Neurotoxicology and teratology最新文献

The assessment of the sensitivity and specificity of any potential biomarker against the gold standard is an important step in the process of its qualification by regulatory authorities. Such qualification is an important step towards incorporating the biomarker into the panel of tools available for drug development. In the current study we analyzed the sensitivity and specificity of T₂ MRI relaxometry to detect trimethyltin-induced neurotoxicity in rats. Seventy-five male Sprague-Dawley rats were injected with a single intraperitoneal dose of either TMT (8, 10, 11, or 12 mg/kg) or saline (2 ml/kg) and imaged with 7 T MRI before and 3, 7, 14, and 21 days after injection using a quantitative T₂ mapping. Neurohistopathology (the gold standard in the case of neurotoxicity) was performed at the end of the observation and used as an outcome qualifier in receiver-operator characteristic (ROC) curve analysis of T₂ changes as a predictor of neurotoxicity. TMT treatment led to a significant increase in T₂ values in many brain areas. The biggest changes in T₂ values were seen around the lateral ventricles, which was interpreted as ventricular dilation. The area under the ROC curve for the volume of the lateral ventricles was 0.878 with the optimal sensitivity/specificity of 0.805/0.933, respectively. T₂ MRI is a promising method for generating a non-invasive biomarkers of neurotoxicity, which shows the dose-response behavior with substantial sensitivity and specificity. While its performance was strong in the TMT model, further characterization of the sensitivity and specificity of T₂ MRI with other neurotoxicants is warranted.

Aim

To describe the neurodevelopmental phenotype of older children and adults with a diagnosis of Fetal Valproate Spectrum Disorder (FVSD).

Methods

In this cross-sectional study, 90 caregivers were recruited and completed a series of questionnaires regarding the neurodevelopmental outcomes of 146 individuals aged 7–37 years (M = 18.1), including individuals with a formal diagnosis of FVSD (n = 99), individuals exposed to Valproate but without an FVSD diagnosis (n = 24), and individuals not exposed to Valproate (N = 23). The mean dose of valproate exposure for individuals with an FVSD diagnosis was 1470 mg/day.

Results

Individuals with a diagnosis of FVSD showed significantly higher levels of moderate (43.4%) and severe (14.4%) cognitive impairment than other groups (p = 0.003), high levels of required formal educational support (77.6%), and poorer academic competence than individuals not exposed to Valproate (p = 0.001). Overall psychosocial problems (p = 0.02), internalising problems (p = 0.05) and attention problems (p = 0.001), but not externalising problems, were elevated in individuals with a diagnosis of FVSD. Rates of neurodevelopmental disorders, particularly autistic spectrum disorders (62.9%) and sensory problems (80.6%) are particularly central to the FVSD phenotype. There was no evidence of a statistical dose-dependent effect, possibly due to the high mean dose of exposure having a uniformly negative impact across the sample. Individuals with FVSD had required a significant number of health and child development services.

Interpretation

Children and young adults with a diagnosis of FVSD are at an increased risk of a range of altered neurodevelopmental outcomes, highlighting the need for a multidisciplinary approach to clinical management across the lifespan.

Paracetamol (PAR) is an over-the-counter analgesic/antipyretic used during pregnancy worldwide. Epidemiological studies have been associating gestational PAR exposure with neurobehavioral alterations in the progeny resembling autism spectrum disorders and attention-deficit hyperactivity disorder symptoms. The endocannabinoid (eCB) dysfunction was previously hypothesized as one of the modes of action by which PAR may harm the developing nervous system. We aimed to evaluate possible effects of gestational exposure to PAR on male and female rat's offspring behavior and if an acute injection of WIN 55,212–2 (WIN, 0.3 mg/kg), a non-specific cannabinoid agonist, prior to behavioral tests, would induce different effects in PAR exposed and non-exposed animals. Pregnant Wistar rats were gavaged with PAR (350 mg/kg/day) or water from gestational day 6 until delivery. Nest-seeking, open field, apomorphine-induced stereotypy, marble burying and three-chamber tests were conducted in 10-, 24-, 25- or 30-days-old rats, respectively. PAR exposure resulted in increased apomorphine-induced stereotyped behavior and time spent in the central area of the open field in exposed female pups. Additionally, it induced hyperactivity in the open field and increased marble burying behavior in both male and female pups. WIN injection modified the behavioral response only in the nest seeking test, and opposite effects were observed in control and PAR-exposed neonate females. Reported alterations are relevant for the neurodevelopmental disorders that have been associated with maternal PAR exposure and suggest that eCB dysfunction may play a role in the action by which PAR may harm the developing brain.

Humans are exposed to phthalates, a class of endocrine-disrupting chemicals used in food packaging/processing, PVC plastics, and personal care products. Gestational exposure may lead to adverse neurodevelopmental outcomes. In a rat model, perinatal exposure to an environmentally relevant mixture and dose of phthalates leads to increased developmental apoptosis in the medial prefrontal cortex (mPFC) and a subsequent reduction in neurons and in cognitive flexibility measured in adults of both sexes (Sellinger et al., 2021b; Kougias et al., 2018b). However, whether these effects generalize to other cognitive regions, like the hippocampus, is less well understood as existing studies used single phthalates at large doses, unrepresentative of human exposure. In the current study, patterns of naturally occurring cell death were first established in the dorsal and ventral hippocampal subfields (CA3 and CA1). Both dorsal and ventral CA3 reached high levels of cell death on P2 while levels in dorsal and ventral CA1 peaked on P5 in both sexes. Exposure to a phthalate mixture (0.2 and 1 mg/kg/day) throughout gestation through postnatal day 10 resulted in subtle age- and region-specific decreases in developmental cell death, however there were no significant changes in adult neuron number or associated behaviors: the Morris water maze and social recognition. Therefore, perinatal exposure to a low dose mixture of phthalates does not result in the dramatic structural and behavioral changes seen with high doses of single phthalates. This study also adds to our understanding of the distinct neurodevelopmental effects of phthalates on different brain regions.

Valproic acid (VPA) is an anti-epileptic medication that increases the risk of neural tube defect (NTD) outcomes in infants exposed during gestation. Previous studies into VPA's mechanism of action have focused on alterations in gene expression and metabolism but have failed to consider how exposure changes the abundance of critical developmental proteins over time. This study evaluates the effects of VPA on protein abundance in the developmentally distinct tissues of the mouse visceral yolk sac (VYS) and embryo proper (EMB) using mouse whole embryo culture. Embryos were exposed to 600 μM VPA at 2 h intervals over 10 h during early organogenesis with the aim of identifying protein pathways relevant to VPA's mechanism of action in failed NTC. Protein abundance was measured through tandem mass tag (TMT) labeling followed by liquid chromatography and mass spectrometry. Overall, there were over 1500 proteins with altered abundance after VPA exposure in the EMB or VYS with 428 of these proteins showing previous gene expression associations with VPA exposure. Limited overlap of significant proteins between tissues supported the conclusion of independent roles for the VYS and EMB in response to VPA. Pathway analysis of proteins with increased or decreased abundance identified multiple pathways with mechanistic relevance to NTC and embryonic development including convergent extension, Wnt Signaling/planar cell polarity, cellular migration, cellular proliferation, cell death, and cytoskeletal organization processes as targets of VPA. Clustering of co-regulated proteins to identify shared patterns of protein abundance over time highlighted 4 h and 6/10 h as periods of divergent protein abundance between control and VPA-treated samples in the VYS and EMB, respectively. Overall, this study demonstrated that VPA temporally alters protein content in critical developmental pathways in the VYS and the EMB during early organogenesis in mice.

Introduction

Many studies have examined changes in marijuana use across adolescence, but few have examined factors associated with transitions from adolescence to young adulthood. We examined prenatal exposures to alcohol and marijuana and adolescent risk and protective factors that best distinguished among abstinence, continuity, or cessation of marijuana use from 16 to 22 years.

Method

Data were from the Maternal Health Practices and Child Development Project at the prenatal and 16- and 22-year follow-up phases. The offspring were of lower socioeconomic status with an average of 12.8 years of education at 22 years. Participants' frequency and quantity of marijuana use over the past year were used to determine change in use. A discriminant analysis was applied to distinguish among the identified groups. The risk factors considered included prenatal substance exposures and age 16 demographics, behavior, and home environment.

Result

Four categories of transitions were defined based on marijuana use from 16 to 22 years: non-users (n = 193), stop/decrease (n = 81), continue at same level/increase (n = 125), and initiation after the 16-year phase (n = 122). The factors that best distinguished among these groups were peers' marijuana use, delinquency, caregivers' financial strain, prenatal exposure to alcohol and marijuana, and race.

Conclusion

Prenatal alcohol and marijuana exposure were significantly related to transitions of marijuana use from adolescence to young adulthood, controlling for peers' use, behavior problems, and home environment. While gestational marijuana exposure was associated with early initiation/increasing use, alcohol exposure was related to later initiation. The findings emphasize the long-term effects of prenatal exposure to alcohol and marijuana.

Background

Exposure to perfluoroalkyl substances (PFAS) has been shown to be neurotoxic in experimental studies, but epidemiological evidence linking prenatal PFAS exposure to child neurodevelopment is equivocal and scarce.

Objective

To quantify associations between prenatal exposure to legacy PFAS and children's intelligence (IQ) and executive functioning (EF) in a Canadian pregnancy and birth cohort and to determine if these associations differ by child sex.

Methods

We measured first-trimester plasma concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) in the Maternal-Infant Research on Environmental Chemicals (MIREC) study and assessed children's full-scale (n = 522), performance (n = 517), and verbal (n = 519) IQ using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Children's working memory (n = 513) and ability to plan and organize (n = 514) were assessed using a parent-reported questionnaire, the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P). We quantified associations between individual log2-transformed PFAS exposure and children's IQ and EF using multiple linear regression analyses and evaluated effect modification by child sex. We also used Repeated Holdout Weighted Quantile Sum (WQS) regression models with effect modification by child sex to quantify the effect of combined exposure to all three PFAS chemicals on IQ and EF. All models were adjusted for key sociodemographic characteristics.

Results

Geometric mean plasma concentrations (IQR) for PFOA, PFOS and PFHxS were 1.68 (1.10–2.50), 4.97 (3.20–6.20) and 1.09 (0.67–1.60) μg/L respectively. We found evidence of effect modification by child sex in all models examining performance IQ (p < .01). Specifically, every doubling of PFOA, PFOS, and or PFHxS was inversely associated with performance IQ, but only in males (PFOA: B = −2.80, 95% CI: −4.92, −0.68; PFOS: B = −2.64, 95% CI: −4.77, −0.52; PFHxS: B = −2.92, 95% CI: −4.72, −1.12). Similarly, every quartile increase in the WQS index was associated with poorer performance IQ in males (B = −3.16, 95% CI: −4.90, −1.43), with PFHxS contributing the largest weight to the index. In contrast, no significant association was found for females (B = 0.63, 95% CI: −0.99, 2.26). No significant associations were found for EF in either males or females.

Conclusions

Higher prenatal PFAS exposure was associated with lower performance IQ in males, suggesting that this association may be sex- and domain-specific.