Growth charts of brain morphometry for preschool children.

Brain development from 1 to 6 years of age anchors a wide range of functional capabilities and carries early signs of neurodevelopmental disorders. However, quantitative models for depicting brain morphology changes and making individualized inferences are lacking, preventing the identification of early brain atypicality during this period. With a sample size of 285, we characterized the age dependence of the cortical thickness and subcortical volume in neurologically normal children and constructed quantitative growth charts of all brain regions for preschool children. While the cortical thickness of most brain regions decreased with age, the entorhinal and parahippocampal regions displayed an inverted-U shape of age dependence. Compared to the cortical thickness, the normalized volume of subcortical regions exhibited more divergent trends, with some regions increasing, some decreasing, and some displaying inverted-U-shaped trends. The growth curve models for all brain regions demonstrated utilities in identifying brain atypicality. The percentile measures derived from the growth curves facilitate the identification of children with developmental speech and language disorders with an accuracy of 0.875 (area under the receiver operating characteristic curve: 0.943). Our results fill the knowledge gap in brain morphometrics in a critical development period and provide an avenue for individualized brain developmental status evaluation with demonstrated sensitivity. The brain growth charts are shared with the public (http://phi-group.top/resources.html).

Developmental population pharmacokinetics of caffeine in Chinese premature infants with apnoea of prematurity: A post-marketing study to support paediatric labelling in China.

AIMS: The aim of the study was to evaluate the suitability of the current caffeine dosing regimen for the Chinese population using modelling and simulation approach. METHODS: Pharmacokinetic samples were collected from 99 Chinese newborns with premature apnoea. The median (range) of gestational age and postmenstrual age were 28.3 (25.0-33.4) weeks and 31.1 (26.4-38.0) weeks, respectively. Newborns were receiving caffeine citrate at a loading dose of 20 mg/kg/d and a maintenance dose of 5-10 mg/kg/d. Caffeine concentrations and CYP1A2 polymorphisms were investigated. Population pharmacokinetic modelling of caffeine in Chinese preterm newborn on a population-wide scale was conducted using NONMEM. RESULTS: A 1-compartment model with first-order elimination was used to describe population pharmacokinetic. With current weight implemented using 0.75 allometric scaling, clearance (CL) was positively related to current weight and postmenstrual age, but a negative relationship was observed with serum creatinine concentration. Eight genotypes of CYP1A2 were tested and none of them had a significant impact on caffeine pharmacokinetic parameters. Interindividual variability of CL and volume of distribution was 7.70 and 65.9%. The median (range) of 95% confidence intervals of CL were 0.0128 (0.0128-0.0131) L/h/kg. Monte Carlo simulation demonstrated that 80% (loading dose) and 98% (maintenance dose) of premature infants treated with a labelled dosing regimen attained the concentration target range of 5-20 mg/L. CONCLUSION: A population PK model of caffeine was developed in Chinese newborns. Body weight-implemented allometric scaling, postmenstrual age and serum creatinine concentration markedly affected caffeine clearance. The labelled dosing regimen is suitable for Chinese premature infants.

Simultaneous quantitation of serum caffeine and its metabolites by ultra-high-performance liquid chromatography-tandem mass spectrometry for CYP1A2 activity prediction in premature infants.

Caffeine (CA) is accepted as a probe of cytochrome P450 1A2 enzyme (CYP1A2) activity and is commonly used in premature infants with great inter-individual variability of metabolism. To evaluate the change characteristics of CYP1A2 activity in premature infants, an ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed and optimized for the simultaneous quantitation of serum CA and its major metabolites, including paraxanthine (PX), theophylline (TP) and theobromine (TB), in premature infants. A C18 column and gradient elution with 0.1% formic acid in methanol and 0.1% formic acid in water at a flow rate of 0.3 mL/min were used for compound separation. The mass spectrometer monitored the transitions of CA (m/z 195.0 → 138.0), CA-d9 (m/z 204.0 → 144.1), PX (m/z 181.0 → 124.1), TP (m/z 181.0 → 123.9) and TB (m/z 181.0 → 138.0) using multiple reaction monitoring in positive ion mode. CYP1A2 activity was evaluated by serum molar concentration ratios of CA and its metabolites. The results showed that CYP1A2 has a significant positive correlation with the clearance of CA, and was affected by current weight and CYP1A2*1C. The results suggested that the serum concentration ratios of CA metabolites could be used to predict the changes in CYP1A2 enzyme activity in premature infants.

A computational method to quantitatively measure pediatric drug safety using electronic medical records.

BACKGROUND: Drug safety in children is a major concern; however, there is still a lack of methods for quantitatively measuring, let alone to improving, drug safety in children under different clinical conditions. To assess pediatric drug safety under different clinical conditions, a computational method based on Electronic Medical Record (EMR) datasets was proposed. METHODS: In this study, a computational method was designed to extract the significant drug-diagnosis associations (based on a Bonferroni-adjusted hypergeometric P-value < 0.05) among drug and diagnosis co-occurrence in EMR datasets. This allows for differences between pediatric and adult drug use to be compared based on different EMR datasets. The drug-diagnosis associations were further used to generate drug clusters under specific clinical conditions using unsupervised clustering. A 5-layer quantitative pediatric drug safety level was proposed based on the drug safety statement of the pediatric labeling of each drug. Therefore, the drug safety levels under different pediatric clinical conditions were calculated. Two EMR datasets from a 1900-bed children's hospital and a 2000-bed general hospital were used to test this method. RESULTS: The comparison between the children's hospital and the general hospital showed unique features of pediatric drug use and identified the drug treatment gap between children and adults. In total, 591 drugs were used in the children's hospital; 18 drug clusters that were associated with certain clinical conditions were generated based on our method; and the quantitative drug safety levels of each drug cluster (under different clinical conditions) were calculated, analyzed, and visualized. CONCLUSION: With this method, quantitative drug safety levels under certain clinical conditions in pediatric patients can be evaluated and compared. If there are longitudinal data, improvements can also be measured. This method has the potential to be used in many population-level, health data-based drug safety studies.

Analysis of job satisfaction among clinical research coordinators.

BACKGROUND: While CRCs play a crucial role in clinical trials, their job satisfaction has not received enough attention. OBJECTIVE: To assess the job satisfaction of CRCs and to explore the relevant factors. METHODS: The survey was programmed into an online questionnaire platform and distributed to CRCs in China for self-evaluation. The Minnesota Satisfaction Questionnaire (MSQ) was used to assess job satisfaction, and data on demographic characteristics, working situations, burnout and social support also were collected to identify factors associated with job satisfaction. Data analysis was performed using the R software program. Factors associated with job satisfaction were explored using ordinal logistic regression models. RESULTS: 2,840 participants were included in this survey, and the mean value of overall job satisfaction was characterized as "moderate to not fully satisfied". Additionally, both burnout and overall social support were reported at moderate levels. Ordinal logistic regression analysis revealed that age, monthly income, sleep duration per day, weekly working time, a fixed workplace, subjective support, utilization of support, emotional exhaustion, depersonalization and reduced personal accomplishment were significantly associated with all types of job satisfaction (p <  0.05). Among all the factors, a fixed workplace was more strongly associated with job satisfaction than the other factors (OR = 0.596, p <  0.001). CONCLUSIONS: Implementing the fixed-point CRC mode to promote the provision of a fixed workplace, improving the CRC career development path, increasing income, subjective support and utilization of support, reducing weekly working time, job burnout will help to predict job satisfaction in CRCs.

Population pharmacokinetics of ciclosporin in Chinese children with aplastic anemia: effects of weight, renal function and stanozolol administration.

AIM: To develop a population pharmacokinetic model for the immunosuppressant ciclosporin in Chinese children with aplastic anemia and to identify covariates influencing ciclosporin pharmacokinetics. METHODS: A total of 102 children with either acquired or congenital aplastic anemia aged 8.8±3.6 years (range 0.9-17.6 years) were included. Therapeutic drug monitoring (TDM) data for ciclosporin were collected. The population pharmacokinetic model of ciclosporin was described using the nonlinear mixed-effects modeling (NONMEM) VI software. The final model was validated using bootstrap and normalized prediction distribution errors. RESULTS: A one-compartment model with first-order absorption and elimination was developed. The estimated CL/F was 15.1, which was lower than those of children receiving stem cell or kidney transplant reported in the West (16.9-29.3). The weight normalized CL/F was 0.45 (range: 0.27-0.70) Lh(-1)·kg(-1). The covariate analysis identified body weight, serum creatinine and concomitant administration of the anabolic steroid stanozolol as individual factors influencing the CL/F of ciclosporin. CONCLUSION: Our model could be used to optimize the ciclosporin dosing regimen in Chinese children with aplastic anemia.

Application of amide proton transfer imaging to pretreatment risk stratification of childhood neuroblastoma: comparison with neuron-specific enolase.

Background: The diagnosis and treatment of childhood neuroblastoma (NB) varies with different risk groups, thus requiring accurate preoperative risk assessment. This study aimed to verify the feasibility of amide proton transfer (APT) imaging in risk stratification of abdominal NB in children, and compare it with the serum neuron-specific enolase (NSE). Methods: This prospective study enrolled 86 consecutive pediatric volunteers with suspected NB, and all subjects underwent abdominal APT imaging on a 3T magnetic resonance imaging scanner. A 4-pool Lorentzian fitting model was used to mitigate motion artifacts and separate the APT signal from the contaminating ones. The APT values were measured from tumor regions delineated by two experienced radiologists. The one-way analysis of variance, independent-sample t-test, Mann-Whitney U-test, and receiver operating characteristic analysis were performed to evaluate and compare the risk stratification performance of the APT value and serum NSE index-a routine biomarker of NB in clinics. Results: Thirty-four cases (mean age, 38.6±32.4 months; 5 very-low-risk, 5 low-risk, 8 intermediate-risk and 16 high-risk ones) were included in the final analysis. The APT values were significantly higher in high-risk NB (5.80%±1.27%) than in the non-high-risk group (3.88%±1.01%) composed of the other three risk groups (P<0.001). However, there was no significant difference (P=0.18) in NSE levels between the high-risk (93.05±97.14 ng/mL) and non-high-risk groups (41.45±30.99 ng/mL). The associated area under the curve (AUC) of the APT parameter (AUC =0.89) in differentiating high-risk NB from non-high-risk NB was significantly higher (P=0.03) than that of NSE (AUC =0.64). Conclusions: As an emerging non-invasive magnetic resonance imaging technique, APT imaging has a promising prospect for distinguishing high-risk NB from non-high-risk NB in routine clinical applications.

The effects of a high-fat and high-energy diet on the hepatic expression of CYP3A in developing female rats.

We aimed to investigate the effects of high-fat and high-energy (HFHE) diets on the hepatic expression of cytochrome P-450 3A (CYP3A) in developing female rats. The pups of the dams fed with the standard diet were defined as the NN group and those fed the HFHE diet were defined as the NH group. The mRNA and protein expression, the protein localization and activity was determined. The mRNA expression of CYP3A1 on day 3 in the NH group were higher versus NN groups (p < 0.05) and the expression of the NH group on days 28 and 56 were lower versus the NN group (p < 0.01). CYP3A1 immunolabeling had a zonal-restricted expressions pattern on day 28 and after in the NN groups, while the obvious zonal expression pattern was observed in the NH group on day 84. The mean activity for the NH groups on days 3, 7, 14 and 28 was higher versus the NN groups (p < 0.05). On day 84, the activity was lower for the NH group versus the NN group (p < 0.05). Our findings provide a basis for further studies on appropriate medication regimen in obese children.

Effects of long-term high-fat/high-energy and high-protein diets on insulin and ghrelin expression in developing rats.

OBJECTIVE: This study investigated the long-term effects of high-fat/high-energy and high-protein diets on insulin secretion and ghrelin expression. METHODS: Dams of Sprague-Dawley rats were fed a standard, high-fat/high-energy, or high-protein diet during pregnancy and lactation, and their pups were defined as control, high-fat and high-energy, and high-protein groups, respectively. The pups were fed the same diet as their dams after weaning. Plasma glucose, ghrelin, and insulin were analyzed on the first, third, seventh, and tenth postnatal days and at the end of second, third, fourth, eighth, and twelfth weeks. Ghrelin and insulin expression in the pancreas was measured using radioimmunoassay, double-staining immunohistochemistry, and confocal microscopy. RESULTS: Fasting blood glucose, plasma insulin concentrations, and homeostasis model assessment-insulin resistance index increased with age. Total plasma ghrelin concentrations decreased with age. Plasma ghrelin concentrations were negatively correlated with glucose levels in all three groups. Plasma ghrelin was negatively correlated with plasma insulin only in the high-fat and high-energy group. Insulin secretion in the high-protein and high-fat and high-energy groups and pancreatic ghrelin content, pancreatic ghrelin-positive cells, and beta cells in all groups decreased with age. The percentage of ghrelin-positive cells correlated with the percentage of beta cells in all groups. CONCLUSION: Insulin and ghrelin expression in the plasma and pancreas was adversely affected by long-term high-fat/high-energy and high-protein diets.

Prognostic factors of pediatric pelvic and genitourinary rhabdomyosarcoma: An analysis based on SEER database.

Background: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcomas in children. This study aimed to investigate the prognostic factors of pelvic and genitourinary RMS in children and evaluate the survival outcomes of these children treated with or without radiation therapy (RT). Methods: The Surveillance, Epidemiology, and End Results Program (SEER) database was required for children with pelvic and genitourinary RMS. Overall survival (OS) and cancer-specific survival (CSS) were analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. Results: For the 262 patients analyzed, the most common biological subtypes were embryonic (n=209, 79.8%) and alveolar (n=29, 11.1%). Patients with alveolar RMS had the worst prognosis (P < 0.05). The testis (n=122, 46.6%) was the most common location, followed by the urinary bladder (n=57, 21.8%) and prostate (n=48, 18.3%). Uterus RMS had the highest survival rate, followed by testis, urinary bladder, and prostate RMS. Favorable prognostic factors were age at diagnosis < 15 years, non-alveolar histological subtype, early tumor stage (localized/regional), specific sites (uterus and testis), and treatment (cancer-directed surgery and chemotherapy) (P < 0.05). Propensity score-matched analyses comparing the cohorts of patients treated with or without RT demonstrated no significant differences in prognostic survival (OS: P=0.872, CSS: P=0.713). Conclusion: The nomogram constructed based on independent prognostic factors may accurately predict survival rates at 1 and 5 years. Surgery and adjuvant chemotherapy can be effective treatments, but RT fails to guarantee a survival benefit. Therefore, prospective trials evaluating RT for pediatric pelvic and genitourinary RMS are warranted.

Metabolomic Differential Compounds Reflecting the Clinical Efficacy of Polyethylene Glycol Recombinant Human Growth Hormone in the Treatment of Childhood Growth Hormone Deficiency.

Understanding metabolite profiles may aid in providing a reference for individualized treatment using PEG-rhGH. Therefore, this study aimed to evaluate the clinical efficacy of PEG-rhGH in treating GHD patients by using a metabolomic approach. Fifty-seven pediatric participants treated with PEG-rhGH were enrolled (28 GHD patients with high clinical efficacy and 29 GHD patients with lower clinical efficacy). Serum samples from all patients were first collected at baseline for biochemical detection; then metabolite levels were measured using gas chromatography time-of-flight mass spectrometry. The candidates included heptadecanoic acid, stearic acid, 2-hydroxybutyric acid, myristic acid, palmitoleic acid, D-galactose, dodecanoic acid, and oleic acid. The related metabolic pathways involved fatty acid metabolism and energy metabolism. This study suggested that growth gains of PEG-rhGH treatment might be differentiated by altered serum levels of fatty acid. Collectively, the metabolomic study provides unique insights into the use of PEG-rhGH as a therapeutic strategy for individualized treatment.

Short-term efficacy and safety of a lower dose of polyethylene glycol recombinant human growth hormone in children with growth hormone deficiency: A randomized, dose-comparison study.

Objective: Polyethylene glycol recombinant human growth hormone (PEG-rhGH, Jintrolong®) is the first long-acting rhGH preparation that is approved to treat children with growth hormone deficiency (GHD) in China. Clinical experience with dose selections of PEG-rhGH is scarce. The present study compared the efficacy and safety of a lower dose to increase dosing regimens of PEG-rhGH treatment. Methods: A multicenter, randomized, open-label, dose-comparison clinical study was conducted to compare the improvements in the height standard deviation score (Ht SDS), height velocity (HV), insulin-like growth factor-1 (IGF-1) SDS, and safety profiles of children with GHD who are treated with 0.2 mg/kg/week of PEG-rhGH dose or 0.14 mg/kg/week for 26 weeks. Results: Ht SDS, HV, and IGF-1 SDS increased significantly after PEG-rhGH treatment in the two dose groups (p < 0.05). The improvements of Ht SDS, HV, and IGF-1 SDS were more significant in the high-dose group than in the low-dose group (p < 0.05). Ht SDS improvement in low-dose group was not non-inferiority to that in the high-dose group (p = 0.2987). The incidences of adverse events were comparable between the two groups. Conclusion: The improvements of Ht SDS, HV, and IGF-1 SDS were more significant in the high-dose group than in the low-dose group (p < 0.05). PEG-rhGH at the dose of 0.14 mg/kg/week was effective and safe for children with GHD. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02908958.

Breastfeeding improves dynamic reorganization of functional connectivity in preterm infants: a temporal brain network study.

Substantial evidences have shown the benefits of breastfeeding to infants in terms of better nutrition and neurodevelopmental outcome. However, the relationship between brain development and feeding in preterm infants, who are physiologically and developmentally immature at birth, is only beginning to be quantitatively assessed, coinciding with the recent advent of neuroimaging techniques. In the current work, we studied a sample of 50 preterm infants-born between 29 and 33 weeks (32.20 ± 0.89 weeks) of gestational age, where 30 of them were breastfed and the remaining 20 were formula-fed. Resting-state functional magnetic resonance imaging (fMRI) was recorded around term-equivalent age (40.00 ± 1.31 weeks, range 39-44 weeks) using a 1.5-T scanner under sedation condition. Temporal brain networks were estimated by the correlation of sliding time-window time courses among regions of a predefined atlas. Through our newly introduced temporal efficiency approach, we examined, for the first time, the 3D spatiotemporal architecture of the temporal brain network. We found prominent temporal small-world properties in both groups, suggesting the arrangement of dynamic functional connectivity permits effective coordination of various brain regions for efficient information transfer over time at both local and global levels. More importantly, we showed that breastfed preterm infants exhibited greater temporal global efficiency in comparison with formula-fed preterm infants. Specifically, we found localized elevation of temporal nodal properties in the right temporal gyrus and bilateral caudate. Taken together, these findings provide new evidence to support the notion that breast milk promotes early brain development and cognitive function, which may have neurobiological and public health implications for parents and pediatricians.Breastfeeding has long been recognized to have beneficial effect on early neurodevelopment in infants. However, the influence of breastfeeding on reorganization of functional connectivity in preterm infants are largely unknown. To this end, we utilized our recently developed temporal brain network analysis framework to investigate the dynamic reorganization of brain functional connectivity in preterm infants fed with breast milk. We found that beyond an optimal temporal small-world topology, breastfed preterm infants exhibited improved network efficiency at both global and regional levels in comparisons with those of formula-fed infants. Graphical abstract: Breastfeeding has long been recognized to have beneficial effect on early neurodevelopment in infants. However, the influence of breastfeeding on reorganization of brain functional connectivity in preterm infants are largely unknown. To this end, we utilized our recently developed temporal brain network analysis framework to investigate the dynamic reorganization of functional connectivity in preterm infants fed with breast milk. We found that beyond an optimal temporal small-world topology, breastfed preterm infants exhibited improved network efficiency at both global and regional levels in comparisons with those of formula-fed infants.

Expression of CYP3A23/1, CYP3A2, PXR, CAR and HNF4alpha in large-for-gestational-age neonatal rats.

BACKGROUND: The available information about hepatic drug-metabolizing enzymes in the large-for-gestational-age (LGA) neonate is limited. OBJECTIVE: To determine whether LGA status alters expression of the cytochrome p450 enzymes, CYP3A23/1 and CYP3A2, and nuclear receptors PXR, CAR and HNF4alpha. METHODS: Appropriate-for-gestational-age (AGA) and LGA pups from 10 litters of rats (n=15 pups/group) were used. Hepatic expression levels of CYP3A23/1, CYP3A2, pregnane X receptor (PXR), constitutive androstane receptor (CAR), and HNF4alpha mRNA were detected by quantitative real-time RT-PCR. Protein expression was determined immunohistochemically and expression levels were evaluated using staining intensity scores and percentage of positive hepatocytes. RESULTS: The mean body weights of AGA and LGA rat pups were 6.20 +/- 0.49 and 7.77 +/- 0.70 g (mean +/- SD), respectively (P < 0.001). Liver weight/body weight ratios trended higher in the LGA group (5.18 +/- 0.50%, mean +/- SD) than in the AGA group (4.90 +/- 0.01%, mean +/- SD), but the difference was not significant. CYP3A2 mRNA levels were higher in LGA than in AGA pups (P < 0.05), but there were no group differences in CYP3A23/1 mRNA levels. HNF4alpha levels were also higher in the LGA group (P < 0.05), but PXR and CAR mRNA levels did not differ between the groups. The staining intensity and frequency of CYP3A23/1-positive and HNF4alpha-positive hepatocytes differed between LGA and AGA pups, whereas no significant differences in CYP3A2 or CAR protein expression were observed between groups. CONCLUSIONS: LGA status affects the hepatic expression of CYP3A23/1, CYP3A2, and HNF4alpha, suggesting that further research on this issue is warranted.

Male-specific induction of CYP3A2 in rats by zolmitriptan.

We report here a novel observation that zolmitriptan induced CYP3A2 in male but not female rats. As part of our research programme to evaluate sex differences in the response to zolmitriptan, we studied the effects of zolmitriptan on CYP3A activity, protein and gene expression in male and female rats. Zolmitriptan was found to induce CYP3A activity, measured as testosterone and diazepam metabolism in-vitro, as well as midazolam pharmacokinetics in-vivo, in male but not female rats. The sex difference in response to zolmitriptan was further evaluated by analysis of CYP3A1/2 mRNA levels using real-time PCR, and CYP3A1/2 protein levels using immunoblotting. Zolmitriptan preferentially induced CYP3A2 in male but not female rats. No obvious effects on CYP3A1 were observed at any dose in either sex. Thus, we concluded that the observed sex-dependent induction of CYP3A by zolmitriptan was largely due to induction of CYP3A2 in male rats.

Effects of intrauterine undernutrition on the expression of CYP3A23/3A1, PXR, CAR and HNF4alpha in neonate rats.

Cytochrome P-450 3A (CYP3A) together with its nuclear receptors plays a critical role in drug metabolism. The present study investigated the effects of undernutrition in utero on hepatic mRNA and protein expression of the enzyme CYP3A23/3A1 and nuclear receptors including pregnane X receptor (PXR; NR1I2), constitutive androstane receptor (CAR; NR1I3) and nuclear factor-4alpha (HNF4alpha; HNF4A) in neonatal rats. At gestational day 2, pregnant rats were randomly divided into two groups: nourished (fed ad libitum) and undernourished (50% of nourished group). The pups delivered by nourished rats were designated as the normal-birth-weight group (NBW, n=15) and those delivered by undernourished rats were designated as the low-birth-weight group (LBW, n=15). Hepatic mRNA expression was detected by quantitative real-time PCR and the corresponding protein expression was examined by immunohistochemistry (IHC). Compared with NBW pups, LBW pups tended to have lower mRNA expression levels of CYP3A23/3A1, PXR and CAR but higher levels of HNF4alpha. Only the CAR mRNA expression differences were significant (p<0.05). mRNA expression of CYP3A23/3A1 correlated with that of HNF4alpha in both the LBW(r=0.808, p=0.007) and NBW (r=0.452, p=0.012) groups. CYP3A23/3A1 and CAR protein expression differed between the two groups (CYP3A23/3A1, chi(2)=7.87, p=0.005; CAR, chi(2)=12.069, p=0.001). In conclusion, these findings suggest that undernutrition may influence the mRNA expression of CAR and protein expression of both CYP3A23/3A1 and CAR in neonatal rats. Since CYP3A23/3A1 and CAR are critically involved in drug metabolism, these results may have clinical implications for optimal medication in LBW children.

A high-fat high-energy diet influences hepatic CYP3A expression and activity in low-birth-weight developing female rats.

BACKGROUND: The objective of this study was to investigate the effects of a high-fat, high-energy (HFHE) diet on the hepatic expression of CYP3A in low-birthweight developing female rats. METHODS: Pregnant rats were divided into nourished and undernourished groups. The offspring of the nourished rats were defined as the normal-birth-weight (NBW) group, and those of undernourished rats were defined as the low-birth-weight (LBW) group. According to their birth weights and diets, the rats were subdivided into the following four groups: NBW-normal diet (NN) group; NBW-HFHE (NH) group; LBW-normal diet (LN) group; and LBW-HFHE (LH) group. Liver samples were isolated on days 3, 7, 14, 21, 28, 56 and 84 after birth. RESULTS: The CYP3A1 mRNA levels in the LH group on days 3, 56 and 84 were significantly higher than those of the NN group (P<0.05). CYP3A1 expression was significantly higher in the LH group than that in the NH group on days 21, 28 and 84 (P<0.05). CYP3A1 mRNA expression was higher in the LH group than that in the LN group on days 3 and 21 (P<0.05). No zonal CYP3A1 expression pattern was observed in the LH developmental group. The LH group had significantly higher mean activity than the LN group on days 7, 14, 28 and 56. CONCLUSION: Our results indicated that an HFHE diet can result in alterations of CYP3A expression in a developmental LBW rat model.

Hepatic CYP3A expression and activity in low birth weight developing female rats.

BACKGROUND: We aimed to investigate the effects of low birth weight (LBW) on the hepatic expression of cytochrome P-450 3A (CYP3A) in developing female rats. METHODS: Pregnant rats were divided into two groups, a nourished group and an under-nourished group. The offspring of the nourished rats were defined as a normal weight, normal diet group (NN group). The offspring of the under-nourished rats were designated as a LBW, normal diet group (LN group). CYP3A mRNA expression, protein expression, protein localization and activity were determined. RESULTS: The CYP3A1 mRNA expression levels of the LN group on days 3, 21, and 56 were significantly higher than those of the same age in the NN group (P≤0.01). The mRNA expression of CYP3A2 in the LN group on day 21 was higher than in rats of the same age in the NN group (P<0.01). The staining intensity and frequency of CYP3A1-positive hepatocytes were significantly lower on days 7 and 21 in the LN group than those of rats of the same age in the NN group (P<0.05). The staining intensity and frequency of CYP3A2-positive hepatocytes on days 14 and 21 were higher in the LN group than those on the same days in the NN group (P<0.05). The mean CYP3A activity of the LN group on day 3 was significantly higher than that of the NN group (P<0.001). CONCLUSIONS: We found the effect of LBW on CYP3A activity was most prominent during the early days of life in rats. Investigators and clinicians should consider the effect of LBW on CYP3A in both pharmacokinetic study design and data interpretation, when prescribing drugs to LBW infants.