Elsevier

Reproductive Toxicology

Volume 42, December 2013, Pages 24-26
Reproductive Toxicology

Short communication
Could genetic polymorphisms related to oxidative stress modulate effects of heavy metals for risk of human preterm birth?

https://doi.org/10.1016/j.reprotox.2013.06.072Get rights and content

Abstract

Human preterm birth (PTB) is a complex medical outcome influenced by a combination of genetic and environmental factors. Research on the causative factors of PTB has mostly focused on demographic, socio-behavioral and environmental risk factors. Recent studies turn the spotlight on the effects of heavy metals exposure on adverse pregnancy outcomes. Here we present and evaluate the hypothesis that heavy metals may cause PTB through oxidative stress, and that this effect may be modified by polymorphisms in genes related to oxidative stress. Indeed, accumulating data suggest that the risk of PTB is correlated with polymorphisms in genes involved in detoxification, oxidative stress and lipid metabolism. These and other polymorphisms have independently been associated with susceptibility to the adverse effects of heavy metals.

Introduction

Preterm birth (PTB), defined as delivery at 37 weeks of gestation or less, is the leading cause of perinatal mortality in the developed world [1]. PTB can be categorized into two distinct types: medically induced PTB, often due to maternal or fetal indications, and spontaneous PTB. Possible mechanisms for spontaneous PTB include intrauterine infection/inflammation, utero-placental vascular pathology, and activation of the maternal–fetal hypothalamic–pituitary adrenal axis as well as pathologic uterine contraction, and susceptibility to environmental toxicants [2].

Until recently, only a few studies have investigated genetic susceptibility and gene–environment interactions in the etiologies of PTB. Available data indicate that familial factors influence PTB, owing to shared environmental features, inherited factors, or both. In addition, several studies indicate that various genetic polymorphisms modulate risk of PTB associated with exposure to environmental toxicants [3], including air pollutants [4], pesticides [5] and cigarette smoking [6]. Heavy metals such as lead, mercury, and arsenic, may have an important role in the pathogenesis of PTB and low birth weight (LBW) [7].

Heavy metals are ubiquitous in our environment as a result of both industrial and household uses. They represent a top 10 ranking on the Registry Priority List of Hazardous Substances published by the Agency for Toxic Substances and Disease [8]. Human exposure to heavy metals may occur through occupational contact, environmental pollution, and accumulation in food. Chronic low-level exposure may lead to hypertension [9], cardiovascular effects [10], cancer [11] and adverse reproductive outcomes, including PTB [9], [12].

In this correspondence, we posit that risk of PTB associated with heavy metals exposure is modified by polymorphisms in genes related to oxidative stress – an area that deserves further inquiry. In particular, we focus on lead, mercury, and arsenic.

According to the American Congress of Obstetricians and Gynecologists (ACOG), gestational lead exposure is associated with decreased fetal growth, reflected by both duration of pregnancy and size of the infant [13], [14]. Offspring of mothers occupationally exposed to lead may have increased risk of LBW [15]. Preterm infants tend to have higher lead levels in their umbilical cord blood [16]. Maternal blood lead levels in the first and second trimesters show an inverse correlation with gestation length and an increased risk for PTB [12], [17]. Mercury exposure has also been associated with PTB risks. Higher mercury levels in maternal hair have been associated with PTB (<35 weeks gestation) and higher maternal blood and cord blood levels associated with LBW [18], [19]. Arsenic has been associated with decreased birth weight [20], but its association specifically with PTB is less well known.

Mechanisms of toxicity for these heavy metals are not fully understood, although enzymatic inhibition, impaired antioxidant metabolism, and oxidative stress have been suggested to play a role [21], [22]. Oxidative stress, defined as an imbalance between cellular reactive oxygen species (ROS) and their control by antioxidants, is one of the most important toxic effects of lead [22], suggested to cause hypertension, cardiovascular disease and cancer [10]. Lead may cause a reduction in the activity of antioxidant enzymes and in glutathione content because of the metal's high affinity to sulfhydryl groups and metal cofactors [23]. In addition to weakening antioxidant defenses, lead may interfere with membrane integrity and fatty-acid composition, contributing to the production of ROS [24]. Arsenic and mercury, may damage cellular components, in a manner similar to lead, via elevated levels of oxidative stress [22].

Several recent works illuminate the role of oxidative stress in placentation and pregnancy complications. Oxidative stress is linked to both normal placental development and to pathophysiology of adverse outcomes ranging from miscarriage, to premature rupture of membranes, intrauterine growth restriction, and preeclampsia [25]. Recent studies have indicated oxidative stress levels during pregnancy may be used as a marker for future pregnancy complications including PTB [25], [26], [27]. Polymorphisms in genes related to oxidative stress have been observed to modulate effects of heavy metals exposure in medical conditions such as cardiovascular disease and cancer. Of note, despite data relating heavy metals exposure and risk for PTB, we are unaware of a published study that explored potential interactive effects between oxidative stress genes and heavy metal exposure on risk susceptibility to PTB.

Heavy metals and oxidative stress interplay by several mechanisms. Heavy metals affect regulation of detoxification genes, which in turn modulate oxidative stress. Detoxification processes involve two major phases: Phase I, entailing the polarization of toxic compounds and phase II, in which the polar intermediates are conjugated to functional groups in order to form stable hydrophilic compounds that are easy to excrete. Assessing potential risk associated with heavy metal exposure should account for polymorphisms in genes coding both enzymatic phases. Cytochrome P450 1A1 (CYP1A1) is a Phase I enzyme whose activity is modulated by heavy metals through their effect on the aryl hydrocarbon receptor signaling pathway [21]. Glutathione transferase (GSTT1) is a phase II detoxification enzyme catalyzing the conjugation of glutathione to heavy metals and other toxicants [28]. Both CYP1A1 and GSTT1 are highly polymorphic genes, and the polymorphisms are associated with differential susceptibility to the adverse effects of heavy metals [29], [30], [31]. For example, GSTT1 polymorphisms were found to modulate arsenic-induced urothelial carcinogenesis among subjects with high exposure levels [32] and deletions in GSTM1 and GSTT1 were found to be associated with higher mercury levels [29], [31].

Polymorphisms in CYP1A1 and GSTT1 have been associated with differential risk for PTB but without assessing the potential interacting influence of heavy metals exposures [33]. Tsai et al. examined the association between maternal cigarette smoking (a potential source of heavy metal exposure), gene polymorphisms, and PTB. Risk was associated with smoking only among mothers who had “high-risk” alleles for CYP1A1 and GSTT1 [34]. Nukui et al. found that women and fetuses exposed to cigarette smoke during pregnancy and who were characterized by a GSTT1 null genotype had an elevated risk for PTB [33].

Human paraoxonases (PONs) are a family of proteins that provide protection from physiological oxidative stress. In particular, PON1 is thought to protect low-density lipoprotein from oxidation [35] and is a primary determinant of the antioxidant action of high-density lipoprotein [36]. Metal ions, in particular those of lead, copper and mercury may bind to free sulfhydryl groups of the PON1 enzyme thus reducing its hydrolytic activity and its antioxidant function [37]. Subjects who are homozygous for the Q192R PON1 allele are more susceptible to lead toxicity [38], or have the 192R alloform have higher levels of arsenic and lead blood levels [39]. Based on the relationship of PON1 with lipoproteins and an association with atherosclerosis, Chen et al. [40] hypothesized that PON1 may be related to adverse pregnancy outcomes. An increased risk of PTB was found among infants with PON1 Q192R genotype compared with other genotypes. Baker et al. found lower mid-gestation PON1 activity in women who later had spontaneous PTB [41]. Recently, Lee at al. found an increased risk for PTB among women with elevated body mass index (BMI > 30) and PON1 Q192R allele [42]. These findings imply that increased lipid peroxidation and reduced PON1 antioxidant activity may promote a pro-oxidant situation and enhance risk for PTB.

Matrix metalloproteinases (MMPs) are also thought to modulate the effects of heavy metals. MMPs hydrolyze extracellular matrix components, in a variety of processes ranging from implantation and embryogenesis to inflammation, wound healing, metastasis and angiogenesis [43]. MMP expression may be promoted by inflammatory cytokines, growth factors, hormones, and ROS. Conversely, MMP secreting cells also produce tissue inhibitors of metalloproteinases (TIMP) [44]. MMPs, whose production is enhanced by prostaglandins, play an important role in promoting uterine contractions and PTB by stimulating cervical ripening and membrane activation [45]. In particular, MMPs degrade extra cellular matrix proteins, such as, collagens and fibronectins, leading to weakening of membranes and their subsequent rupture [3], [46]. In a recent study by Sundrani et al. [47] placental MMP1 and MMP9 levels were significantly increased in women with spontaneous PTB compared to those delivering at term, suggesting that placental MMP1/MMP9 levels may be involved in the initiation of parturition [48]. Polymorphisms in MMPs and TIMP have been found to modulate risks for PPROM and PTB [49]. Several polymorphisms in MMPs and TIMPs have been found to modulate effects of heavy metal exposure on the risk of cardiovascular diseases [50], [51], while other single nucleotide polymorphisms in these genes are associated with differential risk of PTB [45], [47].

Several other oxidative stress related genes have been associated independently with heavy metals exposure and adverse pregnancy outcomes. Heme-oxygenase 1 (HO-1), whose expression can be induced by heavy metals, contributes to the maintenance and development of a healthy pregnancy to term [52]. However, the effects of HO-1 gene polymorphisms have not been studied in association with PTB.

Section snippets

Conclusions

PTB affects 1 in 8 births in the US. Our knowledge base for the etiologies and potential prevention measures for PTB is severely lacking [53]. Recent studies indicate that gestational exposures to heavy metals may influence risks of PTB. We hypothesized in this commentary that exposures to heavy metals may be associated with PTB through oxidative stress, and such an association may be further modified by polymorphisms in genes related to oxidative stress. To confirm or refute such a hypothesis,

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    On behalf of the March of Dimes Prematurity Research Center at Stanford University School of Medicine.

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