A case control study of gene environmental interaction in fetal growth restriction with special reference to organochlorine pesticides

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Abstract

Objectives

Organochlorine pesticides (OCPs) and oxidative stress are reported to be associated with adverse reproductive outcomes. Glutathione S-transferase (GST) is a polymorphic supergene family involved in the detoxification of numerous toxins including OCPs. OCPs are endocrine disrupter and prenatal exposure to them may be associated with fetal growth restriction (FGR). The objectives of the present study were (i) to determine the frequencies of polymorphic alleles of GSTM1 and GSTT1 genes in women with idiopathic FGR, (ii) to analyze the maternal and cord blood levels of the OCPs, and (iii) to identify the gene environment interaction that increases the risk of FGR.

Study design

Maternal and cord blood samples of 50 FGR cases (birth weight <10 percentile for gestational age as per Lubchenco's growth chart) and equal number of normal pregnancies who were occupationally non exposed to OCPs and excluding all the known high risk factors such as anemia, hypertension, antiphospholipid antibody syndrome, medical disease, dietary habit, living style, parity, and BMI. The collected samples at the time of delivery/after delivery were analyzed for OCPs levels by gas chromatography and polymorphic analysis for GSTM1/GSTT1 gene using multiplex PCR.

Results

Significantly higher levels of α,β,γ-HCH and p,p′-DDT were found in maternal blood and significantly higher levels of β and γ-HCH and p,p′-DDT were found in cord blood of FGR cases as compared to controls. The genotypic distribution of GSTM1/GSTT1 was almost similar in both the groups, but the frequency of GSTM1−/GSTT1− (null) genotype was significantly higher in FGR cases as compared to controls (p < 0.05, OR = 6.42). When interaction between GSTM1/GSTT1 genes polymorphism-OCPs levels and birth weight (gene–environment interaction) was ascertained, a significant association was seen between β-HCH and GSTM1− genotype with reduction in birth weight of 213 g.

Conclusion

Higher levels of OCPs in pregnant women may be considered as an important aetiological factor in ‘idiopathic’ FGR. GST polymorphism can influence the relationship between prenatal exposure to pesticides and FGR. The present study provides evidence that polymorphism in xenobiotic metabolising genes may modify the effect of environmental health hazards and increase the risk of FGR.

Introduction

Fetal growth restriction (FGR), which affects 3–10% of pregnancies, is associated with 4–8 times higher perinatal mortality rates and with morbidity among 50% of the surviving infants [1], [2]. When fetal growth is slowed sufficiently to result in clinical intrauterine growth restriction, there is a significantly increased risk of cerebral palsy, short stature, and subnormal intellectual and psychological performance during later childhood. Even within the normal range, smaller size at birth is associated with an increased incidence of cardiovascular and metabolic diseases in later life. FGR may be a consequence of several detrimental factors such as aneuploidies, non-aneuploid syndromes, metabolic factors, maternal infection, under-nutrition before and during pregnancy, drug abuse, hypertension, and placental disorders [3], [4] but in about 40% of cases the cause still remains idiopathic [5].

Organochlorine pesticides (OCPs) are persistent environmental chemicals and have been widely used in India for agriculture and public health programs [6]. Due to their strong lipophilic nature and slow degradation rates; these pesticides tend to bio-accumulate in lipid-rich tissues [7]. The storage of these toxins in women is of great concern because of their higher percentage of body fat [8]. OCPs, being xenoestrogenic in nature, disturb the normal estrogen–progesterone balance which is important in the maintenance of pregnancy [9], [10], [11]. Placental transfer of these pesticides to the developing fetus may affect the growth and development of the baby in the womb [12]. Earlier studies from our laboratory have reported significantly higher levels of OCPs in the maternal and cord blood and their association with preterm birth and recurrent miscarriage [13], [14], [15], and also genetic susceptibility of xenobiotic metabolising genes such as GSTM1/GSTT1 with preterm delivery [16].

The present study is a continuation of previous studies and was designed to investigate the association of metabolic detoxifying gene deletion, OCP levels and risk of FGR. Although environmental factors are important, genetics clearly play a role with heritability in FGR. Recently, a gene–environmental interaction model has been suggested to explain why every woman with known environmental exposure does not have adverse reproductive health effects [17]. Some women are more susceptible to the adverse effects of environmental exposure as a result of polymorphisms in xenobiotic metabolising genes [18].

Glutathione S-transferase (GST) plays a key role in cellular detoxification of various xenobiotics, especially OCPs [19]. This enzyme protects cells against toxicants, neutralizing them and rendering the product more water soluble. Furthermore, these enzymes can be useful biomarkers for metal and organic pollutants such as mercury, polychlorinated benzene, OCPs, and particulate matter10 (PM10) exposure [18], [19], [20]. The polymorphism in GSTM1 and GSTT1 gene loci is caused by a deletion which results in the absence of enzyme activity, especially in individuals with null genotypes. Therefore, the alteration in the activity of the GST enzyme can disturb the activation–detoxification balance operating in different tissues to detoxify potential toxic agents.

Hence, the present study was designed to emphasize the toxicogenomic significance of phase II enzymes GSTM1/GSTT1 which are responsible for differential detoxification and excretion of OCPs. The aim of this study was to investigate the relationship between GSTM1/GSTT1 genotypes, maternal/cord blood OCP levels and their association with FGR and birth weight.

Section snippets

Participant recruitment and collection of samples

This was a hospital-based case control study. Fifty women (cases) delivering FGR babies (birth weight <10 percentile for gestational age as per Lubchenco's growth chart [21]) were included in the study after their admission to Guru Teg Bahadur Hospital, Delhi between September 2008 to April 2011. Gestational age was confirmed by last menstrual period and/or 1st trimester scan. The study group was matched with the same number of low risk women (control group) delivering healthy term neonates and

Results

The women who participated in this study were well matched in terms of age, residential area, occupation, religion, living style, source of water supply and dietary habits. FGR was significantly associated with lower levels of education, lower socio-economic status and less weight gain during pregnancy (Table 1).

Comments

Although environmental factors are important, genetics clearly plays a role in FGR [23]. Genetic susceptibility and the influence of environmental factors such as OCPs in the development of preterm birth have been reported recently from our laboratory [13], [16]. The GSTs are the polymorphic super-gene family of detoxification enzymes that are involved in metabolism of numerous toxins such as OCPs and provide critical defence against xenobiotics [19], [24]. Various studies have shown that

Acknowledgements

The authors are thankful to Ministry of Environment and Forests (Govt. of India) for instrumental support vide research project no. RE-19-10-2007. E.S. is grateful to the Principal, University College of Medical Sciences, University of Delhi for providing the intramural grant support. The authors are also thankful to Mr. Arun, Lab Attendant, for sample collection and technical support.

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