Neurotoxicology and teratology最新文献

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.