Associations of prenatal Cadmium exposure and offspring cardiovascular structure development

doi:10.21203/rs.3.rs-2230624/v1

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Associations of prenatal Cadmium exposure and offspring cardiovascular structure development

https://doi.org/10.21203/rs.3.rs-2230624/v1

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Objective: The association of maternal heavy metal with childhood cardiovascular structure alterations has not been well established. This study aimed to assess the association of maternal exposure to cadmium (Cd) during early pregnancy with offspring cardiovascular structure in childhood.

Methods: A total of 380 mother-children pairs in Shanghai-Birth-Cohort (SBC) were included. Maternal Cd concentration in whole blood was measured in early-pregnancy. Echocardiograghy was done in offspring at 4 years of age. Generalized linear regression models (GLM) adjusted for potential confounders were applied. Mediation analysis was conducted to test the potential mediators.

Results: The mean of maternal blood Cd levels were 0.5 ± 0.3 μg/L. After adjusting for potential confounders, GLM models illustrated that higher maternal Cd level was significantly associated with smaller left ventricle diameters and wall thickness of child at the age of 4, including left ventricle diameter in systole(β =-0.784, 95% CI: -1.470, -0.097; P=0.026), interventricular septal thickness at diastole (β =-0.238, 95% CI: -0.429, -0.047; P=0.015), left ventricular mass index (β =-2.003, 95% CI: -3.507,-0.499; P=0.009), end systolic volume (β = -1.519, 95% CI: -2.834,-0.204; P=0.024), and end diastolic volume (β = -3.098, 95% CI: -6.107,-0.088; P=0.044). Mediation analysis showed that child body mass index (BMI) had uncomplete mediation effect in the association of maternal Cd exposure and offsrping cardiovascular structure.

Conclusions: These findings suggest that maternal Cd exposure during early pregnancy was adversely associated with children’s cardiovascular structure development including smaller ventricle diameters and wall thickness. And these effects would be mediated by lower offspring BMI.

Cd exposure

prenatal exposure

cardiovascular development

birth cohort

Exposure to Cadmium (Cd) is a serious public health concern. Cd is a heavy metal that could be found naturally as well as a contaminant linked to numerous contemporary industrial processes all over the world, and it is a highly toxic metal that have unknown physiological role but can cause adverse health effects even at trace levels[1]. It is ranked seventh on the United States Agency for Toxic Substances and Disease Registry's (US-ATSDR) list of hazardous substances[2]. Cd exposure can come from a variety of sources. Cd-infected food produced in contaminated soil, occupational environment, and living environment are reported as the main causes of Cd exposure for the general population[3]. Among persons that are not occupationally exposed to Cd and who do not smoke, diet is the primary means of environmental exposure[4]. As with many other heavy metals, Cd has a long biological half-life. It has been demonstrated that blood Cd reflects both recent and long-term exposures[5, 6].

Although the rate of Cd excretion is incredibly low after ingestion into the body [7], it leads to long-lasting accumulation as well as toxicity and dysfunction of several organs as a result[8]. In adults, exposure to Cd may affect the kidneys, bones and lungs[6, 9], and it is reported that Cd is classified as group I by the International Agency for Research on Cancer as a human carcinogen[10]. According to epidemiological research, chronic low-dose Cd exposure may harm the cardiovascular system and cause heart failure, cardiomyopathy, coronary heart disease, hypertension, and atherosclerosis[11-14]. Even blood Cd at well below levels were associated with an increased prevalence of cardiovascular system diseases, like peripheral arterial disease found in the 1999–2000 National Health and Nutrition Examination Survey (NHANES)[15].

In contrast to the well-studied effects in adults, the harmful effects of exposure during pregnancy on their children have received relatively less attention, and current evidence is conflicting and limited. Some studies reported that there is no connection between maternal blood, cord blood, or placental tissue Cd levels and child adverse outcomes like gestational age or birth weight[16, 17]. However, some other studies found negative impacts on offspring neurobehavioral development at 6 years of age[18] and intelligence quotient (IQ) at their age of 4.5[19] of Cd exposure during pregnancy. Cd in maternal blood can cross the placenta, accumulate in fetal tissues[20], and may affect child health[21]. The embryo or fetus is vulnerable to environmental exposure factors throughout the prenatal stage, which is a vital period in the establishment and development of the cardiovascular system. Epidemiological researches on cardiac risks from metal exposure have mainly focused on blood pressure[22] to date.

Few studies have examined the association of in utero exposure to Cd with child’s cardiovascular development. The purpose of this study was to explore the effect of maternal exposure to metal Cd concentrations during early pregnancy on child’s cardiovascular health at 4 years of age.

2.1 Study design

Participants of this study were women of the couples in the pregnancy cohort of the Shanghai Birth Cohort (SBC)[23]. In brief, from 2013 to 2016, pregnant women who visited for booking for prenatal care were approached for enrollment at six SBC participating hospitals in the four administrative districts of Shanghai city. Biological samples (maternal venous blood) were collected during the research process and blood Cd concentrations were measured using the whole blood. The collection and treatment of biological samples used unified standard operating procedures. The subjects’ basic information like social environment, educational levels, family income, smoking status and obstetric records of gestational diabetes mellitus (GDM) status during pregnancy were collected. The data related to newborns, regarding gender, gestational age, and anthropometric parameters, were recorded at birth by trained nurses. From 2018 to 2021, physical and cardiovascular ultrasonography tests were performed in the 4-year follow-up survey. We randomly selected 450 women to test for Cd concentration from this cohort. In our study, women who were miscarriage, stillbirth, multiple pregnancies, lost to follow-up, and without available medical records were excluded. For offspring, children with congenital heart disease, lost to follow-up, and without available records were excluded. Finally, 380 mother-offspring pairs were included in the analysis.

This study was approved by the Institutional Review Boards of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine (XHEC-C-2013-001-2). Pregnant women were informed of the purposes and procedures of the study and signed an appropriate informed consent form at the beginning of the study.

2.2 Measurements of Cd in maternal blood in the first trimester

Maternal venous blood (gestational week ≤16 weeks) were collected using trace metal-free ethylenediaminetetraacetic acid (EDTA)-coated tubes by trained phlebotomists in the first trimester. Whole blood Cd levels were determined using inductively coupled plasma mass spectrometry (ICP-MS) (7500ce, Agilent, USA) and using validated, previously described laboratory methods[24]. The detection limits (LOD) for Cd using this method were 0.01 ug /L. Quality control for Cd was performed using a Levey-Jennings chart, with the mean±2SD values set as the allowable range. All samples were above these detection limits.

2.3 Measurement of child characteristics at the age of 4

Transthoracic echocardiography examinations were performed for the children according to the American and European guidelines[25] by trained operators using the Philip EPIQ7C (Philips Healthcare, Andover, USA) ultrasound that uses the X5-1 (1-5MHz) or S8-3 (8-3MHz) matrix-array transducers (Philips Healthcare, Andover, USA). Standard techniques were used to obtain M mode, 2D, and Doppler measurements in accordance with the American Society of Echocardiography[25, 26]. The following measurements were assessed: the subxiphoid long-axis view, the subxiphoid short-axis view, the apical 4-chamber view, the apical 3-chamber view, the apical 2-chamber view, the parasternal long-axis view, the parasternal short-axis view, the suprasternal long-axis and the suprasternal short-axis. And the following measurements were assessed: left ventricle diameter in systole (LVDs), left ventricular internal diameter in end-diastole (LVDd), left ventricular posterior wall thickness at systole (LVPWs), left ventricular posterior wall thickness at diastole (LVPWd), interventricular septal thickness at systole (IVSs), interventricular septal thickness at diastole (IVSd), left ventricular mass index (LVMI), end diastolic volume (EDV), end systolic volume (ESV), cardiac output (CO), stroke volume (SV), early diastolic mitral flow/late diastolic mitral flow (E/A ratio), Tei index (measured using the isovolumetric contraction time, isovolumetric relaxation times and ejection time), heart rate (HR), left ventricular ejection fractions (LVEF), and left ventricular fractional shortening (LVFS).

2.3 Statistical Analysis

Continuous variables are expressed as mean (SD) and categorical variables were expressed as numbers and percentages. Generalized Linear Model (GLM) was used to assess the linear association between maternal Cd exposure during early pregnancy and child cardiovascular measurements at the age of 4.

In the association analyses, a set of potential confounders were adjusted. They included maternal age (continuous), BMI before pregnancy (continuous), education status ("below college " and " college and above "), family annual income ("<100,000 CNY" and">100,000 CNY") and child gender. Except for age and BMI before pregnancy, which were continuously modeled in a linear form, the rest of selected covariates were modeled as categorical variables. Race/ ethnicity was not adjusted in all analyses since 99.2% of participants were of Chinese Han.

Causal mediation analysis[27] was conducted estimate the mediation effect of maternal Cd exposure on child's LV structure, which used generalized additive models (GAMs). Maternal Cd concentration was considered as exposure, child's cardiovascular structure as outcome, child's characteristics (gestational age and child BMI at age of 4 years) as potential mediator, maternal perinatal confounders (maternal age, prepregnancy BMI, education status, and annual income) as covariates.

To assess the robustness of our findings, we performed several sensitivity analyses. First, as Cd exposure was reported associated with GDM[28, 29], we excluded GDM women and then again conducted the association of maternal Cd exposure during pregnancy and child cardiovascular structure. Second, we used GAM to test nonlinear relationships between child cardiovascular structure and maternal Cd exposure, which presented by smooth spline curve. Finally, according to the results of GAMs, we further did piecewise linear regression models for LVDd and LVPWs stratified by Cd quartile.

The results were expressed by β (95% CI) and the P-values. The data were analyzed using Empower Stats (version 4, X&Y solutions, MA, USA) and R software (version 4.0.5). P <0.05 (two tail) was considered statistically significant.

3.1. Statistical characteristics of the studied populations

In this study, a total of 380 mother-child pairs who had both prenatal Cd measurements and child cardiovascular outcomes were finally included in our analyses. Maternal and child characteristics of study participants were shown in Table 1. The participating mothers had a median BMI before pregnancy of 22.0 kg/m², and most of the women had college or above (63.4%) and the Han nationality (95.8%). Of the participating children, 54.2% were males.

3.2. Associations of prenatal Cd exposure and child’s cardiovascular development

The effects of prenatal exposure to Cd on child cardiovascular structure were described in Table 2. After adjusting for related confounders, linear regression model illustrated that higher blood Cd level were significantly associated with lower levels of cardiovascular parameters including LVDs (β =-0.784, 95% CI: -1.470, -0.097; P=0.026), LVDd (β =-0.774, 95% CI: -1.599,0.050; at marginal significance, P=0.067), IVSs (β =-0.315, 95% CI: -0.645,0.015; at marginal significance, P=0.062), IVSd (β =-0.238, 95% CI: -0.429, -0.047; P=0.015), LVMI(β =-2.003, 95% CI: -3.507,-0.499; P=0.009), ESV (β = -1.519, 95% CI: -2.834,-0.204; P=0.024), and EDV (β = -3.098, 95% CI: -6.107,-0.088; P=0.044).

In our study, we found no strong evidence of association between maternal Cd exposure and child’s LV function outcomes at the age of 4 years in unadjusted and adjusted models.

3.3. Mediation effect of child's characteristics in the associations of prenatal Cd exposure and child’s cardiovascular development

Based on previous findings, child's characteristics may be potential mediators[30-34], to further examine the measure to which the link was mediated by the characteristics of child, mediation analysis was carried out. Results showed that the mediated effect of child BMI at 4 was statistically significant for LVDs (28.25%), ESV (28.76%) and EDV (25.54%) in our cohort (Table 3). And for gestational age, we did not find any statistically significant mediation effect of Cd exposure to any heart outcomes (Supplements-Table 2).

3.4. Additional analysis

In sensitivity analyses, exclusion of GDM women did not change the results and statistical significance obviously (Supplements-Table1). Spline smoothing function (GAMs) (Supplements-Figure 1) found no evidence of nonlinear associations between Cd concentration and child LV structure except for IVSd (P=0.018) and LVMI (P=0.017). The results of spline smoothing function (GAMs) analysis proved that the linear models might better fit for the data. Additionally, the two piecewise linear regression models found a significance relationship of LVDd with the fourth quartile of Cd (β = 1.530, 95% CI: 2.974, -0.086; P=0.040) with maternal Cd level (Supplements-Table 3).

Our study used data from SBC to investigate the associations of prenatal Cd exposure with child cardiovascular development and found a negative impact of prenatal exposure to Cd on child’s cardiovascular structure. In our research, Cd exposure during early pregnancy was associated with lower ventricular wall thickness, mass and volume. These findings suggest undesirable cardiovascular development in offspring of women exposed to Cd during early pregnancy.

The first trimester is a critical period for fetal cardiovascular development[35]. Previous studies showed that the development of fetal systems is impacted by Cd exposure during pregnancy[4, 36, 37], and Cd was discovered to be hazardous to the fetus in rats and mice before and during gestation[38-40]. At the zygote stage and during the formation of primordial germ cells, a series of epigenetic changes occur in human embryonic development. Experimental research gave the scientific foundation for looking for potential mechanisms for cardiotoxic effects of human exposure to Cd proposed[41, 42]. In the growing field of research known as toxicoepigenomics, epigenetic mechanisms have attracted interest as potential mediators of the negative effects linked to exposure to environmental toxins [43]. These changes involve two main waves of genome-wide epigenomic reprogramming that result in the sequential activation and repression of genes crucial for the control of growth and metabolism[44, 45]. Abnormal intrauterine environment might affect the epigenetic alterations of genes involved in cardiovascular development and function[46]. Furthermore, relevant researches reported that excessive production of reactive oxygen and nitrogen species (ROS and RNS) and antioxidant defense alteration[47-49], increased inflammation, deoxyribonucleic acid (DNA) damage and repaired abnormalities, and impaired cardiac energy homeostasis are the potential mechanisms of the effects of Cd exposure on the heart[50, 51]. Turdi et al. found that low-dose Cd exposure caused cardiac contractile failure in mice in animal models[52]. For our study, the thinner ventricular wall and interventricular septum thickness and decrease in ventricular mass and ventricular volume in child significantly associated with maternal Cd exposure in early pregnancy could be explained partly by these findings above. To our knowledge, few studies addressed the possible association of cardiovascular structure development with exposure to heavy metals, and additionally, none of studies addressed maternal Cd exposure during pregnancy to date.

Our findings of decrements in cardiovascular structure indicated early cardiac underdevelopment, and the mediating effect of child BMI might further suggest that the heart may be smaller partly due to children stunted growth and development effected by maternal Cd exposure [53]. Smaller cardiovascular structure are reported associated with some diseases like fatigue and heart failure symptomatology[54-57]. According to the "developmental origins of health and disease" hypothesis, early-life environmental exposures may cause long-term alterations in the structure, physiology, and function of tissues, which could eventually result in the pathogenesis of metabolic diseases[58]. In our study, underdevelopment of child resulting from maternal Cd exposure during early pregnancy could be the cause of the decreased ventricular anatomy at the age of 4, which may program individuals for risks of disease in adult life[59].

We found no significant association between cardiovascular function with prenatal Cd exposure in our data. There was a trend in decreased cardiac output, stroke volume, and early diastolic mitral flow/late diastolic mitral flow ratio, which revealed early changes in cardiac function to some extent. It is plausible that young children have better adaptation to chronic volume changes.

In this study, compared with the Cd levels reported in the other regions, the levels of Cd in this region (median values, 0.5 μg/L) was lower in Wuhan (median values, 1.2 μg/L)[60] and Taiwan (median values, 0.8 μg/L)[53, 61]. The relatively low levels of prenatal Cd exposure in this study could be due to the fact that all of the study women were Shanghai locals with relatively good socioeconomic status.

Our study has several advantages. Our analysis was based on a prospective birth cohort study in China and included a thorough evaluation of cardiovascular parameters in childhood, which was infrequently addressed in earlier epidemiology studies. Additionally, our research demonstrated for the first time the relationship between prenatal Cd levels and cardiovascular development in childhood. Our findings showing Cd exposure during the embryonic phase had a deleterious influence on child cardiovascular development are novel, which made the understanding of Cd toxic effect go a step further.

Also, our study had some limitations. First, the mechanism of Cd exposure has not been shown in this study, and further studies are warranted to clarify the underlying mechanisms. Second, there is also concern regarding uncontrolled confounding effects, such as nutritional status and urban/rural housing. The participants in this study mostly lived in cities, and the majority would be expected to have a healthy diet. Thirdly, post-birth Cd exposure of child is not taken into account in this study. As Cd has a long biological half-life, this could be somewhat representative of long-time developmental exposure concentrations. Finally, we only focused on the cardiotoxicity of only one heavy metal to child cardiovascular parameters were relatively weak while child is under threats from a variety of hazardous elements. And to our knowledge, this was the first one reported to explored the single exposure of Cd effects during pregnancy on offspring cardiovascular structure. The ongoing study should be continued to explore various risk factors and determine possible mechanisms. Therefore, our findings need to be confirmed by further studies.

In summary, this study is hitherto the first found study that Cd exposure during early pregnancy in Shanghai women may have a detrimental effect on the offspring cardiovascular development. These results indicate that prenatal Cd exposure may have a relatively long-term influence on child cardiovascular structure. Further prospective and experimental studies are warranted to clarify the underlying mechanisms of prenatal Cd exposure on child cardiovascular health and development. Besides, strategies to reduce Cd exposure pollution in Shanghai and also elsewhere are recommended.

Acknowledgements

Thanks to all the individuals who voluntarily participated in the study.

Funding

This work was partly supported by the National Natural Science Foundation of China (82130015), Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01), the Shanghai Municipal Health Commission Clinical Research Project (201840347), and the Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, the National Human Genetic Resources Sharing Service Platform (2005DKA21300).

Author Contributions

SJ and JW: Conceptualization; Formal analysis; Project administration; Resources; Writing - review & editing; Roles/Writing - original draft. SJ, YW, BD, ZL, HW, YN, QW, JL: Data curation; Investigation; Methodology; Project administration. JH and KS: Funding acquisition. JH, QD, KS: Resources; Supervision; Validation; Writing - review & editing. All authors read and approved the fnal manuscript.

Institutional Review Board Statement

The study was approved by the research ethics boards of Shanghai Xinhua Hospital (M2013−010) and all participating hospitals. Written informed consent has been obtained from each study participant.

Informed Consent Statement

Written informed consent was obtained from all study participants or their legal guardians.

Data Availability Statement

The datasets generated through this study can be provided by the corresponding author upon request.

Conflicts of Interest

The authors declare no conflict of interest.

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Table 1.Basic characteristics of the mother-child pairs was presented as Mean±SD or N ( %)(n=380)

Characteristics

Mean ±SD / N(%)

Maternal age (years)

30.6 ± 3.4

Maternal ethnicity

Han nationality

377 (99.2%)

Others

3 (0.8%)

Maternal education level

Below college

139 (36.6%)

College and above

241 (63.4%)

Annual income

<100,000 yuan

300 (78.9%)

≥100,000 yuan

80 (21.1%)

Maternal BMI before pregnancy（kg/m²)

22.0 ± 3.3

Child gender

male

206 (54.2%)

female

174 (45.8%)

Gestational age (weeks)

39.1 ± 1.4

Child BMI at age of 4 (kg/m2)

15.1 ± 1.7

LV Structure

LVDs (mm)

22.7 ± 2.0

LVDd (mm)

35.5 ± 2.5

LVPWs (mm)

7.9 ± 1.0

LVPWd (mm)

4.1 ± 0.6

IVSs (mm)

6.5 ± 1.0

IVSd (mm)

3.8 ± 0.5

LVMI (g/m^2.7)

26.0 ± 4.6

ESV (ml)

17.7 ± 3.9

EDV (ml)

52.9 ± 9.0

LV Function

CO (L/min)

4.2 ± 1.2

45.9 ± 13.5

E/A ratio

98.6 ± 7.8

Tei index

43.2 ± 6.1

HR (bpm)

91.8 ± 10.2

LVEF(%)

66.7 ± 4.4

LVFS(%)

36.2 ± 3.4

Cd (ug/L)

0.5 ± 0.3

Abbreviations: LVDs, left ventricle diameter in systole; LVDd, left ventricular internal diameter in end-diastole; LVPWs, left ventricular posterior wall thickness at systole; LVPWd, left ventricular posterior wall thickness at diastole; IVSs, interventricular septal thickness at systole; IVSd, interventricular septal thickness at diastole; LVMI, left ventricular mass index; ESV, end systolic volume; EDV, end diastolic volume; CO, cardiac output; SV, stroke volume; E/A ratio: early diastolic mitral flow/late diastolic mitral flow ratio; HR, heart rate; LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; cIMT, carotid intima-media thickness; Cd, Cadmium.

Table 2. Association between maternal Cd concentration during early pregnancy and offspring cardiovascular characteristics.

Cardiovascular parameters	Unadjusted		Adjusted^a
Cardiovascular parameters	β (95% CI)	*P.value*	β (95% CI)	P.value
LV Structure
LVDs (mm)	-0.668(-1.368,0.032)	0.062	-0.784(-1.470,-0.097)	0.026
LVDd (mm)	-0.667(-1.531,0.196)	0.131	-0.774(-1.599,0.050)	0.067
LVPWs (mm)	0.055(-0.278,0.387)	0.747	0.065(-0.271,0.401)	0.706
LVPWd (mm)	-0.058(-0.263,0.147)	0.578	-0.066(-0.272,0.141)	0.533
IVSs (mm)	-0.314(-0.645,0.016)	0.063	-0.315(-0.645,0.015)	0.062
IVSd (mm)	-0.225(-0.414,-0.037)	0.019	-0.238(-0.429,-0.047)	0.015
LVMI (g/m^2.7)	-1.895(-3.404,-0.385)	0.014	-2.003(-3.507,-0.499)	0.009
ESV (ml)	-2.753(-5.864,0.358)	0.084	-1.519(-2.834,-0.204)	0.024
EDV (ml)	-1.301(-2.641,0.039)	0.058	-3.098(-6.107,-0.088)	0.044
LV Function
CO (L/min)	-0.056(-0.495,0.383)	0.803	-0.087(-0.530,0.355)	0.698
SV	-1.515(-6.482,3.452)	0.550	-1.855(-6.834,3.122)	0.466
E/A ratio	-0.718(-3.332,1.896)	0.591	-0.815(-3.412,1.781)	0.539
Tei index	0.091(-2.007,2.190)	0.932	-0.121(-2.239,1.996)	0.911
HR(bpm)	3.005(-0.385,6.395)	0.083	2.768(-0.616,6.154)	0.110
LVEF (%)	0.899(-0.617,2.416)	0.246	1.091(-0.444,2.627)	0.165
LVFS (%)	0.712(-0.468,1.891)	0.238	0.848(-0.346,2.043)	0.165

^aAdjusting for: maternal age, ethnicity, maternal annual income, maternal education level, prepregnancy BMI,child gender

The bold values denoted statistically significant.

Table3. Test for mediating effect by child BMI at 4 between maternal Cd concentration during early pregnancy and offspring cardiovascular structure

LV Structure	Mediation effect	P-value	Propotion mediated
LV Structure
LVDs (mm)	-0.064(-0.146,-0.002)	0.040	28.25%
IVSd (mm)	-0.004(-0.014,0.003)	0.240	5.00%
LVMI (g/m^2.7)	-0.078(-0.237,0.014)	0.094	12.74%
ESV (ml)	-0.125(-0.288,-0.003)	0.044	28.76%
EDV (ml)	-0.232(-0.573,-0.004)	0.043	25.54%

Causal Mediation Analysis: Generalized additive (GAM) model was used to smooth mediator effect on outcome

The bold values denoted statistically significant.

No competing interests reported.

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Associations of prenatal Cadmium exposure and offspring cardiovascular structure development

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Abstract

1. Introduction

2. Materials And Methods

2.1 Study design

2.2 Measurements of Cd in maternal blood in the first trimester

2.3 Measurement of child characteristics at the age of 4

2.3 Statistical Analysis

3. Results

3.1. Statistical characteristics of the studied populations

3.2. Associations of prenatal Cd exposure and child’s cardiovascular development

3.3. Mediation effect of child's characteristics in the associations of prenatal Cd exposure and child’s cardiovascular development

3.4. Additional analysis

4. Discussion

5. Conclusions

Declarations

References

Tables

Additional Declarations

Supplementary Files

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