PBPK modeling to support risk assessment of pyrethroid exposure in French pregnant women.

BACKGROUND: Pyrethroids are widely used pesticides and are suspected to affect children's neurodevelopment. The characterization of pyrethroid exposure during critical windows of development, such as fetal development and prenatal life, is essential to ensure a better understanding of pyrethroids potential effects within the concept of Developmental Origins of Health and Disease. OBJECTIVE: The aim of this study was to estimate maternal exposure of French pregnant women from biomonitoring data and simulate maternal and fetal internal concentrations of 3 pyrethroids (permethrin, cypermethrin and deltamethrin) using a multi-substance pregnancy-PBPK (physiologically based pharmacokinetics) model. The estimated maternal exposures were compared to newly proposed toxicological reference values (TRV) children specific also called draft child-specific reference value to assess pyrethroid exposure risk during pregnancy i.e. during the in utero exposure period. METHODS: A pregnancy-PBPK model was developed based on an existing adult pyrethroids model. The maternal exposure to each parent compound of pregnant women of the Elfe (French Longitudinal Study since Childhood) cohort was estimated by reverse dosimetry based on urinary biomonitoring data. To identify permethrin and cypermethrin contribution to their common urinary biomarkers of exposure, an exposure ratio based on biomarkers in hair was tested. Finally, exposure estimates were compared to current and draft child-specific reference values derived from rodent prenatal and postnatal exposure studies. RESULTS: The main contributor to maternal pyrethroid diet intake is cis-permethrin. In blood, total internal concentrations main contributor is deltamethrin. In brain, the major contributors to internal pyrethroid exposure are deltamethrin for fetuses and cis-permethrin for mothers. Risk is identified only for permethrin when referring to the draft child-specific reference value. 2.5% of the population exceeded permethrin draft child-specific reference value. CONCLUSIONS: A new reverse dosimetry approach using PBPK model combined with human biomonitoring data in urine and hair was proposed to estimate Elfe pregnant population exposure to a pyrethroids mixture with common metabolites.

Cancer risk from chronic exposures to chemicals and radiation: a comparison of the toxicological reference value with the radiation detriment.

This article aims at comparing reference methods for the assessment of cancer risk from exposure to genotoxic carcinogen chemical substances and to ionizing radiation. For chemicals, cancer potency is expressed as a toxicological reference value (TRV) based on the most sensitive type of cancer generally observed in animal experiments of oral or inhalation exposure. A dose-response curve is established by modelling experimental data adjusted to apply to human exposure. This leads to a point of departure from which the TRV is derived as the slope of a linear extrapolation to zero dose. Human lifetime cancer risk can then be assessed as the product of dose by TRV and it is generally considered to be tolerable in a 10-6-10-4 range for the public in a normal situation. Radiation exposure is assessed as an effective dose corresponding to a weighted average of energy deposition in body organs. Cancer risk models were derived from the epidemiological follow-up of atomic bombing survivors. Considering a linear-no-threshold dose-risk relationship and average baseline risks, lifetime nominal risk coefficients were established for 13 types of cancers. Those are adjusted according to the severity of each cancer type and combined into an overall indicator denominated radiation detriment. Exposure to radiation is subject to dose limits proscribing unacceptable health detriment. The differences between chemical and radiological cancer risk assessments are discussed and concern data sources, extrapolation to low doses, definition of dose, considered health effects and level of conservatism. These differences should not be an insuperable impediment to the comparison of TRVs with radiation risk, thus opportunities exist to bring closer the two types of risk assessment.

Accelerometry to measure physical activity in toddlers: Determination of wear time requirements for a reliable estimate of physical activity.

Accelerometry is widely used to evaluate physical activity in toddlers however recommendations regarding wear time are needed to understand physical activity behaviours in this age group. This study aimed to determine the minimum wear time to reliably evaluate physical activity in toddlers. Children from the 3D Birth Cohort (n = 255, 49.8% boys, 2.1 ± 0.2 years) were asked to wear an accelerometer (GT3X+, ActiGraph) for 7 days. Physical activity was expressed in active time (min/day) and counts per minute (CPM). Single day intraclass correlation coefficients (ICCs) were calculated to assess the effect of varying minimal wear time on reliability estimates. The Spearman-Brown formula was used to determine wear time required to achieve reliability levels of 70%, 80% and 90%. For active time, a reliability of 72.1% was achieved with wearing the accelerometer for ≥ 4 days of ≥ 6 h, which comprised 85.9% of the sample. For CPM, ≥ 4 days of ≥ 6 h provided a reliability of 74.7% and comprised 85.9% of the children. Results differed slightly when girls and boys were analysed separately, but restricting analyses to children with a weekend day did not. In summary, a minimum of 4 days with ≥ 6 h of accelerometry data provides a reliable estimate of physical activity in 2-year toddlers.

Determination of peak cardiorespiratory fitness parameters in children: which averaging method should we use?

The purpose of this study was to identify which averaging methods most accurately measures peak cardiorespiratory fitness (CRF) parameters [peak O2 uptake (VO2), peak O2pulse and peak respiratory exchange ratio (RER)] in a sample of healthy children and adolescents. In this cross-sectional multicenter study, we recruited 278 healthy children aged 12-17 years. We compared the mean peak value of three CRF parameters using the recommended averaging methods (30-second block average) with alternative averaging methods such as moving averages or shorter smoothing periods. We also assessed averaging methods for accuracy by individually reviewing breath-by-breath scatter plots. The 30-second block average method resulted in a lower mean peak VO2 and in an increased proportion of underestimated peak values. Using a 30-second moving average significantly increased mean peak values which increased accuracy. Similar results were found for peak RER and peak O2pulse. In conclusion, the currently recommended averaging method (30-second block average) increased the risk of misinterpretation of peak CRF values in children. Using a moving average approach decreased misinterpretation and increased accuracy.

Cerebral blood flow regulation, exercise and pregnancy: why should we care?

Cerebral blood flow (CBF) regulation is an indicator of cerebrovascular health increasingly recognized as being influenced by physical activity. Although regular exercise is recommended during healthy pregnancy, the effects of exercise on CBF regulation during this critical period of important blood flow increase and redistribution remain incompletely understood. Moreover, only a few studies have evaluated the effects of human pregnancy on CBF regulation. The present work summarizes current knowledge on CBF regulation in humans at rest and during aerobic exercise in relation to healthy pregnancy. Important gaps in the literature are highlighted, emphasizing the need to conduct well-designed studies assessing cerebrovascular function before, during and after this crucial life period to evaluate the potential cerebrovascular risks and benefits of exercise during pregnancy.

Physical fitness is associated with prostaglandin F2α isomers during pregnancy.

INTRODUCTION: Pregnancy and physical activity are associated with oxidative stress and immune changes. We hypothesized that pregnant women physically more active in early pregnancy will display a better oxidative stress management and inflammatory response later in pregnancy compared with less active pregnant women. MATERIAL AND METHODS: Maternal physical activity using accelerometry monitors for 1 week and cardiorespiratory fitness (VO2 at anaerobic threshold) were assessed at 14-18 weeks in 58 pregnant women. Plasma and erythrocytes membrane samples were obtained from maternal blood samples at 14-18 and 34-37 weeks of pregnancy. Pro-inflammatory prostaglandin (PG) F2α and oxidative stress-derived F2-isoprostanes were measured by high-performance liquid chromatography coupled to tandem mass spectrometry. RESULTS: Higher physical activity levels at 14-18 weeks measured by mean counts per minute, >30 min/d of moderate to vigorous activity or >6500 steps/d at 14-18 weeks of pregnancy were associated with lower levels of total plasmatic PGF2α later in pregnancy. Concentrations of 5 F2-isomers in erythrocyte membranes in late pregnancy were significantly higher in the third (17.5-19.5 mL kg-1 min-1) and/or fourth (19.6-27.7 mL kg-1 min-1) quartiles of cardio-respiratory fitness compared to the first quartile (13.9-15.9 mL kg-1 min-1). CONCLUSIONS: Overall, higher cardio-respiratory fitness in early pregnancy is associated with enhanced erythrocyte membranes oxidation at 34-37 weeks reflecting a higher oxygen transfer capacity. Also, the most active women experienced lower circulating levels of pro-inflammatory PGF2α in plasma at 34-37 weeks, a marker associated with adverse antenatal inflammation-associated conditions. These results support the practice of physical activity by pregnant women.

New Reference Values for Cardiopulmonary Exercise Testing in Children.

INTRODUCTION: Cardiopulmonary exercise testing is an essential tool to assess cardiorespiratory fitness (CRF) in children. There is a paucity of adequate pediatric reference values that are independent of body size and pubertal stage. The purpose of this study is to provide Z score equations for several maximal and submaximal CRF parameters derived from a prospectively recruited sample of healthy children. METHODS: In this cross-sectional multicenter study, we prospectively recruited 228 healthy children 12 to 17 yr old in local schools. We performed a symptom-limited cardiopulmonary exercise testing progressive ramp protocol on an electronically braked cycle ergometer. Eighteen CRF parameters were analyzed. We tested several regression models to obtain prediction curves that minimized residual association with age, body size, and pubertal stage. Both the predicted mean and the predicted SD were modeled to account for heteroscedasticity. RESULTS: We identified nonlinear association of CRF parameters with body size and significant heteroscedasticity. To normalize CRF parameters, the use of a single body size variable was not sufficient. We therefore used multivariable models with various combination of height, corrected body mass, and age. Final prediction models yielded adjusted CRF parameters that were independent of age, sex, body mass, height, body mass index, and Tanner stages. CONCLUSIONS: We present Z score equations for several CRF parameters derived from a healthy pediatric population. These reference values provide updated predicted means and range of normality that are independent of sex and body size. Further testing is needed to assess if these reference values increase sensitivity and specificity to identify abnormal cardiorespiratory response in children with chronic diseases.

Physical activity during pregnancy and infant's birth weight: results from the 3D Birth Cohort.

AIM: To evaluate the association between maternal physical activity and infant's birth weight or risk of inappropriate weight for gestational age (GA), and whether this association differs by infant's sex, maternal body mass index (BMI) or pregnancy complications in a prospective cohort study. METHODS: 1913 pregnant women from the 3D Birth Cohort (Québec, Canada) completed the Pregnancy Physical Activity Questionnaire at each trimester. Energy expenditure (metabolic equivalent of task (MET)*hours/week) for total activity, sports and exercise and vigorous intensity activities was calculated. The associations with birth weight and risk of inappropriate weight for GA were evaluated by regression modelling. Interactions were tested with infant's sex, maternal prepregnancy BMI, gestational diabetes, hypertensive disorders and prematurity. RESULTS: Each 1 MET/hours/week increase in sports and exercise in the first trimester was associated with a 2.5 g reduction in infant's birth weight (95% CI -4.8 to -0.3) but was not associated with the risk of small weight for GA. In contrast, although not significant, a 17% reduction in the risk of large weight for GA was observed with increasing sports and exercise. Furthermore, in women with subsequent pre-eclampsia (but not normotensive or hypertensive women), each 1 MET/hours/week increment spent in any vigorous exercise in the first trimester reduced the infant's birth weight by 19.8 g (95% CI -35.2 to -4.3). CONCLUSIONS: Pregnant women with higher sports and exercise levels in the first trimester delivered infants with a lower birth weight. The risk of reducing infant's birth weight with vigorous exercise in women who develop pre-eclampsia later in pregnancy requires evaluation.

Physical Activity Volumes during Pregnancy: A Systematic Review and Meta-Analysis of Observational Studies Assessing the Association with Infant's Birth Weight.

Objective This study aims to examine the association between different maternal physical activity exposures during pregnancy and infant's birth weight, body composition, and risk of inadequate weight. Methods Two reviewers (M.B. and J.L.G.) identified observational studies reporting total or leisure time activity during pregnancy and birth weight outcomes. Pooled analyses were performed to summarize the risk associated with high or moderate volumes of physical activity on birth weight. Results A total of 54 studies among 4,080 reported the association between physical activity and birth weight (37 studies) or risks of small or large birth weight. The association between physical activity and birth weight was evaluated by physical activity levels (low, moderate, or high). Despite heterogeneity, pooled results (23 studies) suggested that moderate levels of activity are associated with an increased birth weight (mean difference: 61.5 g, 95% confidence interval [CI]: 16.6, 106.5, 15 studies), while high levels were associated with lower birth weight (mean difference: -69.9 g, 95% CI: -114.8, -25.0, 15 studies). Data were insufficient to provide robust estimates for other outcomes. Conclusions The results of observational studies suggest an inverted u-shaped association between physical activity and birth weight, despite methodological variability. These results could help refining physical activity guidelines for pregnancy and provide guidance for future research.

Could High Volume of Physical Activities in Early Pregnancy Interfere with Deep Placentation?

Background The impact of physical activity (PA) during pregnancy on obstetrical outcomes remains controversial. We followed pregnant women who reported more than 3 hours of sustained PA per week during the first trimester of pregnancy. Cases Total five eligible women were followed. We observed small placenta from the first trimester (median: 0.68; interquartile [IQ]: 0.62-0.97 multiples of median [MoM]) to delivery (median: 0.82; IQ: 0.71-0.94 MoM), high uterine artery pulsatility index in the first (median: 1.82; IQ: 1.68-1.99 MoM) and second trimesters (median: 1.33; IQ: 1.11-1.56 MoM) of pregnancy. Placenta pathology revealed deep vasculopathy in three (60%) cases. However, all participants delivered at term and none of them experienced preeclampsia. Conclusion This small case series suggest that high PA volume in first trimester could interfere with deep placentation.

A 12-Week Exercise Program for Pregnant Women with Obesity to Improve Physical Activity Levels: An Open Randomised Preliminary Study.

OBJECTIVE: To evaluate whether a 12-week supervised exercise program promotes an active lifestyle throughout pregnancy in pregnant women with obesity. METHODS: In this preliminary randomised trial, pregnant women (body mass index ≥ 30 kg/m2) were allocated to either standard care or supervised training, from 15 to 27 weeks of gestation. Physical activity was measured by accelerometry at 14, 28 and 36 weeks, while fitness (oxygen consumption (VO2) at the anaerobic threshold), nutrition (caloric intake and macronutrients percentage) and anthropometry were assessed at 14 and 28 weeks of gestation. Analyses were performed using repeated measures ANOVA. RESULTS: A total of fifty (50) women were randomised, 25 in each group. There was no time-group interaction for time spent at moderate and vigorous activity (pinteraction = 0.064), but the exercise group's levels were higher than controls' at all times (pgroup effect = 0.014). A significant time-group interaction was found for daily physical activity (p = 0.023); similar at baseline ((22.0 ± 6.7 vs 21.8 ± 7.3) x 10(4) counts/day) the exercise group had higher levels than the control group following the intervention ((22.8 ± 8.3 vs 19.2 ± 4.5) x 10(4) counts/day, p = 0.020) and at 36 weeks of gestation ((19.2 ± 1.5 vs 14.9 ± 1.5) x 10(4) counts/day, p = 0.034). Exercisers also gained less weight than controls during the intervention period despite similar nutritional intakes (difference in weight change = -0.1 kg/week, 95% CI -0.2; -0.02, p = 0.016) and improved cardiorespiratory fitness (difference in fitness change = 8.1%, 95% CI 0.7; 9.5, p = 0.041). CONCLUSIONS: Compared with standard care, a supervised exercise program allows pregnant women with obesity to maintain fitness, limit weight gain and attenuate the decrease in physical activity levels observed in late pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01610323.

Modulation of blood pressure response to exercise by physical activity and relationship with resting blood pressure during pregnancy.

OBJECTIVE: To determine whether physical activity and blood pressure (BP) response to exercise in early pregnancy are related to resting BP at the end of pregnancy. Understanding physiological BP responses to exercise during pregnancy will help in improving BP profile and guiding exercise recommendations in pregnant women. METHODS: Maternal physical activity, cardiorespiratory fitness (VO2peak) and BP (systolic and diastolic) at rest and during exercise (submaximal and relative response) were assessed at 16 weeks of gestation in 61 normotensive pregnant women. BP at 36 weeks of gestation and obstetrical outcomes were collected from maternal charts. RESULTS: Related to resting DBP at 16 weeks (r =  -0.28, P = 0.028), total energy expenditure spend at any physical activity in early pregnancy was also associated with resting SBP at 36 weeks (r =  -0.27, P = 0.038). On the contrary, although related to VO2peak (r =  -0.57, P < 0.0001) and energy expenditure spent at sports and exercise (r =  -0.29, P = 0.024), the relative SBP response to exercise at 16 weeks was not associated with resting BP at 36 weeks. Strongly associated with resting BP at 16 weeks and also with total energy expenditure, submaximal BP response to exercise at 16 weeks was related to resting SBP and DBP at 36 weeks (r = 0.41, P = 0.001 and r = 0.26, P = 0.051, respectively). CONCLUSION: In normotensive women, physical activity performed in early pregnancy appears to slightly modulate resting BP in early and late pregnancy. However, further investigations are needed to determine which physical activity-related parameter in response to exercise best predicts BP variations during pregnancy.

Gestational diabetes mellitus and sleep-disordered breathing.

OBJECTIVE: To examine the link between gestational diabetes mellitus (GDM) and sleep-disordered breathing using complete polysomnography and questionnaires in a case-control study of pregnant women. METHODS: Pregnant women (body mass index [BMI] less than 35, no prior diabetes or hypertension) were eligible as cases (n=26) if diagnosed with GDM by routine 75-g oral glucose tolerance test. Women in the control group without GDM (n=26) were matched for gestational age at polysomnography, BMI, and age. Polysomnography were conducted at home at 24-32 weeks of gestation. Sleepiness score (Epworth Sleepiness Scale), subjective sleep quality (Pittsburgh Sleep Quality Index), risk for depression (Edinburgh Postnatal Depression Scale), and restless legs syndrome were assessed by questionnaire. RESULTS: Primary outcome apnea-hypopnea index (4.2±3.9 events per hour in women in the case group compared with 3.8±2.3 events per hour in women in the control group) as well as other objective and subjective sleep measures, including oxygen desaturation index, snoring, and flow limitation, were not significantly different between groups. Sleepiness was greater in women in the case group than in women in the control group (9.8±3.6 compared with 7.2±3.6, P=.05). Additionally, 23% of women in the case group compared with 0% of women in the control group (P<.01) reported an Edinburgh Scale score of at least 10 (suggesting significant depression) and 46% of women with GDM reported restless legs syndrome compared to 19% of women in the control group (P=.07). CONCLUSION: There was no association between GDM and sleep-disordered breathing in pregnant women with prepregnancy BMIs under 35 and no medical comorbidities.