Transgenerational male reproductive effect of prenatal arsenic exposure: abnormal spermatogenesis with Igf2/H19 epigenetic alteration in CD1 mouse.

Developmental exposure to environmental toxicants can induce transgenerational reproductive disease phenotypes through epigenetic mechanisms. We treated pregnant CD-1 (F0) mice with drinking water containing sodium arsenite (85 ppm) from days 8 to 18 of gestation. Male offspring were bred with untreated female mice until the F3 generation was produced. Our results revealed that F0 transient exposure to arsenic can cause decreased sperm quality and histological abnormalities in the F1 and F3. The overall methylation status of Igf2 DMR2 and H19 DMR was significantly lower in the arsenic-exposed group than that of the control group in both F1 and F3. The relative mRNA expression levels of Igf2 and H19 in arsenic-exposed males were significantly increased in both F1 and F3. This study indicates that ancestral exposure to arsenic may result in transgenerational inheritance of an impaired spermatogenesis phenotyping involving both epigenetic alterations and the abnormal expression of Igf2 and H19.

Associations of urinary phenolic environmental estrogens exposure with blood glucose levels and gestational diabetes mellitus in Chinese pregnant women.

BACKGROUND: Endocrine-disrupting chemicals (EDCs) are considered to be related to diabetes, but studies of the association between phenolic EDCs and gestational diabetes mellitus (GDM) are limited. OBJECTIVES: To assess associations of maternal urinary bisphenol A (BPA), nonylphenol (NP), and 2-tert-octylphenol (2-t-OP) with GDM occurrence. METHODS: A cross-sectional study was performed among 390 Chinese women at 24-28 weeks of gestation. GDM was diagnosed with a 2-h 75-g oral glucose tolerance test (OGTT). BPA, NP, and 2-t-OP concentrations were determined in urine samples. Linear and logistic regression tests evaluated associations of BPA, NP, and 2-t-OP with blood glucose levels and GDM prevalence. RESULTS: The 2-t-OP concentrations in GDM patients were significantly higher than in non-GDM women with median values of 2.23 µg/g Cr and 1.79 µg/g Cr, respectively. No significant difference was observed in BPA and NP. Urinary 2-t-OP was positively associated with blood glucose levels after adjustment for several confounding factors and urinary BPA and NP. Higher 2-t-OP levels were associated with higher odds of GDM (OR: 5.78; 95% CI: 2.04, 16.37), whereas higher NP levels were associated with lower odds (OR: 0.22; 95% CI: 0.05, 0.85) in the adjusted models. In addition, compared to the first quartile of 2-t-OP, the adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for GDM in the second, third, and fourth quartiles were 2.81 (1.23, 6.42), 3.01 (1.30, 6.93), and 5.49 (2.24, 13.46), respectively. CONCLUSION: Our study indicates that, for the first time to our knowledge, exposure to 2-t-OP is associated with a higher risk of GDM. However, higher NP exposure is associated with lower GDM risk. Further studies are necessary to affirm the associations of 2-t-OP and NP with GDM, and to elucidate the causality of these findings.

Joint effect of urinary arsenic species and serum one-carbon metabolism nutrients on gestational diabetes mellitus: A cross-sectional study of Chinese pregnant women.

BACKGROUND: Growing evidence indicates that arsenic (As) exposure can increase the risk of gestational diabetes mellitus (GDM). However, little is known about As species and GDM and the combined effect of As and one-carbon metabolism (OCM) on GDM. OBJECTIVES: We aimed to examine the associations between As species and GDM and evaluate the potential interactions of folate, vitamin B12, and homocysteine (Hcy) with As species on GDM prevalence. METHOD: We measured levels of arsenite (As3+), arsenate (As5+), dimethylarsinic acid (DMA), and arsenobetaine (AsB) species in urine and folate, vitamin B12, and Hcy in serum from 396 pregnant women in Tianjin, China. The diagnosis of GDM was based on an oral glucose tolerance test. Associations of As species in urine with GDM were evaluated using generalized linear models (GLMs) and Bayesian kernel machine regression (BKMR). Additive interactions of As and OCM with GDM were estimated by determining the relative excess risk due to interaction (RERI). RESULTS: Of the 396 pregnant women, 89 were diagnosed with GDM. Continuous increases in urinary inorganic As were associated with GDM in the GLMs, with adjusted odds ratios of 2.12 (95% CI: 0.96, 4.71) for As3+, and 0.27 (95% CI: 0.07, 0.98) for As5+. The BKMR in estimating the exposure-response functions showed that As3+ and AsB were positively associated with GDM. However, As5+ showed a negative relationship with GDM. Although the additive interactions between As exposure and OCM indicators were not significant, we found that pregnant women with higher urinary As3+ and total As accompanied by lower serum vitamin B12 were more likely to have higher odds of GDM (3.12, 95% CI: 1.32, 7.38 and 3.10, 95% CI: 1.30, 7.38, respectively). CONCLUSIONS: Our data suggest a positive relation between As3+ and GDM but a negative relation between As5+ and GDM. Potential additive interaction of As and OCM with GDM requires further investigation.

Interactions of arsenic metabolism with arsenic exposure and individual factors on diabetes occurrence: Baseline findings from Arsenic and Non-Communicable disease cohort (AsNCD) in China.

The interaction between arsenic metabolism and potential modifiers on the risk of diabetes is unclear. This research aimed to investigate arsenic metabolism and diabetes prevalence and to identify the interactive effects of arsenic metabolism with some risk factors on diabetes in a Chinese population. A baseline cross-sectional survey was performed in two areas with groundwater arsenic contamination in China. Arsenic levels in water and arsenic metabolites in urine were analyzed. The proportions of each arsenic metabolite (inorganic arsenic [iAs%], monomethylarsonic acid [MMA%], and dimethylarsinic acid [DMA%]) were computed to evaluate arsenic metabolism. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association between arsenic and diabetes. Interaction on the additive scale between arsenic methylation index and effect modifier was evaluated by calculating the relative excess risk due to interaction (RERI). Compared with participants in the lower tertile of MMA%, participants in the middle and upper tertiles of MMA% were less prone to diabetes (OR: 0.47 and 0.31, respectively). However, participants in the upper tertiles of urinary DMA% (OR: 3.18) were more likely to have diabetes than those participants in the lower tertiles. The stratified analyses revealed that a one-unit increase in DMA% was associated with higher odds of diabetes in females (OR: 1.06, 95% CI: 1.01, 1.11), older people (OR: 1.05, 95% CI: 1.00, 1.10), and subjects with body mass index (BMI) under 25 kg/m2 (OR: 1.07, 95% CI: 1.01, 1.14). The additive interactions between DMA% and female gender (RERI: 0.40, 95% CI: 0.01, 11.88), DMA% and age (RERI: 0.02, 95% CI: 0.01, 8.85), as well as DMA% and BMI (RERI: 0.49, 95% CI: 0.01, 9.62), were statistically significant. In conclusion, efficient arsenic metabolism is associated with higher odds of diabetes. Urinary DMA% and individual factors interact to synergistically influence diabetes occurrence in the Chinese population.

Joint effects of folate and vitamin B12 imbalance with maternal characteristics on gestational diabetes mellitus.

BACKGROUND: This study examined whether folate and vitamin B12 imbalance is associated with gestational diabetes mellitus (GDM) and explored interactions between B vitamin imbalance and maternal risk factors for GDM. METHODS: A cross-sectional study was performed in 406 Chinese pregnant women. Serum folate, vitamin B12 , and blood glucose concentrations were measured at 24 to 28 weeks gestation during GDM screening. A diagnosis of GDM was made based on International Association of Diabetes and Pregnancy Study Groups criteria (fasting plasma glucose [FPG] ≥5.1 mM, 1-hour plasma glucose ≥10.0 mM, or 2-hour plasma glucose ≥8.5 mM). Binary logistic regression was used to obtain odds ratios (ORs) after controlling for different confounders. RESULTS: Higher folate levels were associated with higher glucose concentrations and a higher risk of GDM (OR 1.98; 95% confidence interval [CI] 1.00-3.90), whereas higher vitamin B12 levels were associated with lower FPG and a lower risk of GDM (OR 0.30; 95% CI 0.15-0.60). A higher folate: vitamin B12 ratio was associated with higher glucose and a higher risk of GDM (OR 3.08; 95% CI 1.63-5.83). The presence of both a higher folate: vitamin B12 ratio and advanced age further increased the OR to 2.13 (95% CI 1.09-4.15) with a significant additive interaction. Furthermore, a higher folate: vitamin B12 ratio and a higher prepregnancy body mass index (pp-BMI) were synergistically associated with an increased risk of GDM (OR 3.03; 95% CI 1.40-6.57). CONCLUSIONS: An imbalance between folate and vitamin B12 , represented by a higher folate: vitamin B12 ratio, was highly associated with GDM risk, and this association could be further modified by maternal age and pp-BMI.