STZ-induced gestational diabetes exposure alters PTEN/AKT/mTOR-mediated autophagy signaling pathway leading to increase the risk of neonatal hypoxic-ischemic encephalopathy.

Exposure to gestational diabetes mellitus (GDM) during pregnancy has significant consequences for the unborn baby and newborn infant. However, whether and how GDM exposure induces the development of neonatal brain hypoxia/ischemia-sensitive phenotype and the underlying molecular mechanisms remain unclear. In this study, we used a late GDM rat model induced by administration of streptozotocin (STZ) on gestational day 12 and investigated its effects of GDM on neonatal brain development. The pregnant rats exhibited increased blood glucose levels in a dose-dependent manner after STZ administration. STZ-induced maternal hyperglycemia led to reduced blood glucose levels in neonatal offspring, resulting in growth restriction and an increased brain to body weight ratio. Importantly, GDM exposure increased susceptibility to hypoxia/ischemia (HI)-induced brain infarct sizes compared to the controls in both male and female neonatal offspring. Further molecular analysis revealed alterations in the PTEN/AKT/mTOR/autophagy signaling pathway in neonatal male offspring brains, along with increased ROS production and autophagy-related proteins (Atg5 and LC3-II). Treatment with the PTEN inhibitor bisperoxovanadate (BPV) eliminated the differences in HI-induced brain infarct sizes between the GDM-exposed and the control groups. These findings provide novel evidence of the development of a brain hypoxia/ischemia-sensitive phenotype in response to GDM exposure and highlight the role of the PTEN/AKT/mTOR/autophagy signaling pathway in this process.

Exposure to Short- and Medium-Chain Chlorinated Paraffins and the Risk of Gestational Diabetes Mellitus: A Nested Case-Control Study in Eastern China.

Toxicological studies have indicated that exposure to chlorinated paraffins (CPs) may disrupt intracellular glucose and energy metabolism. However, limited information exists regarding the impact of human CP exposure on glucose homeostasis and its potential association with an increased risk of developing gestational diabetes mellitus (GDM). Here, we conducted a prospective study with a nested case-control design to evaluate the link between short- and medium-chain CP (SCCPs and MCCPs) exposures during pregnancy and the risk of GDM. Serum samples from 102 GDM-diagnosed pregnant women and 204 healthy controls were collected in Hangzhou, Eastern China. The median (interquartile range, IQR) concentration of SCCPs was 161 (127, 236) ng/mL in the GDM group compared to 127 (96.9, 176) ng/mL in the non-GDM group (p < 0.01). For MCCPs, the GDM group had a median concentration of 144 (117, 174) ng/mL, while the control group was 114 (78.1, 162) ng/mL (p < 0.01). Compared to the lowest quartile as the reference, the adjusted odds ratios (ORs) of GDM were 7.07 (95% CI: 2.87, 17.40) and 3.34 (95% CI: 1.48, 7.53) in the highest quartile of ∑SCCP and ∑MCCP levels, respectively, with MCCPs demonstrating an inverted U-shaped association with GDM. Weighted quantile sum regression evaluated the joint effects of all CPs on GDM and glucose homeostasis. Among all CP congeners, C13H23Cl5 and C10H16Cl6 were the crucial variables driving the positive association with the GDM risk. Our results demonstrated a significant positive association between CP concentration in maternal serum and GDM risk, and exposure to SCCPs and MCCPs may disturb maternal glucose homeostasis. These findings contribute to a better understanding of the health risks of CP exposure and the role of environmental contaminants in the pathogenesis of GDM.

Association between prenatal perfluorinated compounds exposure and risk of pregnancy complications: A meta-analysis.

BACKGROUND AND OBJECTIVE: Per- and polyfluoroalkyl substances (PFASs) have been shown to be persistent and bioaccumulative. An elevated danger of pregnancy complications perhaps connected with exposure to PFASs, but the potential effects remain elusive. The objective of this study is to investigate the possible association between PFASs exposure and pregnancy complications, drawing upon existing evidence. METHODS: Electronic databases of PubMed, Qvid Medline, Embase, and Web of Science were searched thoroughly to identify eligible research published prior to November 28, 2023, examining the relationship between PFASs and pregnancy-related complications. To evaluate the quality of observational studies incorporated into the article, the Strengthening Reporting of Observational Studies in Epidemiology (STROBE) tool was utilized. The main outcomes assessed in this study included gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), gestational hypertension (GH), and preeclampsia (PE). RESULTS: Twenty-five relevant studies involving 30079 participants were finally selected from four databases. The combined estimates indicate that prenatal exposure to perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorobutane sulfonic acid (PFBS), and perfluoroenanthic acid (PFHpA) is associated with gestational diabetes mellitus (GDM) (PFOA: OR = 1.45, 95%CI: 1.07-1.94, P = 0.015; PFHxS: OR = 1.16, 95%CI: 1.00-1.36, P = 0.055; PFBS: OR = 1.44, 95%CI: 1.16-1.79, P = 0.001; PFHpA: OR = 1.41, 95%CI: 1.10-1.82, P = 0.008). The exposure to PFBS is positively associated with HDP (OR = 1.27, 95%CI: 1.14-1.41, P < 0.001), while both PFOA and PFHpA demonstrate statistically significant positive correlations with GH (PFOA: OR = 1.09, 95%CI: 1.00-1.19, P = 0.049; PFHpA: OR = 1.43, 95%CI: 1.15-1.78, P = 0.001). Negative correlations were observed for prenatal perfluorododecanoic acid (PFDoA) exposure and GH (OR = 0.71, 95%CI: 0.57-0.87, P = 0.001). However, no compelling evidence was identified to link PFASs exposure with the risk of PE. CONCLUSION: According to the meta-analysis findings, exposure to PFASs may be linked to GDM, HDP, and GH, but it does not significantly raise the risk of PE alone. Further research with larger sample size is required to verify this potential association and explore the biological mechanisms.

Epidemic-specific association of maternal exposure to per- and polyfluoroalkyl substances (PFAS) and their components with maternal glucose metabolism: A cross-sectional analysis in a birth cohort from Hong Kong.

Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals that have been linked to increased risk of gestational diabetes mellitus (GDM) and may affect glucose metabolisms during pregnancy. We examined the associations between maternal PFAS exposure and maternal glucose metabolisms and GDM risk among 1601 mothers who joined the Hyperglycaemia-and-Adverse-Pregnancy-Outcome (HAPO) Study in Hong Kong in 2001-2006. All mothers underwent a 75 g-oral-glucose-tolerance test at 24-32 weeks of gestation. We measured serum concentrations of six PFAS biomarkers using high-performance liquid-chromatography-coupled-with-tandem-mass-spectrometry (LC-MS-MS). We fitted conventional and advanced models (quantile-g-computation [qgcomp] and Bayesian-kernel machine regression [BKMR]) to assess the associations of individual and a mixture of PFAS with glycaemic traits. Subgroup analyses were performed based on the enrollment period by the severe-acute-respiratory-syndrome (SARS) epidemic periods in Hong Kong between March 2003 and May 2004. PFOS and PFOA were the main components of PFAS mixture among 1601 pregnant women in the Hong Kong HAPO study, with significantly higher median PFOS concentrations (19.09 ng/mL), compared to Chinese pregnant women (9.40 ng/mL) and US women (5.27 ng/mL). Maternal exposure to PFAS mixture was associated with higher HbA1c in the qgcomp (ß = 0.04, 95 % CI: 0.01-0.06) model. We did not observe significant associations of PFAS mixture with fasting plasma glucose (PG), 1-h and 2-h PG in either model, except for 2-h PG in the qgcmop model (ß = 0.074, 95 % CI: 0.01-0.15). PFOS was the primary contributor to the overall positive effects on HbA1c. Epidemic-specific analyses showed specific associations between PFAS exposure and the odds of GDM in the pre-SARS epidemic period. The median concentration of PFOS was highest during the peri-SARS epidemic (21.2 [14.5-43.6] ng/mL) compared with the pre-SARS (12.3 [9.2-19.9] ng/mL) and post-SARS (20.3 [14.2-46.3] ng/mL) epidemic periods. Potential interactions and exposure-response relationships between PFOA and PFNA with elevated HbA1c were observed in the peri-SARS period in BKMR model. Maternal exposure to PFAS mixture was associated with altered glucose metabolism during pregnancy. SARS epidemic-specific associations call for further studies on its long-term adverse health effects, especially potential modified associations by lifestyle changes during the COVID-19 pandemic.

Association of prenatal exposure to PM2.5 and NO2 with gestational diabetes in Western New York.

BACKGROUND: Although many studies have examined the association between prenatal air pollution exposure and gestational diabetes (GDM), the relevant exposure windows remain inconclusive. We aim to examine the association between preconception and trimester-specific exposure to PM2.5 and NO2 and GDM risk and explore modifying effects of maternal age, pre-pregnancy body mass index (BMI), smoking, exercise during pregnancy, race and ethnicity, and neighborhood disadvantage. METHODS: Analyses included 192,508 birth records of singletons born to women without pre-existing diabetes in Western New York, 2004-2016. Daily PM2.5 and NO2 at 1-km2 grids were estimated from ensemble-based models. We assigned each birth with exposures averaged in preconception and each trimester based on residential zip-codes. We used logistic regression to examine the associations and distributed lag models (DLMs) to explore the sensitive windows by month. Relative excess risk due to interaction (RERI) and multiplicative interaction terms were calculated. RESULTS: GDM was associated with PM2.5 averaged in the first two trimesters (per 2.5 µg/m3: OR = 1.08, 95% CI: 1.01, 1.14) or from preconception to the second trimester (per 2.5 µg/m3: OR = 1.10, 95% CI: 1.03, 1.18). NO2 exposure during each averaging period was associated with GDM risk (per 10 ppb, preconception: OR = 1.10, 95% CI: 1.06, 1.14; first trimester: OR = 1.12, 95% CI: 1.08, 1.16; second trimester: OR = 1.10, 95% CI: 1.06, 1.14). In DLMs, sensitive windows were identified in the 5th and 6th gestational months for PM2.5 and one month before and three months after conception for NO2. Evidence of interaction was identified for pre-pregnancy BMI with PM2.5 (P-for-interaction = 0.023; RERI = 0.21, 95% CI: 0.10, 0.33) and with NO2 (P-for-interaction = 0.164; RERI = 0.16, 95% CI: 0.04, 0.27). CONCLUSION: PM2.5 and NO2 exposure may increase GDM risk, and sensitive windows may be the late second trimester for PM2.5 and periconception for NO2. Women with higher pre-pregnancy BMI may be more susceptible to exposure effects.

Protective effect of tretinoin derivative and TXNRD1 protein on streptozotocin induced gestational diabetes via an age-rage signaling-pathway.

BACKGROUND: In the present study effect of tretinoin derivative was investigated on the pathogenesis of gestational diabetes mellitus (GDM) in mice model in vivo. MATERIALS AND METHODS: Diabetes was induced in mice by injecting Streptozotocin (STZ) for 5consecutive days at a dose of 65 mg/kg body weight through the intraperitoneal route. Tretinoin derivative was given to the mice at 0.12 and 0.25 mg/kg doses through gavage in normal saline alternately for one week after STZ injection. RESULTS: The results demonstrated that tretinoin derivative administration to the diabetic mice significantly (P<0.05) alleviated the blood FBG and FINS levels. Administration of tretinoin derivative to the diabetic mice significantly (P<0.05) promoted the blood HDL level and alleviated TC and TG levels. The administration of tretinoin derivative to the diabetic mice significantly (P<0.05) alleviated the CRP, IL-6and TNF-α production in pancreatic tissues. Tretinoin derivative administration to the diabetic mice significantly (P<0.05) elevated the SOD activity, and CAT level and lowered the MDA level in pancreatic tissues. The TXNRD1 expression in diabetic mice was comparable to that in the normal group after administration of tretinoin derivativeat the dose of 0.25 mg/kg dose. In silico data demonstrated that tretinoin derivativeinteracts with TXNRD1 protein with the binding affinity ranging from -10 to 9.4 kcal/ mol. CONCLUSION: In conclusion, tretinoin derivative administration effectively regulated streptozotocin-induced changes in fasting blood glucose, insulin level, high-density lipid level and triglyceride level in diabetic mice in vivo. The streptozotocin-induced excessive production of C-reactive protein and inflammatory cytokines was also down-regulated in diabetic mice on administration of tretinoin derivative. Therefore, tretinoin derivative can be investigated further as a therapeutic agent for the treatment of gestational diabetes mellitus.

Gestational hypertension, preeclampsia, and gestational diabetes mellitus after high exposure to perfluoroalkyl substances from drinking water in Ronneby, Sweden.

BACKGROUND: Leakage of fire-fighting foam from an airfield caused contamination of the drinking water supplied to a third of the population in Ronneby, resulting in very high serum levels of predominantly perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS). The results of studies investigating the association between exposure to perfluorinated alkyl substances (PFAS) and pregnancy complications are inconsistent, and studies at high exposures of PFOS and PFHxS are lacking. OBJECTIVES: To investigate the association between exposure to high levels of PFAS and gestational hypertension and preeclampsia, and gestational diabetes mellitus. METHODS: We retrieved data on 27 292 childbirths between 1995 and 2013 from the National Medical Birth Register for women that had a residential address in Blekinge county for at least one year before delivery. Residential history was used as a proxy for exposure by categorizing women into high-, intermediate-, or background exposed based on their residential address during the five-year period before childbirth. Data on confounders were retrieved from administrative registers. The outcomes were defined based on International Classification of Diseases codes. We used logistic regression to estimate odds ratios (OR) for gestational hypertension and preeclampsia, and gestational diabetes mellitus. We also investigated effect modification by fetal sex. RESULTS: We found no evidence of increased risk of gestational hypertension and preeclampsia (OR 0.80; CI 0.63-1.03), nor gestational diabetes (OR 1.03; CI 0.67-1.58) after high PFAS exposure. There was no effect modification by fetal sex. DISCUSSION: This was the first study to investigate the association between high exposure to PFOS and PFHxS and pregnancy complications. The results from this study add important knowledge to public health management as new hotspots with high levels of PFAS are continuously discovered.

Metal Exposure during Early Pregnancy and Risk of Gestational Diabetes Mellitus: Mixture Effect and Mediation by Phospholipid Fatty Acids.

Despite existing studies exploring the association between metal exposure and gestational diabetes mellitus (GDM), most of them have focused on a single metal or a small mixture of metals. Our prospective work investigated the joint and independent effects of early gestational exposure to 17 essential and nonessential metals on the GDM risk and potential mediation by plasma phospholipid fatty acids (PLFAs) based on a nested case-control study established with 335 GDM cases and 670 randomly matched healthy controls. The Bayesian kernel machine regression (BKMR) and quantile g-computation analyses demonstrated a joint effect from metal co-exposure on GDM risk. BKMR with hierarchical variable selection indicated that the group of essential metals was more strongly associated with GDM than the group of nonessential metals with group posterior inclusion probabilities (PIPs) of 0.979 and 0.672, respectively. Cu (0.988) and Ga (0.570) had the largest conditional PIPs within each group. We also observed significant mediation effects of selected unsaturated PLFAs on Cu-GDM and Ga-GDM associations. KEGG enrichment analysis further revealed significant enrichment in the biosynthesis of unsaturated PLFAs. C18:1 n-7 exhibited the largest proportion of mediation in both associations (23.8 and 22.9%). Collectively, our work demonstrated the joint effect of early gestational metal exposure on GDM risk and identified Cu and Ga as the key species to the joint effect. The findings lay a solid ground for further validation through multicenter investigations and mechanism exploration via laboratory studies.

Associations between multiple metals during early pregnancy and gestational diabetes mellitus under four statistical models.

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy. Metal exposure is an emerging factor affecting the risk of GDM. However, the effects of metal mixture on GDM and key metals within the mixture remain unclear. This study was aimed at investigating the association between metal mixture during early pregnancy and the risk of GDM using four statistical methods and further at identifying the key metals within the mixture associated with GDM. A nested case-control study including 128 GDM cases and 318 controls was conducted in Beijing, China. Urine samples were collected before 13 gestational weeks and the concentrations of 13 metals were measured. Single-metal analysis (unconditional logistic regression) and mixture analyses (Bayesian kernel machine regression (BKMR), quantile g-computation, and elastic-net regression (ENET) models) were applied to estimate the associations between exposure to multiple metals and GDM. Single-metal analysis showed that Ni was associated with lower risk of GDM, while positive associations of Sr and Sb with GDM were observed. Compared with the lowest quartile of Ni, the ORs of GDM in the highest quartiles were 0.49 (95% CI 0.24, 0.98). In mixture analyses, Ni and Mg showed negative associations with GDM, while Co and Sb were positively associated with GDM in BKMR and quantile g-computation models. No significant joint effect of metal mixture on GDM was observed. However, interestingly, Ni was identified as a key metal within the mixture associated with decreased risk of GDM by all three mixture methods. Our study emphasized that metal exposure during early pregnancy was associated with GDM, and Ni might have important association with decreased GDM risk.

Long-term effects of streptozotocin-induced gestational diabetes mellitus on mechanical sensitivity and intraepidermal nerve fibers in female and male mice offspring.

While the long-term complications of gestational diabetes mellitus (GDM) in the cardiovascular, endocrine, and central nervous systems from offspring have been widely studied, less is known about the long-term outcomes of GDM on the peripheral nervous system. Thus, here we assessed the mechanical sensitivity and density of nerve fibers of the hind paw from middle-aged offspring born from dams with GDM. GDM was induced by the intraperitoneal administration of streptozotocin (STZ) in mouse dams. Mechanical sensitivity in male and female offspring was bi-weekly evaluated from week 18 to week 40 of age. At 40 weeks old, offspring were sacrificed and glabrous hind paw skin was processed for immunohistochemistry to determine the density of intraepidermal CGRP and PGP9.5 positive nerve fibers. Offspring mice born from STZ-treated dams had significantly greater mechanical sensitivity from 18 to 40 weeks of age compared to offspring born from vehicle-treated dams (control group). The density of intraepidermal CGRP+ and PGP9.5+ nerve fibers were significantly lower in the hind paw skin of female but not male offspring, born from STZ-treated dams versus the control group. These results suggest that GDM has long-term sex-dependent complications on the nociceptive system. Further studies are necessary to elucidate the mechanisms underlying the GDM-induced long-term consequences.

Association between exposure to air pollution during preconception and risk of gestational diabetes mellitus: The role of anti-inflammatory diet.

BACKGROUND: Regarding the association between the sensitive time-windows of air pollution (AP) exposure and gestational diabetes mellitus (GDM), epidemiological findings are inconsistent. The dietary inflammatory potential has been implicated in the development of GDM, but it is unclear whether an anti-inflammatory diet during pregnancy reduces the association between AP and GDM. OBJECTIVE: We aimed to characterize the sensitive time-windows of AP to GDM risk. Further, to verify whether a maternal anti-inflammatory diet can reduce the risk of AP-induced GDM, by inhibiting inflammation. METHODS: A total of 8495 pregnant women were included between 2015 and 2021 in the Maternal & Infants Health in Hefei study. Weekly mean AP exposure to fine particles (PM2.5 and PM10), SO2, and NO2 was estimated from the data of Hefei City Ecology and Environment Bureau. High-sensitivity C-reactive protein (hs-CRP) concentrations were measured to evaluate systemic inflammation. The empirical dietary inflammatory pattern (EDIP) score based on a validated food frequency questionnaire was used to assess the dietary inflammatory potential of pregnant women. Logistic regression models with distributed lags were used to identify the sensitive time-window for the effect of AP on GDM. Mediation analysis estimated the mediated effect of hs-CRP, linking AP with GDM. Stratified analysis was used to investigate the potential effect of anti-inflammatory diet on GDM risk. RESULTS: The increased risks of GDM were found to be positively associated with exposure to PM2.5 (OR = 1.11, 95% CI:1.07-1.15), PM10 (OR = 1.12, 95% CI:1.09-1.16), and SO2 (OR = 1.42, 95% CI:1.25-1.60) by distributed lag models, and the critical exposure windows were 21st to 28th weeks of preconception. The proportion of association between PM2.5, PM10, and SO2 with GDM mediated by hs-CRP was 25.9%, 21.1%, and 19.4%, respectively, according to mediation analysis. In the stratified analyses by EDIP, the association between AP and GDM was not statistically significant among women those with anti-inflammatory diets. CONCLUSIONS: Exposure to AP, especially in 21st to 28th week of preconception, is associated with risk of GDM, which is partly mediated by hs-CRP. Adherence to the anti-inflammatory dietary pattern may reduce the risk of AP-induced GDM.

Maternal particulate matter exposure and gestational diabetes mellitus: a population-based cohort study.

BACKGROUND: Gestational diabetes mellitus prevalence is steadily increasing worldwide, posing a significant threat to the short-term and long-term health of both mother and offspring. Because particulate matter air pollution has been reported to affect glucose metabolism, it was suggested that maternal particulate matter exposure may be associated with the development of gestational diabetes mellitus; however, the evidence is limited and inconsistent. OBJECTIVE: This study aimed to determine the association between maternal exposure to particulate matter of diameter ≤2.5 µm and of diameter of ≤10 µm and the risk of gestational diabetes mellitus, to identify critical windows of susceptibility and to evaluate effect modification by ethnicity. STUDY DESIGN: A retrospective cohort study was conducted including pregnancies of women who delivered at a large tertiary medical center in Israel between 2003 and 2015. Residential particulate matter levels were estimated by a hybrid spatiotemporally resolved satellite-based model at 1 km spatial resolution. Multivariable logistic analyses were applied to study the association between maternal particulate matter exposure in different pregnancy periods and gestational diabetes mellitus risk, while adjusting for background, obstetrical, and pregnancy characteristics. Analyses were also stratified by ethnicity (Jewish and Bedouin). RESULTS: The study included 89,150 pregnancies, of which 3245 (3.6%) were diagnosed with gestational diabetes mellitus. First trimester exposure to both particulate matter of diameter ≤2.5 µm (adjusted odds ratio per 5 µg/m3, 1.09; 95% confidence interval, 1.02-1.17) and particulate matter of diameter of ≤10 µm (adjusted odds ratio per 10 µg/m3, 1.11; 95% confidence interval, 1.06-1.17) was significantly associated with increased risk for gestational diabetes mellitus. In the stratified analyses, the association with first trimester particulate matter of diameter of ≤10 µm exposure was consistent among pregnancies of both Jewish and Bedouin women, whereas the association with first trimester particulate matter of diameter ≤2.5 µm exposure was significant among pregnancies of Jewish women only (adjusted odds ratio per 5 µg/m3, 1.09; 95% confidence interval, 1.00-1.19), as well as association with preconception particulate matter of diameter of ≤10 µm exposure (adjusted odds ratio per 10 µg/m3, 1.07; 95% confidence interval, 1.01-1.14). No association was found between second trimester particulate matter exposure and gestational diabetes mellitus risk. CONCLUSION: Maternal exposure to both particulate matter of diameter ≤2.5 µm and diameter of 10 µm or less during the first trimester of pregnancy is associated with gestational diabetes mellitus, suggesting that the first trimester is a particular window of susceptibility to the effect of particulate matter exposure on gestational diabetes mellitus risk. The effects found in this study differed by ethnic group, emphasizing the importance of addressing ethnic disparities when assessing environmental impacts on health.

Environmental pollutants exposure and gestational diabetes mellitus: Evidence from epidemiological and experimental studies.

Except for known sociodemographic factors, long-term exposure to environmental pollutants has been shown to contribute to the development of gestational diabetes mellitus (GDM), but the conclusions remain controversial. To provide a comprehensive overview of the association between environmental pollutants and GDM, we performed a systematic review and meta-analysis. Several electronic databases (PubMed, Embase, Web of Science, Medline and Cochrane) were searched for related epidemiological and experimental studies up to September 2022. For epidemiological studies, a meta-analysis was carried out to appraise the effect of environmental pollutants, including polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), per- and polyfluoroalkyl substances (PFASs), phenols, phthalates (PAEs), polybrominated diphenyl ethers (PBDEs) and parabens exposure on GDM. Moreover, we also summarized possible biological mechanisms linking pollution exposure and GDM based on the included experimental studies. A total of 80 articles were enrolled, including 38 epidemiological studies and 42 experimental studies. Meta-analysis results showed that exposure to PAEs [OR (95%CI) = 1.07 (1.00, 1.14)], PFASs [OR (95%CI) = 1.10 (1.01, 1.19)], as well as PCBs [OR (95%CI) = 1.18 (1.02, 1.36)] and PBDEs [OR (95%CI) = 1.33 (1.17, 1.50)] significantly increased the risk of GDM, but no significant effects were found for phenols, OCPs, and parabens. In addition, experimental studies suggested that the potential biological mechanisms of environmental pollutants contributing to GDM may involve insulin resistance, ß-cell dysfunction, neurohormonal dysfunction, inflammation, oxidative stress, epigenetic modification, and alterations in gut microbiome. In conclusion, long-term environmental pollutants exposure may induce the development of GDM, and there may be a synergistic effect between the homologs. However, studies conducted on the direct biological link between environmental pollutants and GDM were few. More prospective studies and high-quality in vivo and in vitro experiments were needed to investigate the specific effects and mechanisms.

Modeling spatially varying compliance effects of PM2.5 exposure reductions on gestational diabetes mellitus in southern California: Results from electronic health record data of a large pregnancy cohort.

Gestational diabetes mellitus (GDM) is a major pregnancy complication affecting approximately 14.0% of pregnancies around the world. Air pollution exposure, particularly exposure to PM2.5, has become a major environmental issue affecting health, especially for vulnerable pregnant women. Associations between PM2.5 exposure and adverse birth outcomes are generally assumed to be the same throughout a large geographical area. However, the effects of air pollution on health can very spatially in subpopulations. Such spatially varying effects are likely due to a wide range of contextual neighborhood and individual factors that are spatially correlated, including SES, demographics, exposure to housing characteristics and due to different composition of particulate matter from different emission sources. This combination of elevated environmental hazards in conjunction with socioeconomic-based disparities forms what has been described as a "double jeopardy" for marginalized sub-populations. In this manuscript our analysis combines both an examination of spatially varying effects of a) unit-changes in exposure and examines effects of b) changes from current exposure levels down to a fixed compliance level, where compliance levels correspond to the Air Quality Standards (AQS) set by the U.S. Environmental Protection Agency (EPA) and World Health Organization (WHO) air quality guideline values. Results suggest that exposure reduction policies should target certain "hotspot" areas where size and effects of potential reductions will reap the greatest rewards in terms of health benefits, such as areas of southeast Los Angeles County which experiences high levels of PM2.5 exposures and consist of individuals who may be particularly vulnerable to the effects of air pollution on the risk of GDM.

Association between perfluoroalkyl and polyfluoroalkyl substances exposure and fetal overgrowth: A prospective birth cohort study conducted in China.

BACKGROUND: Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) has been associated with gestational diabetes mellitus, obesity or overweight in childhood, but data on fetal overgrowth outcomes including macrosomia and large for gestational age (LGA) and among gestational age diverse infants remain scarce. OBJECTIVE: To evaluate the association between maternal PFASs exposure and macrosomia and LGA, with exploration of the interaction between PFASs exposure and gestational age on fetal overgrowth. METHODS: A total of 1441 mother-infants pairs from Guangxi Zhuang Birth Cohort of China were analyzed. Nine PFASs were measured in maternal serum using ultra-high liquid performance chromatographytandem mass spectrometry. Multivaraible logistical regression and generalized additive models were performed for individual PFAS exposures, piecewise regression analysis was used to estimate the breakpoint values for the non-linear dose-response relationships. Bayesian Kernel Machine Regression was performed for PFASs mixture. RESULTS: In single pollutant models, maternal PFDA and PFOA exposure showed U-shaped relationship with macrosomia and LGA. When PFDA concentration exceeded 0.32 ng/mL was significantly positively associated with risks of LGA and macrosomia (OR=4.66, 95%CI: 1.26, 17.17; OR=14.43, 95%CI: 2.64, 79.02; respectively), while a negatively association was observed when level below 0.32 ng/mL. When PFOA concentration exceeded 1.20 ng/mL was significantly associated with increased risk of macrosomia (OR=7.75, 95%CI: 1.36, 44.06). In mixed exposure models, mixture of PFASs was positively associated with macrosomia, as well as associated with LGA when all the PFASs were at their 30th percentile or below. The maximum risk of LGA was reached when concentrations of PFUnA, PFDA, or PFBS were at the highest concentrations and the gestational age at the minimum of this study. CONCLUSIONS: Maternal exposure to PFDA, PFOA and PFASs mixture were non-monotonically associated with macrosomia and LGA, the direction of the associations depends on the level of exposure.

Joint effect of ambient PM2.5 exposure and vitamin B12 during pregnancy on the risk of gestational diabetes mellitus.

BACKGROUND: Evidence has indicated that the risk of gestational diabetes mellitus (GDM) was linked to PM2.5 exposure during pregnancy, but findings on susceptible exposure windows are inconsistent. Further, previous studies have not paid attention to B12 intake in the relationship between PM2.5 exposure and GDM. The study is aimed to identify the strength and exposure periods for associations of PM2.5 exposure with GDM, followed by exploring the potential interplay of gestational B12 levels and PM2.5 exposure on the risk of GDM. METHODS: The participants were recruited in a birth cohort between 2017 and 2018, and 1396 eligible pregnant women who completed a 75-g oral glucose tolerance test (OGTT) were included. Prenatal PM2.5 concentrations were estimated using an established spatiotemporal model. Logistic and linear regression analyses were used to test associations of gestational PM2.5 exposure with GDM and OGTT-glucose levels, respectively. The joint associations of gestational PM2.5 exposure and B12 level on GDM were examined under crossed exposure combinations of PM2.5 (high versus low) and B12 (insufficient versus sufficient). RESULTS: In the 1396 pregnant women, the median levels of PM2.5 exposure during the 12 weeks before pregnancy, the 1st trimester, and the 2nd trimesters were 59.33 µg/m3, 63.44 µg/m3, and 64.39 µg/m3, respectively. The risk of GDM was significantly associated with a 10 µg/m3 increase of PM2.5 during the 2nd trimester (RR = 1.44, 95 % CI: 1.01, 2.04). The percentage change in fasting glucose was also associated with PM2.5 exposure during the 2nd trimester. A higher risk of GDM was observed among women with high PM2.5 exposure and insufficient B12 levels than those with low PM2.5 and sufficient B12. CONCLUSION: The study supported higher PM2.5 exposure during the 2nd trimester is significantly associated with GDM risk. It first highlighted insufficient B12 status might enhance adverse effects of air pollution on GDM.

The effect of ambient ozone exposure on three types of diabetes: a meta-analysis.

BACKGROUND: Ozone as an air pollutant is gradually becoming a threat to people's health. However, the effect of ozone exposure on risk of developing diabetes, a fast-growing global metabolic disease, remains controversial. OBJECTIVE: To evaluate the impact of ambient ozone exposure on the incidence rate of type 1, type 2 and gestational diabetes mellitus. METHOD: We systematically searched PubMed, Web of Science, and Cochrane Library databases before July 9, 2022, to determine relevant literature. Data were extracted after quality evaluation according to the Newcastle Ottawa Scale (NOS) and the agency for healthcare research and quality (AHRQ) standards, and a meta-analysis was used to evaluate the correlation between ozone exposure and type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2D), and gestational diabetes mellitus (GDM). The heterogeneity test, sensitivity analysis, and publication bias were performed using Stata 16.0. RESULTS: Our search identified 667 studies from three databases, 19 of which were included in our analysis after removing duplicate and ineligible studies. Among the remaining studies, three were on T1D, five were on T2D, and eleven were on GDM. The result showed that ozone exposure was positively correlated with T2D [effect size (ES) = 1.06, 95% CI: 1.02, 1.11] and GDM [pooled odds ratio (OR) = 1.01, 95% CI: 1.00, 1.03]. Subgroup analysis demonstrated that ozone exposure in the first trimester of pregnancy might raise the risk of GDM. However, no significant association was observed between ozone exposure and T1D. CONCLUSION: Long-term exposure to ozone may increase the risk of T2D, and daily ozone exposure during pregnancy was a hazard factor for developing GDM. Decreasing ambient ozone pollution may reduce the burden of both diseases.

Exposure to per- and polyfluoroalkyl substances in early pregnancy, risk of gestational diabetes mellitus, potential pathways, and influencing factors in pregnant women: A nested case-control study.

Although previous studies have reported an association between maternal serum perfluoroalkyl substance (PFAS) exposure and gestational diabetes mellitus (GDM) risk, results have been inconsistent. Few studies have focused on the combined effects of emerging and legacy PFASs on glucose homeostasis while humans are always exposed to multiple PFASs simultaneously. Moreover, the potential pathways by which PFAS exposure induces GDM are unclear. A total of 295 GDM cases and 295 controls were enrolled from a prospective cohort of 2700 pregnant women in Shanghai, China. In total, 16 PFASs were determined in maternal spot serum samples in early pregnancy. We used conditional logistic regression, multiple linear regression, and Bayesian kernel machine regression (BKMR) to examine individual and joint effects of PFAS exposure on GDM risk and oral glucose tolerance test outcomes. The mediating effects of maternal serum biochemical parameters, including thyroid and liver function were further assessed. Maternal perfluorooctanoic acid (PFOA) exposure was associated with an increased risk of GDM (odds ratio (OR) = 1.68; 95% confidence interval (95% CI): 1.10, 2.57), consistent with higher concentrations in GDM cases than controls. Based on mediation analysis, an increase in the free triiodothyronine to free thyroxine ratio partially explained the effect of this association. For continuous glycemic outcomes, positive associations were observed between several PFASs and 1-h and 2-h glucose levels. In BKMR, PFAS mixture exposure showed a positive trend with GDM incidence, although the CIs were wide. These associations were more pronounced among women with normal pre-pregnancy body mass index (BMI). Mixed PFAS congeners may affect glucose homeostasis by increasing 1-h glucose levels, with perfluorononanoic acid found to be a main contributor. Exposure to PFASs was associated with increased risk of GDM and disturbance in glucose homeostasis, especially in normal weight women. The PFAS-associated disruption of maternal thyroid function may alter glucose homeostasis.

Ambient air pollution and gestational diabetes mellitus: An updated systematic review and meta-analysis.

OBJECTIVE: We aimed to evaluate the relationship between the composition of particulate matter (PM) and gestational diabetes mellitus (GDM) by a comprehensively review of epidemiological studies. METHODS: We systematically identified cohort studies related to air pollution and GDM risk before February 8, 2023 from six databases (PubMed, Embase, Web of Science Core Collection, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform and Chongqing VIP Chinese Science and Technology Periodical databases). We calculated the relative risk (RR) and its 95% confidence intervals (CIs) to assess the overall effect by using a random effects model. RESULTS: This meta-analysis of 31 eligible cohort studies showed that exposure to PM2.5, PM10, SO2, and NO2 was associated with a significantly increased risk of GDM, especially in preconception and first trimester. Analysis of the components of PM2.5 found that the risk of GDM was strongly linked to black carbon (BC) and nitrates (NO3-). Specifically, BC exposure in the second trimester and NO3- exposure in the first trimester elevated the risk of GDM, with the RR of 1.128 (1.032-1.231) and 1.128 (1.032-1.231), respectively. The stratified analysis showed stronger correlations of GDM risk with higher levels of pollutants in Asia, except for PM2.5 and BC, which suggested that the specific composition of particulate pollutants had a greater effect on the exposure-outcome association than the concentration. CONCLUSIONS: Our study found that ambient air pollutant is a critical factor for GDM and further studies on specific particulate matter components should be considered in the future.

Gestational Exercise Antagonises the Impact of Maternal High-Fat High-Sucrose Diet on Liver Mitochondrial Alterations and Quality Control Signalling in Male Offspring.

Maternal high-caloric nutrition and related gestational diabetes mellitus (GDM) are relevant modulators of the intrauterine environment, increasing the risk of liver metabolic alterations in mothers and offspring. In contrast, as a non-pharmacological approach against metabolic disorders, exercise is highly recommended in GDM treatment. We analysed whether gestational exercise (GE) protects mothers from diet-induced GDM metabolic consequences and mitigates liver mitochondrial deleterious alterations in their 6-week-old male offspring. Female Sprague Dawley rats were fed with control or high-fat high-sucrose (HFHS) diet and kept sedentary or submitted to GE. Male offspring were sedentary and fed with control diet. Sedentary HFHS mothers and their offspring showed impaired hepatic mitochondrial biogenesis and morphological evidence of mitochondrial remodelling. In contrast, GE-related beneficial effects were demonstrated by upregulation of mitochondrial biogenesis signalling markers and mitochondrial fusion proteins and downregulation of mitochondrial fission protein. Alterations in miR-34a, miR-130b, and miR-494, associated with epigenetic regulation of mitochondrial biogenesis, suggested that GE is a more critical modulator of intergenerational changes in miRs expression than the maternal diet. Our data showed that GE positively modulated the altered hepatic mitochondrial biogenesis and dynamics markers and quality control signalling associated with maternal HFHS-diet-related GDM in mothers and offspring.