Reconstructing hepatic metabolic profile and glutathione-mediated metabolic fate of acrylamide.

The toxicity of acrylamide (AA) has continuously attracted wide concerns as its extensive presence from both environmental and dietary sources. However, its hepatic metabolic transformation and metabolic fate still remain unclear. This study aims to unravel the metabolic profile and glutathione (GSH) mediated metabolic fate of AA in liver of rats under the dose-dependent exposure. We found that exposure to AA dose-dependently alters the binding of AA and GSH and the generation of mercapturic acid adducts, while liver as a target tissue bears the metabolic transformation of AA via regulating GSH synthesis and consumption pathways, in which glutamine synthase (GSS), cytochrome P450 2E1 (CYP2E1), and glutathione S-transferase P1 (GSTP1) play a key role. In response to high- and low-dose exposures to AA, there were significant differences in liver of rats, including the changes in GSH and cysteine (CYS) activities and the conversion ratio of AA to glycidamide (GA), and liver can affect the transformation of AA by regulating the GSH-mediated metabolic pathway. Low-dose exposure to AA activates GSH synthesis pathway in liver and upregulates GSS activity and CYS content with no change in γ-glutamyl transpeptidase 1 (GGT1) activity. High-dose exposure to AA activates the detoxification pathway of GSH and increases GSH consumption by upregulating GSTP1 activity. In addition, molecular docking results showed that most of the metabolic molecules transformed by AA and GA other than themselves can closely bind to GSTP1, GSS, GGT1, N-acetyltransferase 8, and dimethyl sulfide dehydrogenase 1. The binding of AA-GSH and GA-GSH to GSTP1 and CYP2E1 enzymes determine the tendentiousness between toxicity and detoxification of AA, which exerts a prospective avenue for targeting protective role of hepatic enzymes against in vivo toxicity of AA.

Physiologically-based toxicokinetic model for the prediction of perchlorate distribution and its application.

Perchlorate is a stable and readily transportable thyroid hormone disruptor, and prevalent exposure to perchlorate through food and drinking water has raised public concern about its health effects. The physiologically based toxicokinetic (PBTK) model as a dose prediction method is effective to predict the toxicant exposure dose of an organism and helps quantitatively assess the dose-dependent relationship with toxic effects. The current study aimed to establish a multi-compartment PBTK model based on updated time-course datasets of single oral exposure to perchlorate in rats. With adjustment of the kinetic parameters, the model fitted well the toxicokinetic characteristics of perchlorate in urine, blood, and thyroid from our experiments and the literature, and the coefficient of determination (R2) between the fitting values and the experimental data in regression analysis was greater than 0.91, indicating the robustness of the current model. The results of sensitivity analysis and daily repeated exposure simulations together confirmed its effective renal clearance. According to the distribution characteristic of perchlorate, a correlation study of internal and external exposure was conducted using urinary perchlorate as a bioassay indicator. The developed multi-compartment model for perchlorate updates important toxicokinetic data and kinetic parameters, providing analytical and modeling tools for deriving total exposure levels in the short term.

Development of physiologically based toxicokinetic models for 3-monochloropropane-1,2-diol and glycidol.

3-Monochloropropane-1,2-diol (3-MCPD), glycidol, together with their fatty acid esters are commonly presented in various food and have shown carcinogenicity in various laboratory animals. Public health risk assessment of 3-MPCD and glycidol exposure relies on quantitative tools that represent their in vivo toxicokinetics. In order to better understand the absorption, distribution, metabolism, and excretion profiles of 3-MCPD and glycidol in male rats, a physiologically based pharmacokinetic (PBTK) model was developed. The model's predictive power was evaluated by comparing in silico simulations to in vivo time course data obtained from experimental studies. Results indicate that our PBTK model successfully captured the toxicokinetics of both free chemicals in key organs, and their metabolites in accessible biological fluids. With the validated PBTK model, we then gave an animal-free example on how to extrapolate the toxicological knowledge acquired from a single gavage to a realistic dietary intake scenario. Three biomarkers, free compound in serum, urinary metabolite DHPMA, and glycidol-hemoglobin adduct (diHOPrVal) were selected for in silico simulation following constant dietary intakes, and their internal levels were correlated with proposed external daily exposure via reverse dosimetry approaches. Taken together, our model provides a computational approach for extrapolating animal toxicokinetic experiments to biomonitoring measurement and risk assessment.

Structural Characterization of Polysaccharides in Waste Liquor Produced by Wet Decortication of Sesame Seeds.

The wet decortication of sesame seeds produces wastewater containing diverse minerals and organic pollutants that could be valuable resources for the food industry. This investigation aimed to reclaim, purify, and characterize the polysaccharides contained in the waste liquor from the sesame decortication industry. The purified polysaccharide fractions were characterized using monosaccharide analysis, GPC (high-performance gel permeation chromatography), FT-IR (Fourier-transform infrared) spectroscopy, methylation analysis, 1D and 2D Nucleai Magnetic Resonance (NMR) analysis, and thermal analysis. Four fractions were found (SSP-1,-2,-3, -4), of which SSP-2 was proportionately the largest and most interesting. The backbone of SSP-2 is mainly composed of (1→2,4)-ß-D-Xylp residues with side chains connected to the O-4 position, with many T-ß-D-Galp and (1→5)-α-L-Araf residues, and fewer (1→4)-α-D-Glcp, (1→2)-α-L-Rhap, T-α-L-Araf, and (1→2)-ß-D-GlcpA residues. An efficient method for removing the polysaccharides would simplify wastewater treatment while finding a use for them would benefit the sesame, food, and pharmaceutical industries.

Comprehensive profile of DNA adducts as both tissue and urinary biomarkers of exposure to acrylamide and chemo-preventive effect of catechins in rats.

Two representative DNA adducts from acrylamide exposure, N7-(2-carbamoyl-2-hydroxyethyl) guanine (N7-GA-Gua) and N3-(2-carbamoyl-2-hydroxyethyl) adenine (N3-GA-Ade), are important long-term exposure biomarkers for evaluating genotoxicity of acrylamide. Catechins as natural antioxidants present in tea possess multiple health benefits, and may also have the potential to protect against acrylamide-induced DNA damage. The current study developed an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous analysis of N7-GA-Gua and N3-GA-Ade in tissues and urine. The validated UHPLC-MS/MS method showed high sensitivity, with limit of detection and limit of quantification ranging 0.2-0.8 and 0.5-1.5 ng/mL, respectively, and achieved qualified precision (RSD<14.0%) and spiking recovery (87.2%-110.0%) with elution within 6 min, which was suitable for the analysis of the two DNA adducts in different matrices. The levels of N7-GA-Gua and N3-GA-Ade ranged 0.9-11.9 and 0.6-3.5 µg/g creatinine in human urine samples, respectively. To investigate the interventional effects of catechins on the two DNA adducts from acrylamide exposure, rats were supplemented with three types of catechins (tea polyphenols, epigallocatechin gallate, and epicatechin) 30 min before administration with acrylamide. Our results showed that catechins effectively inhibited the formation of DNA adducts from acrylamide exposure in both urine and tissues of rats. Among three catechins, epicatechin performed the best inhibitory effect. The current study provided evidence for the chemo-preventive effect of catechins, indicating that dietary supplement of catechins may contribute to health protection against exposure to acrylamide.

The construction and application of physiologically based toxicokinetic models for acrylamide, glycidamide and their biomarkers in rats and humans.

Acrylamide (AA), a class 2A probable carcinogen to humans classified by the International Agency for Research on Cancer, has attracted extensive attention worldwide since it was widely used in industrial and domestic water treatment and detected in thermal processing foods. The metabolic adducts of AA and its primary metabolite glycidamide (GA) have been served as biomonitoring markers of AA intake, but the physiologically based toxicokinetics (PBTK) models to estimate internal dosimetry still remain unclear. An updated PBTK model for AA, GA and their metabolic biomarkers in rats and humans was developed and extended with time-course datasets from both literatures and our experiments. With adjustments to the model parameters, linear regression correlation coefficient (R2) between the fitting values and the validation datasets of rats and humans was greater than 0.76. The current model fits well with the experimental datasets of urinary N-acetyl-S-(2-carbamoylethyl)-l-cysteine (AAMA) and (N-(R,S)-acetyl-S-(carbamoyl-2-hydroxyethyl)-l-cysteine) (GAMA) of rats exposed to AA from 0.1 to 50 mg/kg b.w. and humans exposed to AA from 0.0005 to 0.020 mg/kg b.w., indicating the robustness of the current models. Parameters for adduct of AA with N-terminal valine of hemoglobin (AAVal) were extended to humans and validated. Kinetic parameters for rats were assessed and validated based upon fit to the experimental datasets for liver N3-(2-carbamoyl-2-hydroxyethyl)-adenine (N3-GA-Ade) and N7-(2-carbamoyl-2-hydroxyethyl)-guanine (N7-GA-Gua) adducts. Compared with the previous model, the developed model included the correlation between AA intake and its mercapturic acid adducts, AAMA and GAMA, in a larger dose range with new experimental data, and parameters for AAVal, N3-GA-Ade and N7-GA-Gua were improved and verified. The current multi-component PBTK models provide a superior foundation for the estimation of short-term to medium and long-term intake levels of human exposure to AA.

Developmental Change in the Influence of Domain-General Abilities and Domain-Specific Knowledge on Mathematics Achievement: An Eight-Year Longitudinal Study.

The contributions of domain-general abilities and domain-specific knowledge to subsequent mathematics achievement were longitudinally assessed (n = 167) through 8th grade. First grade intelligence and working memory and prior grade reading achievement indexed domain-general effects and domain-specific effects were indexed by prior grade mathematics achievement and mathematical cognition measures of prior grade number knowledge, addition skills, and fraction knowledge. Use of functional data analysis enabled grade-by-grade estimation of overall domain-general and domain-specific effects on subsequent mathematics achievement, the relative importance of individual domain-general and domain-specific variables on this achievement, and linear and non-linear across-grade estimates of these effects. The overall importance of domain-general abilities for subsequent achievement was stable across grades, with working memory emerging as the most important domain-general ability in later grades. The importance of prior mathematical competencies on subsequent mathematics achievement increased across grades, with number knowledge and arithmetic skills critical in all grades and fraction knowledge in later grades. Overall, domain-general abilities were more important than domain-specific knowledge for mathematics learning in early grades but general abilities and domain-specific knowledge were equally important in later grades.

Relating psychological and social factors to academic performance: A longitudinal investigation of high-poverty middle school students.

We investigated the relations between middle school students' psychological factors (academic commitment and emotional control), social perceptions (family involvement and school climate), and academic performance over time. Gender differences in these relations were also examined. Based on a two-year longitudinal data set of 942 middle-school students from a high-poverty district in the United States, we found that all four factors measured in 6th grade were predictive of GPA at the end of the 7th grade above and beyond gender, race, and home intellectual materials. Among these factors, emotional control had the strongest relation with GPA, and the importance of family involvement increased over time, especially for female students. The results also revealed the indirect effects of the social factors on GPA through the psychological factors, and mostly through emotional control. These findings highlight the complex relation between the social-emotional factors and academic outcomes in early adolescence.

Children's visuospatial memory predicts mathematics achievement through early adolescence.

A previous study showed that gains in visuospatial memory from first to fifth grade predicted end-of-fifth grade mathematics but not reading achievement, controlling other factors. In this follow up study, these relations were assessed from sixth to ninth grade, inclusive (n = 145). The results showed that growth in visuospatial memory across the elementary school years was related to growth in mathematics achievement after fifth grade, controlling intelligence, the central executive and phonological memory components of working memory, in-class attentive behavior, parental education, and fifth grade mathematics achievement. As found for fifth grade, this relation was not found for reading achievement after fifth grade. In total, the results suggest that visuospatial memory has a unique influence on ease of learning some types of mathematics and that this influence becomes more important across successive grades.

Developmental Foundations of Children's Fraction Magnitude Knowledge.

The conceptual insight that fractions represent magnitudes is a critical yet daunting step in children's mathematical development, and the knowledge of fraction magnitudes influences children's later mathematics learning including algebra. In this study, longitudinal data were analyzed to identify the mathematical knowledge and domain-general competencies that predicted 8th and 9th graders' (n=122) knowledge of fraction magnitudes and its cross-grade gains. Performance on the fraction magnitude measures predicted 9th grade algebra achievement. Understanding and fluently identifying the numerator-denominator relation in 7th grade emerged as the key predictor of later fraction magnitudes knowledge in both 8th and 9th grades. Competence at using fraction procedures, knowledge of whole number magnitudes, and the central executive contributed to 9th but not 8th graders' fraction magnitude knowledge, and knowledge of whole number magnitude contributed to cross-grade gains. The key results suggest fluent processing of numerator-denominator relations presages students' understanding of fractions as magnitudes and that the integration of whole number and fraction magnitudes occurs gradually.

Women's preference for masculine traits is disrupted by images of male-on-female aggression.

Women's preferences for men's masculinized faces and voices were assessed after women (n = 331) were primed with images of male-on-male aggression, male-on-female aggression, pathogens, and neutral scenes. Male-on-male aggression and pathogen primes were associated with increased preference for masculine traits, but the same effect emerged in the neutral condition. We show the increased preference for masculine traits was due to repeated exposure to these traits, not the priming images themselves. Images of male-on-female aggression were an exception; these elicited feelings of disgust and anger appeared to disrupt the preference for masculinized traits. The results suggest women process men's facial and vocal traits as signals of aggressive potential and lose any preference for these traits with cues indicating men might direct this aggression toward them.

Acuity of the approximate number system and preschoolers' quantitative development.

The study assessed the relations among acuity of the inherent approximate number system (ANS), performance on measures of symbolic quantitative knowledge, and mathematics achievement for a sample of 138 (64 boys) preschoolers. The Weber fraction (a measure of ANS acuity) and associated task accuracy were significantly correlated with mathematics achievement following one year of preschool, and predicted performance on measures of children's explicit knowledge of Arabic numerals, number words, and cardinal value, controlling for age, sex, parental education, intelligence, executive control, and preliteracy knowledge. The relation between ANS acuity, as measured by the Weber fraction and task accuracy, and mathematics achievement was fully mediated by children's performance on the symbolic quantitative tasks, with knowledge of cardinal value emerging as a particularly important mediator. The overall pattern suggests that ANS acuity facilitates the early learning of symbolic quantitative knowledge and indirectly influences mathematics achievement through this knowledge.

Developmental gains in visuospatial memory predict gains in mathematics achievement.

Visuospatial competencies are related to performance in mathematical domains in adulthood, but are not consistently related to mathematics achievement in children. We confirmed the latter for first graders and demonstrated that children who show above average first-to-fifth grade gains in visuospatial memory have an advantage over other children in mathematics. The study involved the assessment of the mathematics and reading achievement of 177 children in kindergarten to fifth grade, inclusive, and their working memory capacity and processing speed in first and fifth grade. Intelligence was assessed in first grade and their second to fourth grade teachers reported on their in-class attentive behavior. Developmental gains in visuospatial memory span (d = 2.4) were larger than gains in the capacity of the central executive (d = 1.6) that in turn were larger than gains in phonological memory span (d = 1.1). First to fifth grade gains in visuospatial memory and in speed of numeral processing predicted end of fifth grade mathematics achievement, as did first grade central executive scores, intelligence, and in-class attentive behavior. The results suggest there are important individual differences in the rate of growth of visuospatial memory during childhood and that these differences become increasingly important for mathematics learning.