Association between maternal antibiotic exposure and emotional and behavioural problems in children at four years of age: A biomonitoring-based prospective study.

BACKGROUND: Maternal exposure to multiple antibiotics exposure during pregnancy has attracted extensive attention, but biomonitoring studies linking prenatal antibiotic exposure to emotional and behavioural problems in children are limited. METHODS: A total of 2475 pregnant women from the Ma'anshan Birth Cohort were included, and the Strengths and Difficulties Questionnaire was completed when their children turned four years of age. The levels of 41 maternal urinary antibiotics and two metabolites were measured during the first, second and third trimesters. Generalized estimating equations and binary logistic regression models were applied to analyse the associations between maternal antibiotic exposure and emotional and behavioural problems in children and to determine the sensitive period, respectively. A quantile-based g-computation (QGC) approach was employed to examine the combined effects of multiple antibiotics on emotional and behavioural problems in children. RESULTS: Overall, florfenicol and preferred-as-veterinary antibiotic (PVA) exposure during pregnancy increased the risk of emotional problems in children, and ofloxacin exposure increased the risk of hyperactivity-inattention. Maternal exposure to trimethoprime, ciprofloxacin, florfenicol, other antibiotics and PVA exposure during the first trimester was positively associated with emotional problems in children. Second-trimester trimethoprime concentrations and third-trimester ciprofloxacin concentrations were positively associated with hyperactivity-inattention. Third-trimester veterinary antibiotic (VA) exposure was negatively associated with hyperactivity-inattention, and second-trimester VA and PVA exposure was negatively associated with peer problems. The QGC model revealed that mixed antibiotic exposure in the first trimester exacerbated the risk of childhood emotional problems (the contribution of ciprofloxacin is prominent), and mixed antibiotic exposure in the second trimester increased the risk of hyperactivity-inattention (the contribution of trimethoprime is prominent). CONCLUSION: Maternal mixed antibiotic exposure during the first and second trimesters increases the risk of emotional problems and hyperactivity-inattention in children at four years of age.

Associating prenatal antibiotics exposure with attention deficit hyperactivity disorder symptoms in preschool children: The role of maternal vitamin D.

BACKGROUND: The associations between prenatal antibiotics exposure and attention-deficit/hyperactivity disorder (ADHD) in preschoolers, and the role of maternal vitamin D in these associations, remain to be explored. OBJECTIVES: To evaluate the relationships between multiple maternal urinary antibiotics levels and preschoolers' ADHD symptoms, and to identify the potential modifying effects of maternal vitamin D. METHODS: Based on a prospective birth cohort, the present study included 2033 motherchild pairs. Maternal urine and serum samples were collected during all three trimesters to measure the urinary concentrations of 43 antibiotics (including two metabolites) and the serum vitamin D levels. The ADHD symptoms of preschoolers were assessed using the Diagnostic and Statistical Manual-oriented ADHD problems scale in the Achenbach Child Behavior Checklist. Multiple informant models in the form of logistic regression were conducted to investigate the associations between prenatal antibiotics exposure and preschooler ADHD symptoms, and these associations were stratified by child sex and maternal vitamin D status. RESULTS: Compared with the lowest tertile concentrations, maternal exposure to the middle tertile concentrations of doxycycline and human antibiotics/preferred as human antibiotics (HAs/PHAs), and the highest tertile concentrations of doxycycline during the first trimester were associated with an increased risk of ADHD symptoms in children. An increased risk of ADHD symptoms was observed in girls exposed to the highest tertile levels of sulfamethazine during the second trimester. Furthermore, pregnant women with vitamin D deficiency have a greater risk of ADHD symptoms in their offspring after exposure to doxycycline in the first trimester. CONCLUSIONS: Maternal exposure to doxycycline and HAs/PHAs during the first trimester increases the risk of ADHD symptoms in preschoolers. Mid-pregnancy sulfamethazine exposure increases the risk of ADHD symptoms in girls. Maternal vitamin D deficiency during pregnancy may exacerbate the adverse effects of doxycycline exposure on ADHD symptoms.

Placental inflammatory cytokines mRNA expression and preschool children's cognitive performance: a birth cohort study in China.

BACKGROUND: The immunologic milieu at the maternal-fetal interface has profound effects on propelling the development of the fetal brain. However, accessible epidemiological studies concerning the association between placental inflammatory cytokines and the intellectual development of offspring in humans are limited. Therefore, we explored the possible link between mRNA expression of inflammatory cytokines in placenta and preschoolers' cognitive performance. METHODS: Study subjects were obtained from the Ma'anshan birth cohort (MABC). Placental samples were collected after delivery, and real-time quantitative polymerase chain reaction (RT-qPCR) was utilized to measure the mRNA expression levels of IL-8, IL-1ß, IL-6, TNF-α, CRP, IFN-γ, IL-10, and IL-4. Children's intellectual development was assessed at preschool age by using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV). Multiple linear regression and restricted cubic spline models were used for statistical analysis. RESULTS: A total of 1665 pairs of mother and child were included in the analysis. After adjusting for confounders and after correction for multiple comparisons, we observed that mRNA expression of IL-8 (ß = - 0.53; 95% CI, - 0.92 to - 0.15), IL-6 (ß = - 0.58; 95% CI, - 0.97 to - 0.19), TNF-α (ß = - 0.37; 95% CI, - 0.71 to - 0.02), and IFN-γ (ß = - 0.31; 95% CI, - 0.61 to - 0.03) in the placenta was negatively associated with preschoolers' full scale intelligence quotient (FSIQ). Both higher IL-8 and IL-6 were associated with lower children's low fluid reasoning index (FRI), and higher IFN-γ was associated with lower children's working memory index (WMI). After further adjusting for confounders and children's age at cognitive testing, the integrated index of six pro-inflammatory cytokines (index 2) was found to be significantly and negatively correlated with both the FSIQ and each sub-dimension (verbal comprehension index (VCI), visual spatial index (VSI), FRI, WMI, processing speed index (PSI)). Sex-stratified analyses showed that the association of IL-8, IFN-γ, and index 2 with children's cognitive development was mainly concentrated in boys. CONCLUSIONS: Evidence of an association between low cognitive performance and high expression of placental inflammatory cytokines (IL-8, IL-6, TNF-α, and IFN-γ) was found, highlighting the potential importance of intrauterine placental immune status in dissecting offspring cognitive development.

Mediating effects of DNA methylation in the association between sleep quality and infertility among women of childbearing age.

BACKGROUND: This study aims to investigate the association between sleep quality and infertility among women and to explore the mediating effects of DNA methylation in this association. METHODS: This study is a population-based case-control study. The relationship between sleep quality and infertility was investigated in women with anovulatory infertility (n = 43) and healthy controls (n = 43). Genome-wide DNA methylation was profiled from peripheral blood samples using the Illumina Infinium Human Methylation 850k BeadChip. Differentially methylated CpGs between cases and controls were identified using the ChAMP R package. The mediating effect of DNA methylation between sleep quality and infertility among women was investigated using the Bayesian estimation method provided by the R package "mediation". RESULTS: The survey included 86 women of reproductive age, with 43 participants each in the case and control groups. The average age of the women was 27.6 ± 2.8 years (case group: 27.8 ± 3.0 years, control group: 27.4 ± 2.7 years). A total of 262 differentially methylated CpGs corresponding to 185 genes were identified. Difficulty falling asleep was a risk factor for infertility in women (OR = 3.69, 95%CI = 1.14, 11.99), and a causal mediation effect of DNA methylation CpGs was found. The mediating effect coefficient for cg08298632 was 0.10 (95%CI = 0.01-0.22), and the proportion of the total effect mediated by this methylation site increased to 64.3%. CONCLUSION: These results suggest that DNA methylation CpGs (cg08298632) play a significant role in the relationship between difficulty falling asleep and infertility in females. These findings contribute to our understanding of the underlying mechanisms that connect difficulty falling asleep and infertility in women. Further studies are necessary to fully understand the biological significance and potential therapeutic applications of these findings. The identified DNA methylation sites provide new and valuable insights and potential targets for future studies aiming to prevent and treat female infertility.

Association between antibiotic exposure and the risk of infertility in women of childbearing age: A case-control study.

BACKGROUND: Based on self-report questionnaires, two previous epidemiological studies investigated the association between the exposure of women to antibiotics and their fertility. However, biomonitoring studies on low-dose antibiotic exposure, mainly from food and water, and its relation to the risk of infertility are missing. METHODS: Based on a case-control study design, 302 women with infertility (144 primary infertility, 158 secondary infertility) and 302 women with normal fertility, all aged 20-49 years, were recruited from Anhui Province, China, in 2020 and 2021. A total of 41 common antibiotics and two antibiotic metabolites in urine samples were determined by liquid chromatography-triple quadrupole tandem mass spectrometry (LC-QqQ-MS/MS). RESULTS: Twenty-eight antibiotics with detection rates from 10% to 100% in both cases (median concentration: ∼2.294 ng/mL) and controls (∼1.596 ng/mL) were included in the analysis. Logistic regression analysis revealed that after controlling for confounding factors, high concentrations of eight individual antibiotics (sulfamethoxazole, sulfaclozine, sulfamonomethoxine, penicillin G, chlorotetracycline, ofloxacin, norfloxacin, and cyadox) and four antibiotic classes (sulfonamides, tetracyclines, quinoxalines, and veterinary antibiotics) were related to a high risk of female infertility, with odds ratios (ORs) ranging from 1.30 to 2.86, except for chlorotetracycline (OR = 6.34), while another nine individual antibiotics (sulfamethazine, azithromycin, cefaclor, amoxicillin, oxytetracycline, pefloxacin, sarafloxacin, enrofloxacin, and florfenicol) and classes of chloramphenicol analogs and human antibiotics were related to a reduced risk of infertility, with ORs ranging from 0.70 to 0.20. Based on restricted cubic spline models after controlling for confounding factors, we observed that the relationship between all of the above protective antibiotics and infertility was nonlinear: A certain concentration could reduce the risk of female infertility while exceeding a safe dose could increase the risk of infertility. CONCLUSION: These results provide preliminary evidence that the effects of antibiotics on female fertility vary based on the active ingredient and usage and imply the importance of exposure dose. Future studies are needed to verify these results by controlling for multiple confounding factors.

Preconception exposure to environmental antibiotics among childbearing couples in Anhui and health risk assessment: A multicenter population-based representative study.

Only few studies have assessed the health effects due to preconception exposure to antibiotics among childbearing couples. This study investigated the status of preconception exposure to antibiotics among childbearing couples in Anhui, associated with health risks, and influencing factors. Overall, 1500 childbearing couples were randomly selected from the Reproductive Health of Childbearing Couples - Anhui Cohort (RHCC-AC). The urinary levels of 40 antibiotics and 2 metabolites were determined, and specific gravity (SG) adjusted concentrations of antibiotics were measured to assess health risks. Generalized linear models were used to assess the associations of urinary SG-adjusted concentration of antibiotics with demographic parameters and diet frequency. The total detection rates of all antibiotics were 98.9 % and 99.3 % in wives and husbands, respectively. The detection rates of veterinary antibiotics (VAs) and preferred as VAs (PVAs) were above 90 %. Among eight antibiotics, sulfonamides (95.1 %) and fluoroquinolones (87.6 %) had the highest detection rates in couples. Approximately four-fifths of couples were simultaneously exposed to at least three different antibiotics, and more than half of them were exposed to low concentrations of antibiotics. 8.9 % and 9.2 % of wives and husbands had hazard index value of antibiotics exposure greater than 1. Antibiotic concentrations were associated with residence, sampling season, and diet frequency. In Anhui, nearly 98 % of childbearing couples have environmental exposure to antibiotics, and VAs and PVAs are the primary antibiotics. More than 8 % of couples had health risks due to antibiotic exposure. Several potential determinants of urinary antibiotics deserve more attention in future research.

Urinary antibiotic exposure and low grip strength risk in community-dwelling elderly Chinese by gender and age.

Emerging studies have shown that environmental contaminants were related to decreased handgrip strength. Nevertheless, no prior research has investigated the relationship of exposure to environmental antibiotics with grip strength. Thus, we explored the relationship between urinary antibiotic burden and grip strength among the elderly in China. This study consisted of 451 men and 539 women from the baseline survey of a cohort study. Commonly used antibiotics for humans and animals were detected in 990 urine samples through a biomonitoring method. Grip strength was measured by an electronic dynamometer. We examined the associations of antibiotic exposure with low grip strength (LGS), grip strength, and grip strength index, respectively. Results suggested that 34.9% of participants developed LGS, and 93.0% of individuals were exposed to 1-10 antibiotics. Among women, oxytetracycline (Quartile 2: odds ratio: 2.97, 95% confidence interval: 1.36-6.50), florfenicol (Quartile 3: 2.60 [1.28-5.27]), fluoroquinolones (Quartile 4: 1.88 [1.07-3.30]), and chloramphenicols (Quartile 3: 2.73 [1.35-5.51]) could enhance LGS risk. Among men, ofloxacin (Quartile 2: 3.32 [1.45-7.59]) increased LGS risk, whereas tetracycline (Quartile 2: 0.31 [0.11-0.88]) was implicated in reduced LGS risk. In participants < 70 years, ofloxacin (Quartile 2: 3.00 [1.40-6.42]) could increase LGS risk. For participants who were 70 years of age or older, veterinary antibiotics (Quartile 3: 1.73 [1.02-2.94]) were linked to a 73% increased risk of LGS. Our findings suggested that antibiotics mainly pertained to LGS, and there were gender and age disparities in associations between antibiotic exposure and muscle strength indicators in the elderly Chinese population.

Prenatal single and combined exposure to phthalates associated with girls' BMI trajectory in the first six years.

Evidence of the influence of prenatal phthalate exposure on childhood longitudinal obesity markers is limited. Nested on the Ma'anshan birth cohort study, 990 mother-daughter pairs were included. Seven phthalate metabolites were determined in urine collected in each trimester. Each child underwent a physical examination from birth to 6 years of age twelve times. Latent class growth models were used to identify three trajectories of girls' body mass index (BMI). Logistic regression, quantile g-computation and Bayesian kernel machine regression models analyzed the relationships of prenatal exposure to individual and mixed phthalates with girls' body mass index (BMI) trajectory. Compared to the "lowest trajectory" class, prenatal average concentrations of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP, ORcrude = 2.095, 95 % CI = 1.014-4.328) and di(2-ethylhexyl) phthalate (DEHP, ORcrude = 2.336, 95 % CI = 1.022-5.338) during pregnancy were associated with an increased probability of being in the "highest trajectory" class. The average concentration of DEHP (ORcrude = 1.879, 95 % CI = 1.002-3.522) was associated with an increased probability of being in the "moderate trajectory" class. Stratified analyses by trimester of pregnancy mainly showed that third-trimester exposure to monoethyl phthalate (MEP, ORadjusted = 1.584, 95 % CI = 1.094-2.292), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP, ORadjusted = 2.885, 95 % CI = 1.367-6.088), MEHHP (ORadjusted = 2.425, 95 % CI = 1.335-4.407), DEHP (ORadjusted = 2.632, 95 % CI = 1.334-5.193) and high molecular weight phthalate (ORadjusted = 2.437, 95 % CI = 1.239-4.792) was associated with an increased probability of being in the "highest trajectory" class. However, the mixture of phthalates was not significantly related to the girl's BMI trajectory. In conclusion, in utero exposure to phthalates, including MEP and DEHP metabolites (MEHHP and MEOHP), was significantly associated with early childhood high BMI trajectories in girls. The third trimester of pregnancy seemed to be the window of vulnerability to phthalate exposure for girls' high BMI trajectory at periods of prenatal development. No evidence supported a significant relationship between combined exposure to phthalate metabolites and girls' high BMI trajectory.

Associations of typical antibiotic residues with elderly blood lipids and dyslipidemia in West Anhui, China.

Growing evidence has indicated the association of clinical antibiotic use with abnormal blood lipid levels; however, no epidemiological study has examined the relationship of antibiotic exposure, probably derived from food chains, with blood lipid levels. This study investigated the relationships of urinary antibiotic levels with blood lipid levels and dyslipidemias in the older population. Baseline data of 960 participants from the Cohort of Elderly Health and Environment Controllable Factors were used in the present study. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was performed to detect antibiotic residues in the urine samples of the participants. Our findings revealed that each 1 µg/g increase in enrofloxacin and ciprofloxacin levels was associated with an increase of 0.084 (95 % confidence interval (CI): 0.030, 0.139) and 0.049 (95 % CI: 0.012, 0.086) in triglyceride levels, respectively. Enrofloxacin was associated with an increased risk of hypertriglyceridemia. Each 1 µg/g increase in the enrofloxacin level corresponded to an increase of 0.052 (95 % CI: 0.006, 0.098) in the low-density lipoprotein cholesterol level. Furthermore, florfenicol exposure increased the risks of both hyperbetalipoproteinemia and hypoalphalipoproteinemia. By contrast, each 1 µg/g increase in sulfaclozine and doxycycline levels was associated with a - 0.062 (95 % CI: -0.111, -0.020), and - 0.083 (95 % CI: -0.160, -0.007) decrease in total cholesterol levels, respectively. Sulfaclozine was closely related to a decreased risk of hypercholesterolemia. Stratification analysis revealed specific differences in the correlation between antibiotic exposure and lipid levels based on the waist circumference (WC) values of the participants. Except for sulfaclozine and doxycycline, other antibiotics exerted adverse effects on lipid levels and increased dyslipidemia prevalence. The older participants with higher WC values were vulnerable to antibiotic exposure. Therefore, an appropriate understanding of the epidemiological attributes of antibiotic residues is indispensable to prevent abdominal obesity in the older population.

Prenatal low-dose antibiotic exposure and children allergic diseases at 4 years of age: A prospective birth cohort study.

BACKGROUND: Based on a medical record or questionnaire survey approach, previous epidemiological studies have investigated associations between maternal antibiotic exposure during pregnancy and childhood allergic diseases. However, biomonitoring studies on the prenatal low-dose antibiotic exposure, mainly from the environment and contaminated food, and in relation to children allergic diseases, are missing. OBJECTIVES: This research aimed to examine the associations between prenatal low-dose antibiotic exposure measured at multiple time points and children current allergic diseases at 4 years of age. METHODS: The current study including 2453 mother-child pairs was based on the Ma'anshan Birth Cohort study. Selected 41 antibiotics and their two metabolites, which including human antibiotics (HAs), preferred as human antibiotics (PHAs), veterinary antibiotics (VAs) and preferred as veterinary antibiotics (PVAs), in urine samples from 2453 pregnant women were biomonitored through liquid chromatography-triple quadrupole tandem mass spectrometry. Information on children current allergic diseases were collected via validated questionnaires. Generalized estimating equation were used to explore the associations between the repeated measurements of maternal urinary antibiotic over three trimesters and current allergic diseases in children. RESULTS: The detection rates of nine individual antibiotics in the three trimester during pregnancy are greater than 10%, and the 90th percentile concentration of the detected antibiotics ranges from 0.07 to 22.34 µg/g, and the 95th percentile concentration ranges from 0.17 to 59.57 µg/g. Among the participants, each one-unit concentration increment of sulfamethazine (adjusted OR=1.28, 95% CI: 1.10, 1.49, P-FDR=0.014) in the first trimester and ciprofloxacin (adjusted OR=1.17, 95% CI: 1.07, 1.28, P-FDR=0.008) in the second trimester were associated with an increased risk of current eczema in children. In the third trimester, each one-unit concentration increment of oxytetracycline (adjusted OR=1.90, 95% CI: 1.30, 2.78, P-FDR=0.014) was associated with an increased risk of current asthma in children. Gender-stratified analyses demonstrated that no gender differences were observed in the associations between prenatal antibiotic exposure and current allergic diseases in children. CONCLUSIONS: Maternal exposure to certain specific VAs or PVAs (sulfamethazine, ciprofloxacin and oxytetracycline) in different trimesters was associated with an increased risk of current asthma and current eczema in 4-year-old children. No gender differences were found in these associations. Further studies are warranted to confirm our findings and explore the potential mechanisms.

Prenatal antibiotics exposure and preschoolers' internalizing and externalizing problems: A biomonitoring-based prospective birth cohort study.

BACKGROUND: Biomonitoring-based epidemiological studies on prenatal antibiotic exposure and behavioral problems in preschoolers are lacking. The present study aimed to investigate the relationship between prenatal antibiotic exposure and internalizing and externalizing problems in preschoolers. METHODS: Data from 2449 mother-child pairs were analyzed. Urine samples were repeatedly collected across three trimesters, and 43 antibiotics and 2 metabolites were measured, including preferred as veterinary antibiotics (PVAs), VAs, preferred as human antibiotics and human antibiotics. Preschoolers' internalizing and externalizing problems were evaluated by the Achenbach Child Behavior Checklist. Poisson regression models with generalized estimating equations were used to estimate risk ratios (RRs) and 95 % confidence intervals (CIs) for preschoolers' internalizing, externalizing and total problems across tertiles of antibiotic concentrations during three periods of pregnancy, and performed several subgroup analyses. RESULTS: First-trimester urinary oxytetracycline (RR = 1.69, 95%CI: 1.20, 2.39, P-FDR = 0.011), tetracycline (RR = 1.91, 95%CI: 1.36, 2.68, P-FDR < 0.001), doxycycline (RR = 1.66, 95%CI: 1.28, 2.17, P-FDR < 0.001) and PVAs (RR = 1.79, 95%CI: 1.29, 2.48, P-FDR < 0.001) concentrations in the highest tertile were related to an elevated risk of internalizing problems compared with concentrations in the lowest tertile. First-trimester urinary doxycycline concentrations in the third tertile were also associated with an increased risk of externalizing problems compared with the first tertile (RR = 2.00, 95%CI: 1.28, 3.15, P-FDR = 0.042). Compared with concentrations in the lowest tertile, first-trimester urinary doxycycline (RR = 1.63, 95%CI: 1.19, 2.22, P-FDR = 0.028) and PVAs (RR = 1.67, 95%CI: 1.14, 2.43, P-FDR = 0.047) concentrations in the middle tertile were related to an increased risk of total problems. Furthermore, the type of main caregiver and children's outdoor activities time modified the relationships between specific prenatal antibiotic exposure and preschoolers' behavioral problems. CONCLUSIONS: Exposure to specific antibiotics during the first trimester may be related to an increased risk of internalizing and externalizing problems in preschoolers.

Associations between antibiotic exposure and abnormal cardiac enzyme profiles in older Chinese adults.

Biomonitoring methods can be used to measure exposure to antibiotics in the general population; however, epidemiological data on the associations between urinary antibiotic levels and the cardiac profiles of enzymes lactate dehydrogenase, creatine kinase, and creatine kinase isoenzyme in older adults remain sparse. We investigated these associations in 990 individuals from the Cohort of Elderly Health and Environment Controllable Factors. Antibiotic residues in urine samples were analyzed using high-performance liquid chromatography-tandem mass spectrometry. Urinary levels of 34 antibiotics were measured. The participants' cardiac enzyme profiles were influenced by sex, age, marital status, education level, cohabitation status, physical activity, dietary structure, body mass index, depression presence and salt, sugar, and oil consumption (P < 0.05). Oxytetracycline, tetracycline, doxycycline, sulfaclozine, and, florfenicol concentrations were negatively associated with the risk of having an abnormal cardiac enzyme profile. Older adults exposed to higher concentrations of norfloxacin had a higher risk of LDH anomalies. After antibiotics were classified, we identified associations between exposure to chloramphenicols, sulfonamides, or veterinary antibiotics and a lower risk of having an abnormal cardiac enzyme profile. Obtaining an accurate epidemiological profile of antibiotic exposure is indispensable for the prevention and detection of cardiac enzyme profile abnormalities in older adults.

Association of maternal and cord blood barium exposure with preschoolers' intellectual function: Evidence from the Ma'anshan Birth Cohort (MABC) study.

OBJECTIVES: Barium is widely involved in drilling fluids, plastics, and personal care products. Although the neurodevelopmental toxicity of barium has been reported in animals, human data are scarce. This study aimed to investigate the effect of prenatal barium concentrations on preschoolers' intellectual function based on a birth cohort study. METHODS: A total of 2164 mother-child pairs from Ma'anshan city, China were included in this study. We measured serum barium concentrations in the first, second, and third trimesters and in cord blood. Intellectual function in children aged 3.0-6.0 years old was assessed using the Chinese version of the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition (WPPSI-IV). Linear regression models were used to analyze the association between averaged barium exposure during pregnancy and intellectual function. Multiple informant models were performed to jointly test for differences in associations between four repeated barium exposure and intellectual function. All models were further stratified by child sex. RESULTS: Collectively, we observed significant inverse associations of average maternal barium exposure levels with verbal comprehension index (VCI), visual spatial index (VSI), processing speed index (PSI), and full-scale intelligence quotient (FSIQ) scores. Maternal serum log10-transformed barium levels in the second trimester were inversely associated with VCI [-2.33 (95%CI: -4.02, -0.64)], VSI [-2.30 (95%CI: -4.08, -0.52)], working memory index (WMI) [-2.09 (95%CI: -3.71, -0.46)], PSI [-2.23 (95%CI: -3.82, -0.65)], and FSIQ scores [-2.73 (95%CI: -4.23, -1.22)]. Prenatal barium exposure was inversely associated with VCI, VSI, WMI, PSI, and FSIQ in girls, except for the fluid reasoning index (FRI). Additionally, inverse associations were found between prenatal barium exposure and VSI, PSI, and FSIQ in boys. CONCLUSIONS: Prenatal barium exposure had detrimental effects on intellectual function in preschoolers and girls drove these inverse associations more than boys. The second trimester may be the critical window of neurotoxicity to barium exposure.

Associating phthalate exposure during pregnancy with preschooler's FMI, ABSI and BRI trajectories via putative mechanism pathways.

Phthalates are well-known obesogens, but a few studies have explored their impacts on the childhood fat mass index (FMI), body shape index (ABSI) and body roundness index (BRI). Information from 2950 participants recruited in the Ma'anshan Birth Cohort was analyzed. The relationships between six maternal phthalate metabolites and their mixture and childhood FMI, ABSI and BRI were investigated. FMI, ABSI and BRI in children aged 3.5 y, 4.0 y, 4.5 y, 5.0 y, 5.5 y and 6.0 y were calculated. The latent class trajectory modeling categorized the FMI trajectories into "rapidly increasing FMI" (4.71%) and "stable FMI" (95.29%) groups; ABSI trajectories were categorized as "decreasing ABSI" (32.74%), "stable ABSI" (46.55%), "slowly increasing ABSI" (13.26%), "moderately increasing ABSI" (5.27%) and "rapidly increasing ABSI" (2.18%) groups; BRI trajectories were categorized as "increasing BRI" (2.82%), "stable BRI" (19.85%), and "decreasing BRI" (77.34%) groups. Prenatal MEP exposure was associated with repeated measurements of FMI (ß = 0.111, 95% CI = 0.002-0.221), ABSI (ß = 0.145, 95% CI = 0.023-0.268) and BRI (ß = 0.046, 95% CI = -0.005-0.097). Compared with each stable trajectory group, prenatal MEP (OR = 0.650, 95% CI = 0.502-0.844) and MBP (OR = 0.717, 95% CI = 0.984-1.015) were linked to a decreased risk of "decreasing BRI" in children; there was a negative relationship between MBP and the "decreasing ABSI" group (OR = 0.667, 95% CI = 0.487-0.914), and MEP increased the risks of "slowly increasing ABSI" (OR = 1.668, 95% CI = 1.210-2.299) and "rapidly increasing ABSI" (OR = 2.522, 95% CI = 1.266-5.024) in children. Phthalate mixture during pregnancy showed significant relationships with all anthropometric indicator trajectories, with MEP and MBP always being of the largest importance. In conclusion, this study suggested that prenatal phthalate coexposure increased the childhood probability of being in higher ABSI and BRI trajectory groups. That is, children were more likely to be obese when they were exposed to higher levels of some phthalate metabolites and their mixture. The low-molecular weight phthalates, including MEP and MBP, contributed the greatest weights.

Combined effects of prenatal phthalate exposure on cardiometabolic risk score among 4- to 7-year-old children: MABC study.

There is currently no consensus about the impact of prenatal phthalate exposure on blood pressure and glycolipids in children. Few studies consider the health effects as an integrated indicator. The combined effect of multiple phthalate exposures is often ignored. Based on the Ma'anshan Birth Cohort, 2298 woman-child pairs were included in this study. Maternal urine was collected in each trimester to analyze 6 phthalate metabolites. The overall cardiometabolic risk (CMR) score was calculated based on serum glycolipids and blood pressure for children aged 4-7 years. A higher score represents a less favorable CMR profile. The restricted cubic spline model was used to explore the relationship between prenatal phthalate exposure and childhood CMR score. In addition, the quantile g-computation and the Bayesian kernel machine regression were used to evaluate the combined effect. The MBP exposure in the 1st trimester (MBP-1st) and the MEP-2nd were non-linearly associated with the CMR score (Fnonlinear = 3.28 and 5.60, Pnonlinear = 0.0378 and 0.0038, respectively). The MBP-3rd (Flinear = 5.31, Plinear = 0.0012) and the ∑LMWP-3rd (Flinear = 4.37, Plinear = 0.0045) were negatively associated with the score in a linear manner. The phthalate mixture in the 2nd trimester increased the score (psil = 0.1747, 95% CI = 0.0077-0.3416), with the MEP being the most common [weights = 0.5290; posterior inclusion probability (PIP) = 0.40]. The phthalate mixture in the 3rd trimester decreased the score (psil = -0.2024, 95% CI = -0.4097－0.0048), with the MEHP (weights = -0.5101; PIP = 0.14) and the MBP (weights = -0.3993, PIP = 1.00) being the greatest contributors. In conclusion, the MBP-1st and the MEP-2nd are non-linearly associated with the cardiometabolic risk in children. The MBP-3rd and the ∑LMWP-3rd decrease the childhood risk. The combined exposure to phthalate mixture in the second and third trimester elevates and decreases the risk of childhood cardiometabolism, respectively.

Associations of social jetlag and emotional and behavioral problems among Chinese preschoolers.

To describe the prevalence of social jetlag among preschoolers and explore its association with emotional and behavioral problems, we conducted a cross-sectional survey of healthy development among preschool children in 11 cities in October and November 2017. The study included 27 200 children aged 3-6 years and the questionnaires were completed exclusively by their parents or main caregivers. Social jetlag was calculated by difference of sleep midpoint between weekdays and weekends. Emotional and behavioral problems (emotional symptoms, conduct problems, hyperactivity, peer interaction, and prosocial behavior) among preschoolers were assessed by the Strengths and Difficulties Questionnaire (SDQ). The binary logistic regression model was used to examine the association between social jetlag and emotional/behavioral problems in preschool children. The social jetlag was 0.60 hours in boys and 0.64 hours in girls. After adjusting for confounding factors as children' s gender, age, only child, living area, family economic status, mother's age and education, father's education, screen time and full-day sleep time, we found that longer social jetlag (≥1 h/d) was positively associated with overall emotional and behavioral problems (OR = 1.20, 95%CI: 1.10-1.32; P < .001), emotional symptoms (OR = 1.23, 95% CI: 1.11-1.15, P < .001), hyperactivity (OR = 1.20, 95%CI: 1.11-1.30, P < .001) and conduct problems (OR = 1.18, 95%CI: 1.07-1.31, P < .01). We found that social jetlag is prevalent among Chinese preschool children and is positively associated with emotional and behavioral problems.

Relationship of individual and mixed prenatal phthalate exposure with placental structure and efficiency in the prospective Ma'anshan Birth Cohort Study.

BACKGROUND: Few studies have investigated the associations between prenatal phthalate exposure and placental structure and function with inconsistent conclusions. METHODS: Nested on the Ma'anshan Birth Cohort study, 2723 women provided spot urine samples during the first, second and third trimesters of pregnancy to analyze six phthalate metabolites. The outcomes of interest were placental weight, efficiency (birth weight/placental weight), chorionic disc area and disc eccentricity. The relationships of prenatal exposure to a single phthalate with placental measures were analyzed. The associations between prenatal phthalate mixture exposure and placental measures were also evaluated. RESULTS: Most phthalate metabolites were significantly associated with placental weight, efficiency and chorionic disc area during the whole gestation and in each trimester of pregnancy, with different directions of relationships. Sensitivity analyses revealed similar findings, indicating the robustness of the statistical results. Furthermore, inverted U-shaped nonlinear relationships of prenatal exposure to some phthalate metabolites with placental weight, efficiency and chorionic plate area were observed. However, quantile g-computation mixture models did not reveal any association between maternal combined exposure to the total phthalate metabolites and placental measures. CONCLUSIONS: Maternal exposure to most phthalates and their metabolites was associated with placental weight, efficiency and chorionic plate area in both a linear manner and an inverted U-shaped nonlinear manner. However, the mixture of multiple phthalate metabolites was not observed to be associated with any placental measure.

Sex Discrepancy Observed for Gestational Metabolic Syndrome Parameters and Polygenic Risk Associated With Preschoolers' BMI Growth Trajectory: The Ma'anshan Birth Cohort Study.

Background: Few studies have investigated the associations of childhood growth trajectories with the prenatal metabolic risks of mothers and their interaction with children's genetic susceptibility. Objective: To investigate the effects of gestational metabolic syndrome (GMS) risks and children's polygenic risk scores (PRSs), and their interaction effect on the BMI trajectory and obesity risk of offspring from birth to 6 years of age. Methods: A total of 2,603 mother-child pairs were recruited from the Ma'anshan birth cohort (Anhui Province of China) study. Data on maternal prepregnancy obesity, gestational weight gain (GWG), gestational diabetes mellitus (GDM), and hypertensive disorders of pregnancy (HDP) were used to evaluate maternal GMS risk. In addition, 1,482 cord blood samples were used to genotype 11 candidate single-nucleotide polymorphisms (SNPs) to calculate children's PRSs. The latent class growth model using the longitudinal BMI-for-age z scores (BMIz) was applied to validly capture the BMIz growth trajectory. Results: Maternal GMS status was associated with higher BMIz scores and with an increased risk of overweight/obesity. Positive relationships were revealed between PRS and the risk of overweight/obesity among girls. Additionally, maternal GMS significantly interacted with the child's PRS on BMIz scores and the risk of overweight/obesity among girls. Hierarchical BMI trajectory graphs by different exposure groups showed consistent findings, and both boys' and girls' BMIz trajectories were divided into three groups. Among girls, the higher the GMS risk or PRS they had, the higher the probability of being in the high BMIz trajectory group. Conclusions: Maternal GMS status increased BMIz scores and the risk of obesity in both boys and girls and elevated the child's BMI trajectory from birth to 6 years of age among girls. PRSs were significantly associated with children's BMI trajectory and the risk of obesity and modified the associations between maternal GMS status and obesity biomarkers only among girls. Thus, regarding childhood obesity, steps should be taken to decrease maternal metabolic risks before and during pregnancy, and sex discrepancies should be noted to identify high-risk populations after birth to hierarchically manage them.

Urinary tetracycline antibiotics exposure during pregnancy and maternal thyroid hormone parameters: A repeated measures study.

BACKGROUND: Studies on potential maternal thyrotoxicity related to tetracycline antibiotics exposure during pregnancy are lacking. Based on a large prospective cohort study, this study aimed to examine the associations between tetracycline antibiotics exposure in maternal urine and maternal thyroid hormone parameters. METHODS: Based on the Ma'anshan Birth Cohort study, urine and serum samples of 2969 pregnant women were collected in the first, second and third trimesters. Tetracycline antibiotics, including oxytetracycline, chlorotetracycline, tetracycline and doxycycline in urine samples, as well as free thyroxine (FT4), thyroid stimulating hormone (TSH), total triiodothyronine (TT3) and total thyroxine (TT4) levels in serum samples, were measured. Linear mixed models and multivariate linear regression models were employed to examine associations between tetracycline antibiotics exposure during pregnancy and maternal thyroid hormone parameters. RESULTS: The detection rates of four individual tetracycline antibiotics and all antibiotics (sum of four individual tetracycline antibiotics) in the three trimesters were 5.0%-52.3%, and the 95th percentile concentration ranged from 0.11 to 4.84 ng/mL. After adjusting for potential confounding factors, the repeated measures analyses indicated that pregnant women exposed to doxycycline and all antibiotics during the entire pregnancy were negatively associated with serum FT4 and TT4 levels but positively associated with serum TSH and TT3 levels. Trimester-stratified analyses found that doxycycline and all antibiotics exposure during the first trimester were negatively associated with serum FT4 and TT4 levels, while doxycycline was positively associated with TSH levels. In the third trimester, a significant association was only found between all antibiotics and TSH levels. CONCLUSIONS: Our results suggest that exposure of pregnant women to tetracycline antibiotics is associated with maternal thyroid hormone parameters, and the first trimester might be the most critical window. More studies are needed to substantiate our findings and determine the underlying biological mechanisms.

Sex-specific mediation of placental inflammatory biomarkers in the effects of prenatal phthalate coexposure on preschooler cognitive development.

The objective of this study is to investigate the mediating effect of placental inflammatory biomarkers on the relationship between prenatal phthalate coexposure and cognitive development in preschoolers. A subgroup of 1660 mother-child pairs from the Ma'anshan Birth Cohort study were included. We measured the levels of phthalate metabolites of dibutyl phthalate (DBP), butyl benzyl phthalate (BBzP), and di (2-ethylhexyl) phthalate (DEHP) in all the women included in the study from three urine samples collected in each of the trimesters. A potency-weighted sum of coexposure to DBP, BBzP, and DEHP (indicator: ∑PAE) was calculated. The mRNA of the proinflammatory cytokine IL-6 and the classically activated macrophage (M1) biomarker CD68 was analyzed using placental tissues. The Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition-Chinese was used to evaluate the full-scale intelligence quotient (FSIQ) of children aged 2.5-6 years. Average ∑PAEs and ∑PAEs in each trimester were associated with IL-6 and CD68. ∑PAE in the first trimester was positively associated with IL-6 (ß = 0.11, 95% CIs = 0.03-0.19) and CD68 (ß = 0.16, 95% CIs = 0.04-0.28), and negatively associated with FSIQ (ß =-0.06, 95% CIs = -0.11 to -0.02), verbal comprehension (ß =-0.06, 95% CIs = -0.11 to -0.01), and processing speed (ß =-0.07, 95% CIs = -0.12 to -0.01). Additionally, sex discrepancies were observed for the mediating effects of placental inflammation on the relationships between ∑PAE and children's cognitive development. For instance, the association between ∑PAE in early pregnancy and FSIQ was partially mediated by IL-6 (estimated proportion mediated: 21.85%) and CD68 (estimated proportion mediated: 16.2%). Gender-specific associations and trimester-specific relationships of prenatal multiple phthalate coexposure were revealed. ∑PAE in the first trimester of pregnancy was associated with increased of placental inflammation, and a decrease in preschoolers' cognitive development. In boys, placental IL-6 and CD68 elevation resulting from phthalates might be potential mechanisms of poor cognitive development.