Neurotoxicology and teratology最新文献

Alcohol use, which alters the epigenome, increases the probability that it could affect subsequent generations, even if they were never directly exposed to ethanol or even in utero.

We explored the effects of parental ethanol exposure before conception on behavioral changes in the offspring. Considering the role of Monoamine oxidase-B (MAO-B) in dopamine turnover in the prefrontal cortex (PFC) and its influence on behavior, and taking into account that ethanol exposure could alter MAO-B, we assessed the protein levels in the offspring.

Male and female rats were exposed to ethanol for 30 days and then allowed ten days of abstinence. Afterward, they were mated with either control or ethanol-exposed rats. The F1 and F2 male offspring underwent tests to assess behavioral changes. Additionally, the levels of MAO-B in the PFC were evaluated.

Results revealed that in the F1, anxiety increased only in the bi-parental ethanol-exposed male offspring in the elevated plus maze test (p < 0.05), while depressive-like behavior rose only in maternal and bi-parental ethanol-exposed offspring (p < 0.01). However, compulsive-like behavior increased in all ethanol-exposed offspring (p < 0.01). No significant phenotypic changes were observed in the F2. The levels of MAO-B in the PFC increased in the maternal (p < 0.05) and bi-parental ethanol-exposed offspring (p < 0.01).

Our study demonstrates that parental ethanol exposure, even in the days preceding mating, adversely affects behaviors and induces molecular changes in the brain. Given these findings, it becomes imperative to monitor children exposed to parental (especially maternal) ethanol for the prevention of mental disorders.

Developmental stress, including low socioeconomic status (SES), can induce dysregulation of the hypothalamic-pituitary-adrenal axis and result in long-term changes in stress reactivity. Children in lower SES conditions often experience more stress than those in other SES groups. There are multiple model systems of early environmental stress (EES), one of which is reduced cage bedding. Here we tested the effects of both prenatal and lactational EES in rats on a range of long-term behavioral and cognitive outcomes. There were persistent reductions in body weight in the EES rats in both sexes. The behavioral results showed no effects on learning and memory using tests of spatial learning or cognitive flexibility in the Morris water maze, egocentric learning in the Cincinnati water maze, or working memory in the radial-arm maze. There were no effects on basic open-field activity, elevated zero-maze, or forced swim test, but EES rats had reduced time in the dark side of the light/dark test. When rats were drug challenged in the open-field with d-amphetamine or MK-801, there were no differential responses to d-amphetamine, but the EES group under responded compared with the drug-induced hyperactivity in the control group in both males and females. The objective was to establish a developmental stress model that induced cognitive deficits and to the extent that this method did not cause such effects it was not the model we sought. However, the data showed several long-term effects of EES, including the reduced response to the irreversible NMDA antagonist MK-801. This effect merits further investigation.

Background

Psychosocial stress and psychopathology frequently co-occur, with patterns differing by race and ethnicity. We used statistical mixtures methodology to examine associations between prenatal stress and child temperament in N = 382 racially and ethnically diverse maternal-child dyads to disentangle associations among maternal stressful life events, maternal psychological functioning in pregnancy, childhood neurobehavior, and maternal race and ethnicity.

Methods

This study utilized data from a longitudinal pregnancy cohort, PRogramming of Intergenerational Stress Mechanisms (PRISM). Mothers completed the Lifetime Stressor Checklist-Revised, Edinburgh Postnatal Depression Scale, and Spielberger State-Trait Anxiety Scale during pregnancy. When their children were 3–5 years of age, they completed the Children's Behavior Questionnaire, which yields three temperament dimensions: Negative Affectivity (NA), Effortful Control (EC), and Surgency (S). We used weighted quantile sum regression to derive a weighted maternal stress index encompassing lifetime stress and depression and anxiety symptoms and examined associations between the resulting stress index and child temperament. Differential contributions of individual stress domains by race and ethnicity also were examined.

Results

Mothers self-identified as Black/Black Hispanic (46.1 %), non-Black Hispanic (31.9 %), or non-Hispanic White (22 %). A higher maternal stress index was significantly associated with increased child NA (β = 0.72 95 % CI = 0.35, 1.10). Lifetime stress was the strongest contributor among Hispanic (36.7 %) and White (17.8 %) mothers, whereas depressive symptoms in pregnancy was the strongest contributor among Black (16.7 %) mothers.

Conclusion

Prenatal stress was most strongly associated with negative affectivity in early childhood. Consideration of multiple stress measures as a mixture accounted for differential contributions of individual stress domains by maternal race and ethnicity. These findings may help elucidate the etiology of racial/ethnic disparities in childhood neurobehavior.

Aversive caregiving in early life is a risk factor for aberrant brain and behavioral development. This outcome is related to epigenetic dysregulation of the brain-derived neurotrophic factor (Bdnf) gene. The Bdnf gene encodes for BDNF, a neurotrophin involved in early brain development, neural plasticity, learning, and memory. Recent work suggests that exercise may be neuroprotective in part by supporting BDNF protein and gene expression, making it an exciting target for therapeutic interventions. To our knowledge, exercise has never been studied as a therapeutic intervention in preclinical rodent models of caregiver maltreatment. To that end, the current study investigated the effect of an adult voluntary wheel running intervention on Bdnf methylation and expression in the prefrontal cortex of rats who experienced aversive caregiving in infancy. We employed a rodent model (Long Evans rats) wherein rat pups experienced intermittent caregiver-induced stress from postnatal days 1–7 and were given voluntary access to a running wheel (except in the control condition) from postnatal days 70–90 as a young adulthood treatment intervention. Our results indicate that maltreatment and exercise affect Bdnf gene methylation in an exon, CG site, and sex-specific manner. Here we add to a growing body of evidence of the ability for our experiences, including exercise, to permeate the brain. Keywords: Early life stress, Bdnf, exercise, prefrontal cortex.

Background

Organophosphates and pyrethroids are two major groups of insecticides used for crop protection worldwide. They are neurotoxicants and exposure during vulnerable windows of brain development may have long-term impact on human neurodevelopment. Only few longitudinal studies have investigated associations between prenatal exposure to these substances and intelligence quotient (IQ) at school age in populations with low, mainly dietary, exposure.

Objective

To investigate associations between maternal urinary concentrations of insecticide metabolites at gestational week 28 and IQ in offspring at 7-years of age.

Materials and methods

Data was derived from the Odense Child Cohort (OCC). Metabolites of chlorpyrifos (TCPy) and pyrethroids (3-PBA, cis- and trans-DCCA, 4-F-3PBA, cis-DBCA) were measured in maternal urine collected at gestational week (GW) 28. An abbreviated version of the Danish Wechsler Intelligence Scale for Children fifth edition (WISC-V) consisting of four subtests to estimate full scale IQ (FSIQ) was administered by trained psychologists. Data were analyzed by use of multiple linear regression and adjusted for confounders.

Results

812 mother/child-pairs were included. Median concentrations were 0.21 μg/L for 3-PBA, 1.67 μg/L for TCPy and the mean IQ for children were 99.4. Null association between maternal 3-PBA and child IQ at 7 years was seen, but with trends suggesting an inverse association. There was a significant association for maternal TCPy and child IQ at mid-level exposure. Trans-DCCA above the level of detection (LOD) was also associated with slightly lower child IQ, but the association was also not statistically significant.

Conclusions

We found no significant associations between maternal 3-PBA metabolites and child IQ at 7 years, but with trends suggesting an inverse association. A non-significant trend between maternal TCPy exposure and child IQ in 7-year-children was seen even in this low exposed population. Given the widespread exposure and increasing use of insecticides, this should be elaborated in future studies.

Bisphenol F (BPF) and Bisphenol S (BPS) are being widely used by the industry with the claim of “safer substances”, even with the scarcity of toxicological studies. Given the etiological gap of autism spectrum disorder (ASD), the environment may be a causal factor, so we investigated whether exposure to BPF and BPS during the developmental period can induce ASD-like modeling in adult flies. Drosophila melanogaster flies were exposed during development (embryonic and larval period) to concentrations of 0.25, 0.5, and 1 mM of BPF and BPS, separately inserted into the food. When they transformed into pupae were transferred to a standard diet, ensuring that the flies (adult stage) did not have contact with bisphenols. Thus, after hatching, consolidated behavioral tests were carried out for studies with ASD-type models in flies. It was observed that 1 mM BPF and BPS caused hyperactivity (evidenced by open-field test, negative geotaxis, increased aggressiveness and reproduction of repetitive behaviors). The flies belonging to the 1 mM groups of BPF and BPS also showed reduced cognitive capacity, elucidated by the learning behavior through aversive stimulus. Within the population dynamics that flies exposed to 1 mM BPF and 0.5 and 1 mM BPS showed a change in social interaction, remaining more distant from each other. Exposure to 1 mM BPF, 0.5 and 1 mM BPS increased brain size and reduced Shank immunoreactivity of adult flies. These findings complement each other and show that exposure to BPF and BPS during the development period can elucidate a model with endophenotypes similar to ASD in adult flies. Furthermore, when analyzing comparatively, BPS demonstrated a greater potential for damage when compared to BPF. Therefore, in general these data sets contradict the idea that these substances can be used freely.

Developmental exposure to either polycyclic aromatic hydrocarbons (PAHs) or heavy metals has been shown to cause persisting and overlapping neurobehavioral effects in animal models. However, interactions between these compounds have not been well characterized, despite their co-occurrence in a variety of environmental media. In two companion studies, we examined the effects of developmental exposure to cadmium (Cd) with or without co-exposure to prototypic PAHs benzo[a]pyrene (BaP, Exp. 1) or fluoranthene (FA, Exp. 2) using a developing zebrafish model. Zebrafish embryos were exposed to Cd (0–0.3 μM), BaP (0–3 μM), FA (0–1.0 μM), or binary Cd-PAH mixtures from 5 to 122 h post fertilization (hpf). In Exp. 1, Cd and BaP produced independent effects on an array of outcomes and interacting effects on specific outcomes. Notably, Cd-induced deficits in dark-induced locomotor stimulation were attenuated by BaP co-exposure in the larval motility test and BaP-induced hyperactivity was attenuated by Cd co-exposure in the adolescent novel tank test. Likewise, in Exp. 2, Cd and FA produced both independent and interacting effects. FA-induced increases on adult post-tap activity in the tap startle test were attenuated by co-exposure with Cd. On the predator avoidance test, FA- and 0.3 μM Cd-induced hyperactivity effects were attenuated by their co-exposure. Taken together, these data indicate that while the effects of Cd and these representative PAHs on zebrafish behavior were largely independent of one another, binary mixtures can produce sub-additive effects for some neurobehavioral outcomes and at certain ages. This research emphasizes the need for detailed risk assessments of mixtures containing contaminants of differing classes, and for clarity on the mechanisms which allow cross-class toxicant interactions to occur.