Neurotoxicology and teratology最新文献

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.

Prenatal exposure to alcohol or cannabinoids can produce enduring neurobiological, cognitive, and behavioral changes in the offspring. Furthermore, prenatal co-exposure to alcohol and cannabinoids induces malformations in brain regions associated with reward and stress-related circuitry. This study examined the effects of co-exposure to alcohol and the synthetic cannabinoid (SCB) CP55,940 throughout gastrulation and neurulation in rats on basal corticosterone levels and a battery of behavioral tests during adolescence and alcohol self-administration in adulthood. Importantly, we find that prenatal alcohol exposure (PAE) caused lower baseline corticosterone levels in adolescent males and females. Co-exposure to alcohol + CP produced hyperactivity during open field test in males, but not females. During the two-bottle choice alcohol-drinking procedure, prenatal cannabinoid exposed male and female adolescent rats drank more alcohol than their vehicle-exposed controls. In adulthood, female rats treated with prenatal cannabinoid exposure (PCE), showed an overall total increase in alcohol intake during alcohol self-administration; but this was not found in males. When the reinforcer was changed to a 1% sucrose solution, male rats exposed to PCE, showed a reduced self-administration compared to vehicle-exposed males, potentially indicative of an anhedonic response. This lower self-administration persisted when 20% alcohol was reintroduced to the sucrose solution. Lastly, following an abstinence period, there were no changes due to prenatal drug exposure in either males or females. Overall, these data suggest lasting consequences of prenatal alcohol and cannabinoid exposure during adolescence and adulthood in male and female rats.

Studies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Maternal choline supplementation (MCS) during pregnancy/lactation may hold promise as a protective strategy because it has been shown to lessen cognitive dysfunction caused by numerous early insults. Our objectives were to determine whether (1) developmental Mn exposure alters behavioral reactivity/emotion regulation, in addition to impairing learning, attention, impulse control, and sensorimotor function, and (2) MCS protects against these Mn-induced impairments. Pregnant Long-Evans rats were given standard diet, or a diet supplemented with additional choline throughout gestation and lactation (GD 3 - PND 21). Male offspring were exposed orally to 0 or 50 mg Mn/kg/day over PND 1–21. In adulthood, animals were tested in a series of learning, attention, impulse control, and sensorimotor tasks. Mn exposure caused lasting dysfunction in attention, reactivity to errors and reward omission, learning, and sensorimotor function, recapitulating the constellation of symptoms seen in ADHD children. MCS lessened Mn-induced attentional dysfunction and partially normalized reactivity to committing an error or not receiving an expected reward but provided no protection against Mn-induced learning or sensorimotor dysfunction. In the absence of Mn exposure, MCS produces lasting offspring benefits in learning, attention, and reactivity to errors. To conclude, developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology, and MCS offered some protection against the adverse Mn effects, adding to the evidence that maternal choline supplementation is neuroprotective for offspring and improves offspring cognitive functioning.

Objective

To examine the association between prenatal cannabis use and structural birth defects in exposed offspring.

Methods

In line with the preregistered protocol (PROSPERO: CRD42022368623), we systematically searched PubMed/Medline, CINHAL, EMBASE, Web of Science, ProQuest, Psych-Info, and Google Scholar for published articles until 25 January 2024. The methodological quality of the included studies was appraised by the Newcastle-Ottawa Quality Assessment Scale (NOS). A meta-analysis was carried out to report the pooled effect estimates from the included studies. We further performed subgroup, leave-one-out sensitivity, and meta-regression analyses, which increased the robustness of our findings.

Results

In this cumulative meta-analysis, thirty-six observational studies, consisting of 18 case-control and 18 cohort studies, with 230, 816 cases of birth defects and 18,049,013 controls (healthy babies) were included in the final analysis. We found that offspring exposed to maternal prenatal cannabis are at greater risks of a wide range of structural birth defects: cardiovascular/heart [OR = 2.35: 95 % CI 1.63 – 3.39], gastrointestinal [OR = 2.42: 95 % CI 1.61 – 3.64], central nervous system [OR = 2.87: 95 % CI 1.51 – 5.46], genitourinary [OR = 2.39: 95 % CI 1.11 – 5.17], and any (unclassified) birth defects [OR = 1.25: 95 % CI 1.12 – 1.41].

Conclusion

The findings from the current study suggest that maternal prenatal cannabis exposure is associated with a higher risk of different forms of structural birth defects in offspring. The findings underscore the significance of implementing preventive strategies, including enhanced preconception counselling, to address cannabis use during pregnancy and mitigate the risk of birth defects in offspring.

Microglial cells mediate diverse homeostatic, inflammatory, and immune processes during normal development and in response to cytotoxic challenges. During these functional activities, microglial cells undergo distinct numerical and morphological changes in different tissue volumes in both rodent and human brains. However, it remains unclear how these cytostructural changes in microglia correlate with region-specific neurochemical functions. To better understand these relationships, neuroscientists need accurate, reproducible, and efficient methods for quantifying microglial cell number and morphologies in histological sections. To address this deficit, we developed a novel deep learning (DL)-based classification, stereology approach that links the appearance of Iba1 immunostained microglial cells at low magnification (20×) with the total number of cells in the same brain region based on unbiased stereology counts as ground truth. Once DL models are trained, total microglial cell numbers in specific regions of interest can be estimated and treatment groups predicted in a high-throughput manner (<1 min) using only low-power images from test cases, without the need for time and labor-intensive stereology counts or morphology ratings in test cases. Results for this DL-based automatic stereology approach on two datasets (total 39 mouse brains) showed >90% accuracy, 100% percent repeatability (Test-Retest) and 60× greater efficiency than manual stereology (<1 min vs. ∼ 60 min) using the same tissue sections. Ongoing and future work includes use of this DL-based approach to establish clear neurodegeneration profiles in age-related human neurological diseases and related animal models.

This is a report from the most recent adult follow-up of the longest running cohort study of prenatal cocaine exposure (PCE), in which women were enrolled prenatally and offspring were assessed in infancy, childhood, adolescence, and young adulthood. In previous studies, PCE was linked to offspring behavior problems such as early substance use and externalizing behavior problems. The current analyses examine pathways from PCE to behavioral outcomes in offspring at the 25-year assessment. Prenatal cocaine exposure was moderate in this cohort; most women decreased or discontinued use after the first trimester. During the first and third trimesters, 38% and 11% used cocaine, respectively. This represents the most common pattern of PCE in non-treatment samples. At this phase, the adult offspring were, on average, 27.3 years old (range = 25–30), had 13.4 years of education, 83% were employed, 55% were Black, and 55% were female. Offspring who were exposed to cocaine during the first trimester were significantly more likely to use marijuana in the past year, report more arrests, and have poorer scores on a decision-making task, controlling for other prenatal substance exposure, demographic, and socioeconomic factors. In mediation analyses, there were indirect pathways from PCE to current marijuana use through early initiation of marijuana use and 21-year marijuana use, and through 15-year status offenses and 21-year marijuana use. There was also an indirect pathway from PCE to lifetime arrests through early initiation of marijuana use and 21-year Conduct Disorder, although the direct pathway from PCE to arrests also remained significant. These findings are consistent with those from previous phases and are an indication that there are detrimental associations with PCE that persist across developmental stages and into adulthood.

Background

Research reveals small and inconsistent findings linking prenatal tobacco exposure and early fetal growth, but failure to consider confounding and amount of exposure many explain inconsistencies.

Goal

To examine whether fetal growth effects following exposure to tobacco are evident in the second trimester, specific to certain growth parameters, and dose dependent.

Methods

Participants were pregnant women (64 smokers, 100 controls) with no other drug use. Available data included background/medical information and ultrasound measurements coded as percentiles.

Results

Controlling for background differences, 10+ cig/day predicted a 10+ percentile point reduction in estimated fetal weight, femur length, head circumference, and biparietal diameter compared to non-exposed controls. Exposure to <10 cig/day predicted significant reduction in only biparietal diameter. Exposure was unrelated to abdominal circumference.

Conclusions

Results demonstrate utility of considering amount of exposure when examining/quantifying fetal growth effects, and suggest even reduction in early pregnancy smoking may positively benefit aspects of fetal development.