Associations of prenatal heavy metals exposure with placental characteristics and birth weight in Hangzhou Birth Cohort: Multi-pollutant models based on elastic net regression

doi:10.1016/j.scitotenv.2020.140613

Science of The Total Environment

Volume 742, 10 November 2020, 140613

https://doi.org/10.1016/j.scitotenv.2020.140613 Get rights and content

Highlights

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Associations of multiple metals with placental and fetal growth were evaluated.
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Both urine and blood Cd levels were inversely associated with placental weight.
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Placental weight may mediate the relationship between Cd exposure and birth weight.

Abstract

Background

The human placenta is vulnerable to environmental pollutants, but the associations between exposure to multiple, correlated metals and placental characteristics have not been studied.

Methods

The current study population was derived from the Hangzhou Birth Cohort Study. Whole blood and urine samples were collected from mothers during 20–28 gestational week. The concentrations of 11 metals in blood and 11 metals in urine were evaluated by inductively coupled plasma mass spectrometry. The data on placental characteristics and birth weight were retrieved from medical records. The elastic net (ENET) model combined with unpenalized regression model was employed to estimate the relationship between levels of metals and placental characteristics (placental weight, chorionic disc area, chorionic disc eccentricity, placental thickness, placental-fetal birth weight ratio) and birth weight. Mediation analysis was performed to explore the mediated effect of placenta on the association of prenatal metals exposure with birth weight.

Results

Among 512 participants with urine metal levels, the ENET model retained Cadmium (Cd) and Selenium (Se) for placental weight. Further unpenalized regression model including Cd and Se simultaneously showed that one-unite increased natural-logarithm (ln)-transformed urine creatinine corrected (CC) Cd levels was associated with reductions in placental weight of −7.2 g (95% confidence interval (CI): −14.0, −0.4). Among 483 participants with blood metal levels, similarly, blood Cd levels were negatively associated with placental weight (β = −7.5, 95% CI: −17.0, 1.9). Furthermore, mediation analysis demonstrated that urine CC-Cd level was associated with a 21.3 g decrease (95% CI: −42.0, −2.5, p = 0.024) in birth weight through a reduction in placental weight, while blood Cd levels presented a negative association at borderline significance.

Conclusion

Our findings suggest a mediation effect of the placenta in the relationship between prenatal Cd exposure and lower birth weight. Additional studies with repeated assessment of exposure and more placental parameters are warranted to confirm this relationship.

Graphical abstract

Introduction

The human placenta, which performs a crucial role in transporting nutrients and gas, and eliminating waste for fetal development during pregnancy, acts as the main interface between the mother and the fetus (Donnelly and Campling, 2014). Various hormones, which are important for fetal growth, such as estrogens, progesterone and human chorionic gonadotropin, are also generated, metabolized and regulated transfer by the placenta.

Placental weight is proportional to birth weight to the three-quarters power, and can be used as a proxy for fetal metabolic rate (Salafia et al., 2009). Placental efficiency, commonly defined as the grams of fetus produced per gram of placenta (Fowden et al., 2009) or placental-fetal birth weight ratio (PFR) (Little, 1960), has been used as a proxy measure of placental development/function. Lower PFR indicates higher placental activity and nutrient transfer capacity, whereas higher PFR reflects less placental efficiency (Hayward et al., 2016). Chorionic disc area and thickness reflect the potential blood flow supply and the extent of maternal-fetal exchange, respectively (Salafia et al., 2005). The placental eccentricity is directly related to the placental stress experienced during growth, whereby shape alterations reflect changes in the vascular architecture of the placenta that occur in response to nutrient limiting conditions (Yampolsky et al., 2008). Measurement of placental characteristics was associated with birth weight and birth outcomes, and even long-term health (Salafia et al., 2009; Salafia et al., 2010; Yampolsky et al., 2013).

Previous studies have reported that exposure to metals was negatively associated with placental characteristics (Al-Saleh et al., 2015; Al-Saleh et al., 2014; Mikelson et al., 2019; Murcia et al., 2016; Punshon et al., 2019). These cross-sectional studies conducted in Saudi Arabia, the United States and Spain, with sample sizes ranged from n = 374 to n = 1869, examined specimens that were collected at delivery including cord blood, placenta and maternal blood. Notably, increased cadmium (Cd) levels in maternal blood and placenta have been associated with reduced placental thickness (Al-Saleh et al., 2015; Al-Saleh et al., 2014) and weight (Mikelson et al., 2019; Punshon et al., 2019). Inverse associations between lead (Pb) levels in maternal blood and placental thickness were also observed (Al-Saleh et al., 2014). Mercury levels in cord and maternal blood were also found to be significantly associated with reduced placental thickness (Al-Saleh et al., 2014) and weight (Murcia et al., 2016). However, prenatal exposure to some other metals (such as Arsenic (As)) was not associated with placental weight (Laine Jessica et al., 2015). Potential mechanisms for metals exposure on placental development include reducing trophoblast cell proliferation, promoting apoptosis, inhibiting migration, and reducing the process of placental cell energy production (Geng and Wang, 2019).

In summary, the limited prior epidemiological studies were focused on estimating the cross-sectional associations between exposure to individual heavy metal and placental characteristics, while the associations have not been well studied between multiple, correlated metals exposure during pregnancy and placental characteristics. Recognizing that populations are exposed to a mix of heavy metals, the desire has grown to quantify the health effects of complex mixtures of pollutants in recent years (Taylor et al., 2016).

In this study, we use data from the Hangzhou Birth Cohort Study (HBCS) to evaluated the associations between prenatal exposure to multiple, correlated metals during second trimester and placental characteristics at delivery, as well as birth weight, using a variable selection method, elastic net (ENET) regression model, combined with unpenalized regression models. Since placental characteristics account for birth weight variation, we also performed a mediation analysis to explore whether placental characteristics act as a mediator in the association of blood and urine metals levels with birth weight.

Section snippets

Study population

The population of the current study was derived from HBCS, which has been described in our previous articles (Guo et al., 2018; Luo et al., 2020). Briefly, the pregnant women in the latter part of their second trimester (20–28 weeks) were recruited between January and December 2016 in the Women's Hospital, Zhejiang University School of Medicine. The inclusion criteria included a) residents of Hangzhou City with intention to remain in Hangzhou over the next three years, b) and willing to give

Population

Among the 512 mother-newborn pairs with urine metals levels and completed interest data available, average maternal age at conception [mean plus or minus the standard deviation (±SD)] was 29.6 ± 3.7 years. Approximately 90% (89.3%) of the pregnant women in the study had completed college or equivalent education, and over 80% (82.6%) had over 100 thousand Yuan per year in household income, and 71.7% were nulliparous. The percent of pre-pregnancy BMI between 18.5 to <24.0 was 65.4%. Most of the

Discussion

In this study of mother-newborn pairs from the HBCS, our data indicated that prenatal Cd exposure was associated with placental weight. Furthermore, mediation analysis also indicated that placental weight might act as a potential mediator in the relationship between Cd exposure and lower birth weight, in pregnant women during 20–28 weeks of gestation.

The findings of negative associations between urine or blood Cd level and placental weight were consistent with previous studies based on

CRediT authorship contribution statement

Hao Zhao: Conceptualization, Data curation, Formal analysis, Visualization, Writing - original draft, Writing - review & editing. Jun Tang: Data curation, Formal analysis, Methodology, Project administration, Validation. Qinheng Zhu: Investigation. Hongsen He: Methodology. Shuai Li: Investigation. Lanfei Jin: Investigation. Xue Zhang: Methodology. Longtao Zhu: Investigation. Jing Guo: Data curation, Investigation. Dan Zhang: Project administration, Resources. Qiong Luo: Funding acquisition,

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We would like to acknowledge our gratefulness and thankfulness to all the anonymous participants, medical staff and investigators who contributed to the present study. We thank Professors Paul Kadetz and Therese Hesketh from Zhejiang University for their critical review of our manuscript. This study was supported by the National Natural Science Foundation of China (No. 81773382, 81571447).

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¹: Both authors contributed equally to this work.

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Associations of prenatal heavy metals exposure with placental characteristics and birth weight in Hangzhou Birth Cohort: Multi-pollutant models based on elastic net regression

Highlights

Abstract

Background

Methods

Results

Conclusion

Graphical abstract

Introduction

Section snippets

Study population

Population

Discussion

CRediT authorship contribution statement

Declaration of competing interest

Acknowledgements

Int. J. Hyg. Environ. Health

Int. J. Hyg. Environ. Health

Environ. Int.

Anaesth. Intensive Care Med.

Environ. Toxicol. Pharmacol.

Placenta

Environ. Int.

Environ. Pollut.

Environ. Res.

Am. J. Obstet. Gynecol.

Environ. Int.

Environ. Res.

Environ. Res.

Environ. Int.

Environ. Res.

Placenta

Placenta

Placenta

Placenta

Ann. Glob. Health

Controlling the false discovery rate: a practical and powerful approach to multiple testing

J. R. Stat. Soc. Ser. B Methodol.

Placental weight and placental ratio as predictors of later blood pressure in childhood

J. Hypertens.

Direct and indirect effects: classical and bootstrap estimates of variability

Sociol. Methodol.

Heavy metals and placental fetal-maternal barrier: a mini-review on the major concerns

Eur. Rev. Med. Pharmacol. Sci.