Yingshuang Zhu

Perinatal exposure to 4-nonylphenol affects adipogenesis in first and second generation rats offspring

Maternal exposure to 4-nonylphenol (4-NP) during pregnancy was shown to alter adipogenesis in rodents, yet whether the effects are restricted to 4-NP-exposed offspring only or can be transmitted to the next generation are not known. Pregnant Wistar rats received either vehicle or 4-NP (5, 25 and 125μg/kg/day) from gestation to postnatal day 21. F1 pups were subjected to blood biochemistry tests, or killed to obtain their gonadal fat to determine gene expression. Some F1 adult female rats were mated with F1 males from control group to obtain F2 pups, but without any exposure to 4-NP in the perinatal stage. F2 pups underwent studies similar to those performed on F1 pups. Serum total cholesterol, leptin levels were significantly elevated, the quantity and size of fat cells were increased, gene expression of key regulators of adipogenesis and lipogenic pathway of fat tissue were perturbed by 4-NP (p<0.05 or p<0.01). In addition, the expression of mRNA levels and protein of ERα were downregulated in adipose tissue in the two generation offspring. Perinatal exposure to 4-NP affects the adipogenesis in both male and female F1 offspring, and this effect can be progressed to the F2 offspring through the maternal line.

Mitochondrial dysfunction in early life resulted from perinatal bisphenol A exposure contributes to hepatic steatosis in rat offspring

An emerging literature suggests that bisphenol A (BPA), a widespread endocrine disrupting chemical, when exposure occurs in early life, may increase the risk of metabolic syndrome. In this study, we investigated the hypothesis that perinatal exposure to BPA predisposed offspring to fatty liver disease: the hepatic manifestation of metabolic syndrome, and its possible mechanism. Pregnant Wistar rats were administered with BPA (40μg/kg/day) or vehicle during gestation and lactation. Liver histology, biochemical analysis, transcriptome, and mitochondrial function were examined in male offspring at postnatal 3, 15 and 26 weeks. At 3 weeks of age, abnormal liver morphology and function were not observed in the BPA-exposed offspring, but a decrease in mitochondrial respiratory complex (MRC) activity (I and III) and significant changes in gene expression involved in mitochondrial fatty acid metabolism were observed compared with controls. At 15 weeks, micro-vesicular steatosis in liver, up-regulated genes involved in lipogenesis pathways, increased ROS generation and Cytc release were observed in the BPA-exposed offspring. Then, extensive fatty accumulation in liver and elevated serum ALT were observed in BPA-exposed offspring at 26 weeks. In the longitudinal observation, hepatic mitochondrial function including MRC activity, ATP production, ROS generation and mitochondrial membrane potential were progressively worsened in the BPA-exposed offspring. Perinatal BPA exposure contributes to the development of hepatic steatosis in the offspring of rats, which may be mediated through impaired hepatic mitochondrial function and up-regulated hepatic lipid metabolism.

BPA-induced DNA hypermethylation of the master mitochondrial gene PGC-1α contributes to cardiomyopathy in male rats.

Implication of environmental endocrine disruptors, such as bisphenol A (BPA), on the development of cardiopathy has been poorly investigated. The aim of the study was to investigate the effects of long-term exposure to BPA at the reference dose on the myocardium of rats, and the underlying mechanisms. Male rats received corn oil or 50 μg/kg/day of BPA since delactation. At 24 and 48 weeks (wk), cardiac function and mitochondrial function were examined. The mRNA expression and the methylation status of PCG-1α, a major regulator of mitochondrial biogenesis in cardiac muscle, were also tested. At 48 wk, BPA-exposed rats displayed cardiomyopathy, characterized by myocardium hypertrophy, cardiomyocyte enlargement, and impairment of cardiac function. At 24 wk, significantly reduced ATP production, dissipated mitochondrial membrane potential (Ψm) and declined mitochondrial respiratory complex (MRC) activity in cardiomyocytes were observed in BPA-exposed rats compared with the control rats, indicating a decrease in mitochondrial function occurs before the development of cardiomyopathy. Additionally, BPA exposure decreased the expression of PGC-1α and induced hypermethylation of PGC-1 α in heart tissue in 24- and 48-week-old rats. The change in methylation of PGC-1α was observed more pronounced in BPA-exposed rats at 48 wk. Overall, long-term BPA exposure induces cardiomyopathy in male rats, and the underlying mechanism may involve the impairment of cardiac mitochondrial function and the disturbance of methylation of PGC-1α.

Maternal urinary bisphenol A levels and infant low birth weight: A nested case–control study of the Health Baby Cohort in China

BACKGROUND Exposure to bisphenol A (BPA), a known endocrine disruptor, has been demonstrated to affect fetal development in animal studies, but findings in human studies have been inconsistent. OBJECTIVES We investigated whether maternal exposure to BPA during pregnancy is associated with an increased risk of infant low birth weight (LBW). METHODS A total 452 mother-infant pairs (113 LBW cases and 339 matched controls) were selected from the participants enrolled in the prospective Health Baby Cohort (HBC) in Wuhan city, China, during 2012-2014. BPA concentrations were measured in maternal urine samples collected at delivery, and the information of birth outcomes was retrieved from the medical records. A conditional logistic regression was used to evaluate the relationship between urinary BPA levels and LBW. RESULTS Mothers with LBW infants had significantly higher urinary BPA levels (median: 4.70μg/L) than the control mothers (median: 2.25μg/L) (p<0.05). Increased risk of LBW was associated with higher maternal urinary levels of BPA [adjusted odds ratio (OR)=3.13 for the medium tertile, 95% confidence interval (CI): 1.21, 8.08; adjusted OR=2.49 for the highest tertile, 95% CI: 0.98, 6.36]. The association was more pronounced among female infants than among male infants, with a statistical evidence of heterogeneity in risk (p=0.03). CONCLUSIONS Prenatal exposure to higher levels of BPA may potentially increase the risk of delivering LBW infants, especially for female infants. This is the first case-control study to examine the association in China.

Novel Chlorinated Polyfluorinated Ether Sulfonates and Legacy Per-/Polyfluoroalkyl Substances: Placental Transfer and Relationship with Serum Albumin and Glomerular Filtration Rate

Per- and polyfluoroalkyl substances (PFASs) may cross the placental barrier and lead to fetal exposure. However, little is known about the factors that influence maternal-fetal transfer of these chemicals. PFAS concentrations were analyzed in 100 paired samples of human maternal sera collected in each trimester and cord sera at delivery; these samples were collected in Wuhan, China, 2014. Linear regression was used to estimate associations of transfer efficiencies with factors. Chlorinated polyfluorinated ether sulfonates (Cl-PFAESs, 6:2 and 8:2) were frequently detected (>99%) in maternal and cord sera. A significant decline in PFAS levels during the three trimesters was observed. A U-shape trend for transfer efficiency with increasing chain length was observed for both carboxylates and sulfonates. Higher transfer efficiencies of PFASs were associated with advancing maternal age, higher education, and lower glomerular filtration rate (GFR). Cord serum albumin was a positive factors for higher transfer efficiency (increased 1.1-4.1% per 1g/L albumin), whereas maternal serum albumin tended to reduce transfer efficiency (decreased 2.4-4.3% per 1g/L albumin). Our results suggest that exposure to Cl-PFAESs may be widespread in China. The transfer efficiencies among different PFASs were structure-dependent. Physiological factors (e.g., GFR and serum albumin) were observed for the first time to play critical roles in PFAS placental transfer.

Free and total urinary phthalate metabolite concentrations among pregnant women from the Healthy Baby Cohort (HBC), China.

Total urinary phthalate metabolites (the free plus glucuronidated forms) have been frequently measured in the general population. However, data are limited on the free forms which may be more bioactive, especially for sensitive population such as pregnant women. Here the data gap was addressed by measuring concentrations of free and total forms of six phthalate metabolites in 293 urine samples from pregnant women at delivery, who were randomly selected from the prospective Healthy Baby Cohort (HBC), China. We observed detectable concentrations of the total amount of phthalate metabolites in all urine samples. The geometric mean (GM) urinary concentrations of free and total mono-butyl phthalate (MBP) (5.20, 54.49ng/mL) were the highest, followed by mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) (4.52, 7.27ng/mL). For most of phthalate metabolites, urinary concentrations were significantly higher in women who were nulliparous. Significantly higher concentrations of mono-ethyl phthalate (MEP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) were found in women who had higher educational level. To our knowledge, this is the first study to report the free and total forms of phthalate metabolites among pregnant women in China. The results suggest that exposure characteristics may be related to parity and education.

Relationship between maternal phthalate exposure and offspring size at birth

Research findings on effects of prenatal phthalate exposure on fetal growth were inconsistent. Increasing evidence from animal studies has indicated a potential sex-specific effect of phthalates on fetal growth, but the current human data was limited. In this study, we aimed to estimate the relationships between maternal phthalate exposure and infant birth size. Six major phthalate metabolite levels of urine samples were measured among pregnant women (n=1002) from the Healthy Baby Cohort (HBC), China. The associations between urinary phthalate metabolites levels and birth size (birth weight, birth length, birth weight z-scores and ponderal index) were estimated using linear regression models. In boys, the ln-transformed di-2-ethylhexyl phthalate (DEHP) metabolite levels were significantly associated with increased birth weight and birth weight z-scores. Additionally, each ln-unit increase in mono-(2-ethyl-5-carbox-ypentyl) phthalate (MECPP) was associated with a 0.25kg/m3 [95% confidence interval (CI): 0.03, 0.47] increase in ponderal index in boys. However, we did not observe any significant association of maternal phthalate metabolite levels with any of the outcomes in girls. Our data suggested potential sex-specific associations of maternal phthalate exposure with increased birth weight and ponderal index, which were merely apparent in boys.

Relationship between maternal exposure to bisphenol S and pregnancy duration

Bisphenol S (BPS) has been progressively used due to the potential safety problems of bisphenol A (BPA). Thus Human studies are needed to investigate the developmental effects of BPS. In this study, the impact of maternal BPS exposure on birth outcomes was evaluated with linear and logistic regression models. BPS was analyzed in spot urine samples collected from 985 pregnant women at admission to labor. It was found in 93.7% of the urine samples with the specific gravity adjusted geometric mean concentration of 0.17 μg/L. One ln-unit increase in urinary BPS was associated with a 0.72-day increase in pregnancy duration (95% CI: 0.34, 1.09). When stratified by fetal sex, each ln-unit increase in maternal urinary BPS was significantly correlated with increased gestational age [adjusted β = 1.02, 95% confidence intervals (CI): 0.47, 1.57] and increased odds of late term birth [adjusted odds ratio = 1.29, 95% CI: 1.00, 1.67] for girls, but not significantly for boys. Including maternal urinary BPA and BPS in one model did not change the results. Associations of BPS with birth weight or length were not observed. This is the first report about BPS exposure for pregnant women from China. Higher maternal urinary BPS concentrations were associated with increased gestational age, suggesting maternal BPS exposure may interfere with pregnancy duration. The findings require replication but reveal the probable risks posed by the developmental BPS exposure.

Urinary concentrations of phthalate metabolites associated with changes in clinical hemostatic and hematologic parameters in pregnant women

BACKGROUND Exposure to phthalates, one kind of widely used plasticizers, has been demonstrated to be associated with some clinical hematological changes in circulatory system from animal studies and in vitro experiments, but their relations to hemostatic and hematologic changes in human are unknown. OBJECTIVES We explored the relationships of urinary phthalate metabolites with clinical hemostatic and hematologic parameter changes in pregnant women. METHODS The present study population included 1482 pregnant women drawn from an ongoing prospective birth cohort study in Wuhan, China. Eight urinary phthalate metabolites and eight blood clinical parameters, including activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (Fg), total white blood cell counts (WBC), red blood cell counts (RBC), hemoglobin (Hb), and platelet counts (PLT) were measured in the late third trimester. The associations between phthalate metabolites and blood parameters were analyzed using general linear model. The odds ratios (ORs) for anemia during pregnancy associated with phthalates were also explored by using logistic regression models. RESULTS After adjustment for false discovery rate, a significantly negative association between ln-transformed urinary mono-ethyl phthalate (MEP) concentration and blood Fg, and a positive association between urinary mono-butyl phthalate (MBP) and APTT were found in this study. Higher concentrations of mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) were associated with lower Hb concentrations. In addition, higher levels of MEHP, MEOHP and MECPP were also associated with increased likelihood of anemia. No significant associations were found between phthalates and other hematologic parameters. CONCLUSIONS Higher urinary phthalate metabolites in late third trimester were associated with prolonged blood clotting time, decreased Hb concentrations, and increased likelihood of anemia in pregnant women. Further research is needed to replicate the observed findings and clarify the potential biological mechanism.