamine levels were measured. Male offspring from dams that were exposed to 9 mg/kg showed an increase in locomotion in the open-field test, an increased frequency of entries and time spent in open arms in elevated plus-maze test, as well as decreased swimming time. In the female offspring from dams that were exposed to 9 mg/kg, there was an increased time of climbing in forced swimming and intensity of stereotyped behavior. The histological study indicates an increase in the number of multinucleated cells in the liver (6 and 9 mg/kg). In neurotransmitter analysis, specifically in the striatum, we observed change in dopamine and serotonin levels in the middle dose. Thus, our results indicate that prenatal exposure to integerrimine N-oxide changed behavior in adulthood and neurotransmitter levels in the striatum. Our results agree with previous studies, which showed that integerrimine N-oxide impaired physical and neurobehavioral development in childhood that can persist until adulthood.

High-quality draft genome sequence of Kocuria marina SO9-6, an actinobacterium isolated from a copper mine.

An actinobacterial strain, designated SO9-6, was isolated from a copper iron sulfide mineral. The organism is Gram-positive, facultatively anaerobic, and coccoid. Chemotaxonomic and phylogenetic properties were consistent with its classification in the genus Kocuria. Here, we report the first draft genome sequence of Kocuria marina SO9-6 under accession JROM00000000 (http://www.ncbi.nlm.nih.gov/nuccore/725823918), which provides insights for heavy metal bioremediation and production of compounds of biotechnological interest.

Prenatal exposure to integerrimine N-oxide impaired the maternal care and the physical and behavioral development of offspring rats.

Plants that contain pyrrolizidine alkaloids (PAs) have been reported as contaminants of pastures and food, as well as being used in herbal medicine. PAs are responsible for poisoning events in livestock and human beings. The aim of this present study was to evaluate effects of prenatal exposure to integerrimine N-oxide, the main PA found in the butanolic residue (BR) of Senecio brasiliensis, on both physical and behavioral parameters of Wistar rat offspring. The toxicity and maternal behavior were also evaluated. For this, pregnant Wistar rats received integerrimine N-oxide from the BR of Senecio brasiliensis, by gavage, on gestational days 6-20 (during organogenesis and fetal development period) at doses of 3, 6 and 9 mg/kg. During treatment, maternal body weight gain, and food and water intake were evaluated. After parturition, maternal behavior and aggressive maternal behavior were analyzed. In addition, physical development and behavioral assessments were observed in both male and female pups. Results showed that prenatal exposure to integerrimine N-oxide of S. brasiliensis induced maternal toxicity, impairment in maternal behavior and aggressive maternal behavior, mainly in the highest dose group. Between sexes comparison of pups showed loss of body weight, delayed physical development such as pinna detachment, hair growth, eruption of incisor teeth, eye and vaginal openings. These pups also showed a delay of palmar grasp, surface righting reflex, negative geotaxis and auditory startle reflexes. Thus, prenatal exposure to integerrimine N-oxide induces maternal toxicity, impairment of maternal care and delayed in physical and behavioral development of the offspring.

Prenatal lipopolysaccharide disrupts maternal behavior, reduces nest odor preference in pups, and induces anxiety: studies of F1 and F2 generations.

The present study analyzed the transgenerational effects of lipopolysaccharide (LPS; 100 µg/kg) administration on gestational day 18 (GD18) of parental generation on maternal-pups interaction of F1 and F2 generations. Also the long term behavioral effects were observed in male of F2 generation. In F1 generation, the reproductive performance, maternal behavior, maternal aggressive behavior, and general activity in the open field in adulthood were analyzed. In F2 generation, body weight at birth and at weaning, nest odor preference, and general activity in the open field and elevated plus maze in adulthood were assessed. Compared to controls, results showed that in the F1 generation, prenatal LPS exposure (1) increased the latency to full maternal behavior, but all of the females grouped the pups and presented full maternal behavior, (2) reduced the total time boxing and fighting, increased the frequency of retrieving the pups, and increased the number of bites, and (3) did not affect reproductive performance or general activity. In F2 generation, compared with controls, the LPS group exhibited (1) a decrease in body weight at weaning, (2) a decrease in nest odor preference, (3) a decrease in the percentage of time spent in the open arms, a decrease in the percentage of time spent in the center, and an increase in the time spent in the closed arms in the elevated plus maze, and (Huang et al.) no affect behavior in the open field. Prenatal LPS exposure improved maternal care in the F1 generation with regard to nursing and pup survival but did not improve the motivational parameters of maternal behavior likely because of a reduction of maternal stimulation by the pups. In the F2 generation, the reduction of nest odor preference in the pups suggests a less maternal recognition. In adulthood, these rats exhibited increased anxiety-like behavior. These data did not result from motor alterations because rats in both the F1 and F2 generations did not show alterations in open field behavior. This transfer of information across generations likely occurred through nongenetic means because the endotoxin was administered at the end of pregnancy. These results may have implications for clinical therapeutics in human disorders and evolution.