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International Journal of Medical and Clinical Research ISSN: 0976-5530 & E-ISSN: 0976-5549, Volume 7, Issue 2, 2016, pp.-341-349. Available online at http://www.bioinfopublication.org/jouarchive.php?opt=&jouid=BPJ0000232

Research Article INORGANIC CONTAMINANTS OF DRINKING WATER: IMPACT ON PREGNANCY OUTCOME AND RELATED CONGENITAL DEFECTS QUADRI J.A.1*, ALAM M.M.2, SARWAR S.3, SINGH S.1, SHARIFF A.1, ROY T.S.1 AND DAS T.K.1 1Department of Anatomy,

AIIMS, New Delhi, India Guwahati Medical College, Guwahati, Assam, India 3Department of Bioinformatics, JMI, New Delhi, India *Corresponding Author: Email- [email protected] 2Department of Surgery,

Received: April 27, 2014; Revised: August 06, 2016; Accepted: August 07 2016; Published: August 14 2016 Abstract- Birth defects are characterized by structural and functional anomalies causing physical / physiological or mental disability at birth and some of which can be fatal also. It has been estimated that every year, approximately 7.9 million of infants are born with serious birth abnormalities and 3.2 million children are disabled for life. Birth defects are generally caused by several interrelated factors including physiologically produced endogenous and e xogenous environmental toxins. Adverse pregnancy outcome due to environmental exposure to toxic chemicals may include congenital anomalies, increased risk for miscarriage, preterm delivery, intrauterine growth restriction, and stillbirth. Environmental factors associated with birth defects include, in-utero exposure to toxic chemicals like, Arsenic, Cadmium, Fluoride, Lead, Mercury and Uranium ingested through contaminated drinking water. The exact mechanism by which these chemicals act is not fully understood. Although recent research reports suggesting that, induction of oxidative stress, macromolecular (DNA, RNA, Protein & Lipids) damage and disruption of the various vital endocrine & other signaling pathways are the major cause of pathogenesis. Drinking water gets contaminated with various non-essential inorganic toxic elements by natural and/or anthropogenic activities. Various non-essential elements, like arsenic, cadmium, fluoride, lead, mercury & uranium contaminate ground water and when consumed by the people unknowingly, put their adverse effects on maternal and child health. The present review summarizes epidemiological and experimental studies, which are related to environmental exposures with inorganic chemicals and its harmful effects on reproductive outcomes. Keywords- Environmental toxicity, Pregnancy, Birth defects, Oxidative stress, Nutrition Citation: Quadri J.A., et al., (2016) Inorganic Contaminants of Drinking Water: Impact on Pregnancy Outcome and Related Congenital Defects. International Journal of Medical and Clinical Research, ISSN: 0976-5530 & E-ISSN: 0976-5549, Volume 7, Issue 2, pp.-341-349. Copyright: Copyright©2016 Quadri J.A, et al., This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Academic Editor / Reviewer: Sally Zierler, Manoj Kumar Introduction Many types of congenital defects are a major threat for infant morbidity and mortality and single to multiple defects can be induced in several organs of the children [1]. It has been estimated that every year, approximately 7.9 million of infants (approximately 6% of worldwide births) are born with serious birth abnormalities and 3.2 million of these children are severally disabled for life [2]. On an average time period of every 4.5 minutes, a baby is born with birth anomaly and about one in every 33 babies is born with a birth defect [3]. Adverse pregnancy outcomes are a leading cause of infant mortality, accounting for more than 1 of every 5 infant deaths [4]. Although some adverse pregnancy outcome / birth defects are inherited, others are a product of toxic environmental exposure, and still others are interrelated multifactorial, resulting from the interaction of genetic and environmental factors. However, the actual cause of approximately half of the total numbers of birth defect cases are still not known [5]. Many different factors thought to be associated with birth defects, such as in-utero exposure to various environmental toxic chemicals, including Arsenic, Cadmium, Fluoride, Lead, Mercury and Uranium ingested through contaminated drinking water. All of these factors may interfere with normal fetal growth and development, and may leads to different types of adverse pregnancy outcomes [6]. Genetic causes of birth defects fall into three general categories: chromosomal abnormalities, gene defects, and multifactorial interaction. Many endogenous and external environmental factors may work together to induce following abnormalities-

1. Chromosomal: Genetic makeup of an individual is determined at the time of conception and at the same time various types of chromosomal abnormalities may arise due to the influence of endogenous and environmental toxicity, which may lead to birth defects. 2. Gene: genetic mutations induced by environmental toxins (mutagens) by various ways, including generation reactive oxygen species (ROS) and induction of oxidative stress, macromolecular (DNA, RNA, Protein) injuries and disruption of endocrine and other signaling pathway. 3. Multifactorial: In certain cases, a combination of genetic makeup and environmental pollutants (Arsenic, Cadmium, Fluoride, Lead, Mercury and Uranium), ingested through contaminated drinking water leads to multifactorial birth defects. It is established that genes might play a role in the induction of birth & developmental defects, but may not be independent rather influenced by the environmental factors and environmental toxins may pose a greater risk of altered gene expression and induction of congenital defects [7]. Environmental toxicity and adverse reproductive outcomes During pregnancy, maternal health status, dietary condition, and level of exposure to toxic environmental chemicals (Arsenic, Cadmium, Fluoride, Lead, Mercury and Uranium) put there direct or indirect impact on normal fetal development. Many chemical contaminants of drinking water that might harm a fetal development and organogenesis are usually consumed unknowingly with contaminated drinking

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Inorganic Contaminants of Drinking Water: Impact on Pregnancy Outcome and Related Congenital Defects water. Approximately 10-15% of congenital & structural anomalies are the result of the adverse effect of environmental toxins on prenatal exposure [8]. The findings indicate that approximately 1 in 250 newborn infants have structural and/or developmental defects caused by a toxic environmental exposure. Because the most of the available data gathered from animal model based studies and the dose impact varies from the species to species, therefore a dose-response relationship should be established in humans, so that the exposure during pregnancy and severity of the adverse effects on the fetus will be estimated [9]. The time of exposure with teratogens/ pollutants during pregnancy is also one of the important factors, which will put different teratogenic or congenital effect in a time dependent manner. To evaluate a teratogen, the characterization of physical and chemical nature of that teratogen, exposure dose, route of exposure, and stage of pregnancy at which exposure had occurred is essential to make a conclusion [10]. Most structural defects caused by teratogenic or toxic environmental exposures, occur during the embryonic period, especially when critical fetal developmental events are taking place and the foundations of organ systems are being started [11]. Different organ systems have different periods & dose of susceptibility to environmental toxic chemicals. Arsenic, Cadmium, Fluoride, Lead, Mercury and Uranium have been reported to cause different types of pregnancy complications and birth defects and these chemicals are usually consumed with contaminated water. In many developing countries, including India, drinking water contamination is one of the devastating problems and different countries of the world suffering from different types of water contamination & quality problems. India and many other countries are characterized by non-uniformity in level of awareness, socioeconomic development, educational status, poverty and practices, which add complexity in management of drinking water quality and related health affairs. The major chemical parameters of concern in India are fluoride, arsenic, lead, mercury, cadmium, Uranium etc. The average availability of water is reducing steadily with the growing population and it is estimated for India that by 2020, India will become a water stressed nation. (www.wateraid.org) Due to the increasing water consumption and rapidly increasing chemical contamination of water is a major health concern for coming generations. During the course of sample collection and field visits, we observed different types of water related health problems, which forces us to summarize the research reports on the topic. And it will help scientific community in designing holistic and people-centered research approaches for the management of water contaminants induced adverse pregnancy outcome and birth defects. Therefore, following non-essential inorganic chemical elements and their adverse effects on pregnancy outcomes, and their mechanistic pathway of toxicity will be evaluated in this review. Review objective: Our objective was to systematically review the data interrogating the association between different types of toxic chemical exposure through drinking water contamination and adverse reproductive outcomes. We identified articles related to the topic related to Arsenic, Cadmium, Fluoride, Mercury, Lead toxicity and its impact on pregnancy outcomes. A positive association observed between inorganic elemental toxicity and developmental defects. We also observed that literature on birth defects and pregnancy outcomes are limited to experimental animal models and epidemiological studies. Arsenic toxicity and adverse pregnancy outcomes Drinking water contamination with Arsenic: Arsenic is a natural element to which humans are routinely exposed through food, water, air, and soil. Arsenic may be naturally introduced into groundwater during the normal process of weathering of rocks leaching & runoff and by anthropogenic activities [12]. More than 100 million people worldwide have been estimated to be chronically exposed to drinking water containing high level of arsenic [13]. Arsenic is placed at number one substance in Comprehensive, Environmental, Response, Compensation and Liability Act (CERCLA), Priority List of Hazardous Substances recently published by the Agency for Toxic Substances and Disease Registry (ATSDR) [14]. The substances are ranked on the basis of abundance, and potential toxic effects on human health [14]. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) has also placed arsenic in the list of toxic elements [15]. Natural

arsenic salts are present in all source of water, with concentrations of less than 10 parts per billion (ppb). In some areas of the world, significantly high levels of arsenic present in drinking water and are a major health concern [16]. Unfortunately, there are an increasing number of countries, including India, where toxic arsenic compounds are present in groundwater, used for drinking significantly higher than WHO recommended limit (10 ppb). In Bangladesh and India, it is estimated that there are more than 1 million people drinking arsenic-rich water (above 50 ppb). Elevated arsenic concentration in drinking water sources is associated with increased risks of adverse pregnancy outcomes including fetal loss and infant death [17-19] and also put its adverse impact on in intellectual abilities in children [20]. An increase in mortality rate due to several cancer types in an adult Japanese population documented following neonatal exposure to arsenic-contaminated milk powder [21]. Depending on the dose, chronic arsenic exposure may affect several major organ systems. A major concern of ingested arsenic is congenital anomalies and cancer. The exact action mechanism of arsenic toxicity is not fully understood, but recent research reports have been suggesting that arsenic in its different oxidative state interacts with sulfur containing molecules and also induce oxidative stress by excessive generation of ROS [18]. Arsenic metabolism and toxicity: Soluble arsenic compounds are rapidly absorbed from the gastrointestinal tract [22] and maximum part of it is eliminated via the kidneys [23]. On the other hand, Inorganic arsenic usually accumulates in skin, bone, liver, kidney and muscle [24]. The dose of inorganic arsenic exposure can be determined by measuring arsenic in urine. The concentrations of inorganic arsenic in urine from individuals not exposed to arsenic are reported to be generally below 10 μg / l, however, in arsenic endemic areas of the world, including India, and Bangladesh, urinary arsenic concentrations have been observed above 1 mg/l of urine [25]. In case of pregnancy, trans-placental transfer of arsenic occurs significantly in both experimental animals [26] and in humans [27]. In experimental animals, a high dose of arsenic exposure adversely affects developing embryo and in case of humans, exposure to high arsenic levels through drinking water is associated with reduction in birth weight [28] and also increase the risk of fetal loss [17]. Arsenic toxicity and generation of ROS: Arsenic reactivity with sulfur containing molecules in the cell and generation of reactive oxygen species has been established [18]. However, humans are exposed to both the trivalent and pentavalent forms of arsenic and in-vivo metabolism of all forms of arsenic proceeds through sequential reduction and oxidative steps [29]. The generation of reactive oxygen & nitrogen species by arsenic is one of the possible mode of arsenic toxicity which cause macromolecular damages [30]. Arsenic also induces expression of “stress proteins” in in-vitro condition[31], while mutagenesis & DNA strand breaks in mammals exposed to arsenic is very usual event [32]. ROS generated by arsenic interfere with several physiological processes, such as, impaired signal transduction, altered cell proliferation, and inhibition of DNA repair and causes genotoxicity. Increased production of ROS can be detected by measuring oxidative DNA damage (8-hydroxy- 2-deoxyguanosine), lipid peroxidation and stress response genes activation, and loss of antioxidant defenses machinery (glutathione) [33]. Administration of antioxidants and other free radical scavengers decrease arsenic induced ROS generation. The exact mechanism by which arsenic activates the ROS generation is not fully known, but it may take place during oxidation of arsenite to arsenate [34]. Arsenic also stimulates NADH / NADPH oxidase [35], ferritin iron release and reactive oxygen generation by the Fenton reaction [36]. Arsenic induced genotoxicity and birth defects: Arsenic is genotoxic element, can induce different types of deletions & mutations, oxidative DNA damage, sister chromatid exchanges, DNA strand breaks, various chromosomal aberrations, aneuploidy and inhibition of DNA repair lead to genomic instability [37]. Arsenicexposed newborns had significantly higher levels of arsenic in cord blood [38] and in-utero exposure to arsenic is associated with congenital defects and long-term disease consequences including cancers due to genomic instability and aberrations.

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Quadri J.A., Alam M.M., Sarwar S., Singh S., Shariff A., Roy T.S. and Das T.K. Teratogenicity of arsenic: Arsenic induces teratogenicity in many experimental animals [39] and in chines hamsters arsenic exposure on days 4 -7 of gestation, produce offspring’s with significant birth defects [40]. Arsenic crosses the placental barrier and thus enters into the fetal circulation and interferes with normal fetal development process. Higher rates of spontaneous abortions and stillbirths have been observed in the area where drinking water contamination with arsenic is high (arsenic concentration in drinking water > 0.1 mg/L), as compared to the control area (arsenic concentration in drinking water < 0.1 mg/L) [41]. In Bangladesh, where the arsenic concentration in ground water is very high, birth defects are also more in the exposed population [42]. Therefore, in the light of available data on arsenic toxicity and adverse reproductive outcomes it may be suggested that chronically exposed pregnant women will have a high risk of adverse pregnancy outcomes. Arsenic induced altered DNA methylation: Epigenetic mechanisms such as altered DNA methylation play significant role in arsenic toxicity. Gene transcription is regulated by the level of DNA methylation in the regulatory regions of genes. Arsenic alters DNA methylation pattern by hypo- and hyper-methylation of DNA [43]. In individuals chronically exposed to arsenic, the p53 gene promoter region of blood cells shows a dose-dependent hypermethylation [44]. Inhibition of vital gene expression by hypermethylation of its promoter region could potentially alter the level of gene expression & gene function, which lead to the development of abnormal fetal development. Cadmium as drinking water contaminant Cadmium is a ubiquitous environmental pollutant to which humans are continually exposed to the toxic effects of cadmium through drinking water and food. Cadmium induced in the environment from natural and anthropogenic processes. Major natural activities which add cadmium to water sources include weathering and erosion of parent rocks and transportation to oceans and ground water, erosion of soil, forest fire and volcanic eruptions [45]. Marine phosphates and phosphorites also have very high concentration (500 ppm), of cadmium and also contribute to ground water contamination. In addition, anthropogenic activities add approximately 3 to 10 times greater amounts of cadmium to the environment than natural activities [46]. Since Cadmium cannot be degraded biologically and get accumulated by biomagnifications through the food chain [47]. Cadmium intake (from food and drinking water) per person per day varies from 10 -35 μg in the different part of the world [48]. Although transplacental permeability of cadmium is low and after in-utero exposure, neonatal rats cadmium content is very low (about 0.1 mg), while the cadmium concentration in an adult body is about 15-30 mg and increases with age [49], due to extremely long half-life of cadmium (10-30 human years, an average of approximately 20 years) [50]. It is toxic, nonessential element and classified as a human carcinogen by the North Carolina National Toxicology Program [51]. Cadmium absorption and excretion: Nutritional status of an individual, chemical components of the diet, exposure time, age and gender significantly influence intestinal absorption of dietary cadmium [52]. Cadmium is excreted mainly in the urine and its quantity in the urine is an indicator of the amount deposited in the body. The daily excretion of cadmium from the body (by the kidneys) does not exceed 0.01% of the amount consumed [53]. Cadmium toxicity: Cadmium is non-essential toxic element poses a great health risk to human health, even at very low concentrations, because it cannot be biotransformed to less toxic species and also due to poor excretion by the kidneys [12]. Women have a higher cadmium body burden than men [54, 55], the main reason for the higher body burden in women is increased intestinal absorption of dietary cadmium [56]. Blood cadmium concentration is considered as a more valid marker of cadmium exposure. The main target organs for cadmium toxicity in animals include reproductive, nervous, immune system, liver, kidney, lungs, testes, prostate and heart [57]. Interference with essential metals: Cadmium being a divalent cation enters into

the cell using transport mechanisms available for essential metals (zinc, iron, magnesium, manganese, calcium and selenium), due to its similarity in physical and chemical properties. Cadmium may interact and mimic with these elements and cause their secondary deficiency and thereby disrupting normal metabolic process, which leads to morphological and functional changes in many organs and birth defects [58-60]. Cadmium induced epigenetic changes: Since cadmium is not a potential mutagen, but it may induce an epigenetic changes and can cause indirect genotoxicity. Another possible impact of cadmium toxicity includes modulation of gene expression by inhibition of DNA methylation in the regulatory region of genes [61]. Due to hypomethylation, over expression of genes and excessive synthesis, functional products of those genes may lead to the physiological, developmental and other types of anomalies [62-64]. In addition to this, cadmium can also directly activate endonucleases, resulting in cleavage of genomic / chromosomal DNA [65]. Cadmium and oxidative stress: Increased lipid peroxidation (LPO) in mice hepatocytes after exposure to cadmium is known hepatotoxic effects [66] and induction of ROS generation reported in a variety of other cultured cell types, as well as in animals via all possible routes of exposure [67]. Cadmium can induce oxidative stress and lipid peroxidation in the liver of mice and ROS generation increases in dose dependent manner [68]. Because cadmium has no redox activity, it may enhance ROS production by suppressing free-radical scavengers such as glutathione (GSH) and by inhibiting detoxifying enzymes like superoxide dismutase, catalase, and GSH peroxidase in the cells [69]. Excessive ROS react with macromolecules and induce mutations in DNA, alteration of protein structure & function, peroxidation of membrane lipids, as well as modulation in gene expression and increased apoptosis [70]. Cadmium toxicity also affects antioxidant defense systems and induces apoptosis in the liver and pancreas of experimental animals [71] which indicate that cadmium induces apoptosis by increasing oxidative stress [72]. In male experimental animals, cadmium toxicity reduces testis weight, sperm counts and also causes impairment in sperm motility [73]. It is well known that the level of ROS production and oxidative stress play an important regulatory role during the early stage of pregnancy. Therefore, any deviation from the normal level of oxidative stress due to cadmium toxicity may leads to different types of developmental and congenital defects. In addition to it, during early stage of pregnancy cells are dividing rapidly and differentiated to specialize themselves. In such a dynamic developmental phase of pregnancy, increased level of ROS may induce genetic mutations, which may leads to congenital and developmental defects. Cadmium and adverse reproductive outcomes: Neonatal birth weight is one of the best markers of a favourable pregnancy outcome and is a determinant of neonatal mortality and morbidity [74]. The increase cadmium levels in blood & placenta of smoker mothers associated with delivery of low weight, birth babies and increased incidents of abortion. Zinc is an essential element for normal fetal development & organogenesis and cadmium can compete with zinc due to its similar chemical properties. Cadmium toxicity poses severe risk to maternal and fetal health, by inducing derangement in the level of micronutrients (Zn, Cu, Se, & iron). In one of the recent study, it is found that neonatal head circumference and length were significantly low in women exposed to cadmium through drinking water as compared to non-exposed pregnant women [75]. Cadmium toxicity also reported to induce preterm birth [76]. Various toxic effects of cadmium on reproductive endocrinology have been reported, but definitive conclusions about its actions on target tissues vary depending on the experimental model and the dosage employed. For example, cadmium toxicity in rodents leads to downregulation of pituitary hormones (gonadotropins, prolactin, ACTH, growth hormone, and thyroid-stimulating hormone) [77]. Similarly, in pseudo-pregnant rats and in cultured granulosa cells from both rats and humans, cadmium inhibits progesterone synthesis [78]. Cadmium exposure also associated with a decline in the number of corpora lutea & reductions in their vascular area, blebbing of the ciliated cells in the oviduct and decrease in the ratio of ciliated to secretory cells in

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Inorganic Contaminants of Drinking Water: Impact on Pregnancy Outcome and Related Congenital Defects the ampulla, decreased uterine length and an increased number of uterine implantation sites [79]. Cadmium also inhibits placental progesterone synthesis in human trophoblast cultured cells [80] and thereby causes alteration in endocrine signaling which leads to miss-signaling associated developmental defects. As per the available research, report it can be concluded that cadmium toxicity directly or indirectly affect male and female reproductive system and cause birth defects. Cadmium and Pregnancy: In-utero exposure to cadmium is associated with low birth weight and an increased incidence of spontaneous abortion [81]. However, Pharmacokinetic studies have demonstrated that cadmium cannot readily cross the placental barrier and gets deposited in placenta [82]. In both human and experimental animals, chronic and acute cadmium toxicity cause lysosomal vesiculation, nuclear chromatin clumping, and mitochondrial calcification in trophoblast cells. While in perfused human placenta, cadmium toxicity decreases chorionic gonadotropins secretion in human [83], which is required for early pregnancy maintenance. The placental trophoblast, which is the site of hCG synthesis, is also engaged in production of progesterone [84] a steroid hormone that plays a vital role in the maintenance of pregnancy by promoting uterine myometrial quiescence [85]. It is evidenced that older women with higher body burdens of the cadmium (accumulate in the placenta during pregnancy), are at a greater risk for adverse pregnancy outcomes. In rodents exposed to cadmium, a 16% increase in placental load of cadmium occurs after 5 days of exposure [86]. Cadmium exposure in rat, between 14 and 16 days of pregnancy exhibit an enhanced frequency of oxytocin induced uterine myometrial contractions, which may leads to abortion [87]. Fluoride toxicity and reproductive health In many countries drinking water contamination with fluoride, and related health problems are one of the major challenges. Endemic fluorosis is widely prevalent in India, China, and many countries around the world [88]. Alone in India 21 out of 35 states are found endemic for high fluoride contamination in ground water and at risk for fluoride toxic [89]. It is estimated that about 45% of drinking water sources in India are contaminated by fluoride. Chronic fluoride toxicity (fluorosis) is endemic in areas where fluoride content is high enough in ground water. Apart from skeletal and dental fluorosis, fluoride may also induce metabolic bone disease, endocrine disruption, gastrointestinal and reproductive abnormalities [90-92]. Various studies on fluoride induced adverse reproductive outcome have revealed that fluoride put its adverse effect on male & female reproductive system. Data from epidemiological studies showed that fluoride could affect human birth rates and decrease total fertility rate with increasing fluoride levels in the drinking water in fluorosis endemic areas [93]. In experimental female animal, fluoride exposure for 30 days 22.6 mg/kg/day dose able to induce fetotoxic effects such as reduction in the number of viable fetuses and an increased risk of low birth weight baby [94]. Similarly about twenty municipalities of Okinawa, Japan showed a positive correlation between fluoride concentration in drinking water and uterine lesion, which affects the uterus [95]. The main function of the uterus is to harbor, developing fetus during pregnancy and after full term maturation push out the product of conception from the maternal body. Therefore, any fluoride induced histological changes in the uterus can put adverse effects on fetal development. The same has been confirmed in experimental animal in which fluoride induced destruction of columnar epithelial cell lining of uterine lumen and stromal cells observed [96]. The destruction of stromal and epithelial cells due to fluoride toxicity may result in non-proliferation of these cells and will impair the paracrine relationship between endometrial stromal cells and epithelial cells, which may interfere with the normal signaling process during fetal development and organogenesis. Fluoride toxicity and anemia in pregnancy: India and many other nations face a serious problem of anemia during pregnancy, which leads to low birth weight babies. According to UNICEF 2008 Report, the highest percentage of low birth weight babies below 5 years of age, namely 43%, is in India [97]. Consequences of iron deficiency (anemia), in pregnant women could result in- (i) increased maternal mortality and morbidity, (ii) increased fetal morbidity and mortality, (iii) increased risk factor of low birth weight babies resulting in brain and thyroid gland damage which may be irreparable and lethal [98]. Fluoride also causes serious

damage to the gastrointestinal (GI) mucosa by destroying microvilli, resulting in non-absorption of nutrients from the diet which causes various types of nutritional deficiency [99-101] and destroy erythrocytes, thereby contributing to loss of hemoglobin and cause anemia [102]. Fluoride exposure during intrauterine growth period is a risk factor for thyroid hormone production and may cause altered development [103]. During pregnancy hemoglobin level and body mass index (BMI), increase significantly after withdrawal of fluoride ingestion by drinking water replacement and followed by nutritional intervention. Sushila et al, also reported that the number of low birth weight babies was reduced after fluoride withdrawal and nutritional supplementations in fluorosis endemic areas of India [104]. Fluoride toxicity and oxidative stress: Induction of oxidative damage and lipid peroxidation by fluoride have been reported earlier in experimental animals [105] and in cultured cells [106]. An increase in the level of lipid peroxides along with decrease in activities of glutathione peroxidase, superoxide dismutase (SOD) and catalase was observed in rats after fluoride administration [107] and in ameloblasts, fluoride alters the cytoskeleton through interference with Rho signaling pathway [108]. A recent proteomic study demonstrated that chronic fluoride toxicity induces changes in renal proteomic status [109] and the identified proteins in which change occur are mainly related to cellular metabolism and oxidative stress. Fluoride toxicity also induces apoptosis by caspase-3 activation [110] and mediated by oxidative damage of mitochondria [111] Elevation in p53 expression is also reported by fluoride in human embryonic hepatocytes [109] and effects of fluoride on corticosteroids metabolism and its role in bone mineralization has also been reported by Das et al. [92] Fluoride induced generation of free radicals and oxidative stress in animals is reported [112]. We have also observed that the fluoride induces lipid peroxidation and its products bind with cellular proteins and may cause protein modifications. Therefore, like other inorganic contaminants of drinking water fluoride toxicity also induces oxidative stress and put its detrimental effects on pregnancy outcomes. Fluoride toxicity, endocrine disturbance and congenital abnormalities: In 2006, the U.S. National Research Council, a scientific committee for examining the toxicity of fluoride concluded that fluoride is an endocrine disruptor. Fluoride induced endocrine disruption include altered thyroid function or increased goiter prevalence, impaired glucose tolerance, a decrease in age at menarche in girls and alteration in calcium metabolism. Fluoride induced maternal sub‐clinical hypothyroidism has been proposed as a cause of development of autism in the children [113] and hypothyroidism may be either congenitally present (at birth) or acquired later. Fluoride induced hypothyroidism may also lead to the reduced neuro-cognitive development in children. Ireland has the highest incidence of congenital hypothyroidism in the EU, and is the only EU member States with a national legislative policy mandating artificially fluoridation of its drinking water supplies [114]. Consequently, the majority of pregnant women & newborn babies in Ireland are exposed to fluoride above recommended levels. Interestingly Surgeons of Royal College (Ireland), observed that thyroid cancer has increased many fold in the last 30 years [115] which coincide with the period when Ireland commenced artificial fluoridation of public water supplies. Many research reports have pointed out a prevalence rate higher for children with Down’s syndrome in Ireland than that in the population not exposed to fluoride and Ireland has the highest incidence of Down’s syndrome in the EU [114]. Therefore, fluoride toxicity can induce congenital and other developmental defects by various ways, including induction of anemia, disruption of endocrine function and oxidative stress. Drinking water contamination with lead and pregnancy The source of most lead poisoning is dust from gasoline, lead paint which contaminates drinking water [115]. Lead plumbing has been contaminating drinking water, and lead in water can contribute to elevated blood lead concentrations in children. The major sources of lead in drinking water are corrosion of household plumbing systems and erosion of natural deposits [115]. Lead leaches into water through corrosion of metal caused by a chemical reaction between water and plumbing pipes. The amount of lead in drinking water also

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Quadri J.A., Alam M.M., Sarwar S., Singh S., Shariff A., Roy T.S. and Das T.K. depends on the mineral content of the water, duration of water stays in the pipes, pH and temperature of the water. Water born lead toxicity is prevalent in many countries and in India, some of the states are endemic for lead toxicity. Recently an analysis of 123 blood samples of Pune residents showed that 30% of them had unsafe lead level in their blood [116]. During pregnancy, lead crosses the placenta and enter into the fetal circulation, and can also be transferred to the infant through breast feeding [117]. The source of lead in the infant’s blood seems to be a mixture of approximately two thirds dietary and one third from chronically exposed maternal bone deposits [118]. Because lead enters into fetal circulation through placenta and will certainly put its toxic effects on fetal development specially on central nervous system. Lead toxicity, oxidative stress and pregnancy outcomes: It has been observed that the increased placental lead levels are associated with preterm birth and lead, induce a significant increase in TBARS while the decrease GSH level in the placenta of women. Lead also increases the activities of antioxidant enzymes (SOD, CAT, GPx, and GR), in the placenta of women lead to preterm deliveries [119]. Exposure to lead also caused a significant inhibition of blood deltaaminolevulinic acid dehydratase (ALAD), an important enzyme in the haem synthesis pathway and changes in platelet counts in whole blood suggesting disturbed haem synthesis pathway. After lead exposure activities of membranebound enzymes, acetyl cholinesterase (AChE) and monoamine oxidase (MAO), significantly inhibited [120]. In the fetus and infants, developing brain is highly vulnerable to the toxic effect of lead exposure and various abnormalities, including learning impairment, decrease hearing and impaired cognitive functions have been documented in human and animal models. Reactive oxygen species generation and induction of oxidative stress has been reported as one of the mechanism of lead toxicity [121]. Lead induced in-vivo generation of reactive oxygen species may be the result of depletion of the cells intrinsic antioxidant defenses system [122]. Lead toxicity and Infant Health: Lead toxicity adversely affects the central nervous system (CNS) and the best-studied effect is cognitive impairment [123]. As blood, lead concentrations increase by 10 _g/dL, the IQ decreases by 2 to 3 points at 5 years of age and later [124]. A low-dose lead exposure to experimental animals induces significant cognitive and behavioral changes, but the mechanisms by which lead affects CNS function are not fully understood [125]. Children with high blood lead concentrations (greater than 60 _g/dL) may suffer from headaches, abdominal pain, loss of appetite, constipation, clumsiness, agitation, and/or decreased activity & somnolence. These are the symptoms of CNS involvement and may rapidly proceed to vomiting, stupor, and convulsions [126]. In addition to these symptoms, lead can also cause clinically significant colic, peripheral neuropathy and chronic renal damage in infants [127]. From the available data on lead toxicity, it can be concluded that maternal chronic exposure and in-utero fetal exposure with lead may induce developmental and birth defects. Mercury and Developmental Defects Mercury is a naturally occurring metal and its chronic exposure can cause various health problems. Mercury exist in many forms like metallic mercury, methyl mercury and mercury salts. Metallic mercury and Methyl mercury are better able to reach the brain and are more harmful than mercury salts. The main source of mercury includes, contaminated drinking water, eating mercury contaminated food (usually fishes), and inhaling airborne mercury vapors. Various adverse impact of mercury on health is well known. Especially pregnant women, their fetuses, and young children are highly vulnerable to the harmful effects of mercury exposure [128]. The nervous system is very sensitive to the effects of mercury. Exposure to mercury can result in- damage of the brain, kidney, lung, digestive system complications etc. Some common symptom of Hg toxicity is tremors, abrupt changes in vision and/or hearing, insomnia and generalized weakness, loss of memory, headache, nausea, vomiting, diarrhea, increases in blood pressure and/or heart rate, eye irritation, nervousness, breathing discomforts, painful mouth, abdominal cramp, and acrodynia. Mercury easily crosses placenta and

reach up to the fetus and may induce brain damage, intellectual disability, lack of coordination, blindness, seizures, inability to speak [129]. Methyl mercury has been demonstrated as neurotoxicant and fetal brain is very sensitive for methyl mercury [130]. Studies found that prenatal exposure to organic mercury during pregnancy was associated with subtle neuro-developmental deficits in childhood, such as poorer performance on some tests of intelligence [131]. In 2001, the US Environmental Protection Agency recommended that pregnant women avoid consuming fish, which have high mercury content [132]. A study from US reported that the pregnant women who ate more fish had higher erythrocyte mercury levels. Among their children, higher prenatal mercury exposure was associated with lower developmental test scores at the age of 3 years [133]. Therefore, in-utero exposure to different forms of mercury ingested with drinking water and food will put their severe repercussions on fetal development. Drinking water contamination with uranium and birth defects Uranium is ubiquitous in the environment and it has no known metabolic and physiological role in normal functioning of the body and is currently kept in the category of non-essential element [134]. Uranium often is grouped into a broader classification of contaminants, particularly for Drinking water, known as the radionuclides. It is a naturally occurring, radioactive mineral present in certain types of rocks and soils. Uranium from the environment enters the human body by consuming uranium contaminated food and drink water, and also by inhalation of airborne uranium-containing dust particles [135]. Absorption of uranium from the gastrointestinal tract depends upon many factors, including solubility of the uranium compound [138], previous food consumption time and type [136]. The average human gastrointestinal absorption of uranium varies from 1 to 2%. After ingestion, uranium rapidly appears in the blood of exposed individual and can be detected in the bloodstream [137]. In blood uranium may get associated primarily with the RBCs and also an irony–albumin complex formed (hydrogen carbonate complex UO2HCO3+) in the blood plasma [138] Because of the high affinity of uranium for phosphate, carboxyl and hydroxyl groups, the uranyl compounds readily combine with proteins and nucleotides to form stable complexes and interfere with the normal structure and function of macromolecules. The uranyl ion replaces calcium in the hydroxyapatite complex of bone crystals and also gets deposited in the placenta during pregnancy [138]. Based on the results of studies conducted on experimental animals, it appears that the amount of soluble uranium accumulated internally is proportional to the intake from ingestion through drinking water and food and/or by inhalation. When equilibrium is attained in the skeletal tissues, uranium is excreted in the urine and feces. Various experimental findings are suggesting that the reproductive systems are adversely affected by uranium toxicity [139]. Uranium exposure can induce both chemical as well as radiological toxicity and uranium induces chemical toxicity at lower exposure levels than radiological toxicity [140]. A poor attention has been paid to the potential toxic effects of uranium on reproduction and fetal development till recent years, but now it is known that uranium can induce various types of birth defects and pregnancy related complications [141]. Most of the study aimed to evaluate uranium toxicity and congenital defects are based on experimental animals and studies on uranium-induced developmental toxicity has been performed in a sole species of mammals is mice [141], and a very few reports available on human. Uranium induced Genotoxicity: A study of reproductive toxicity of uranium noted damage to genetic material, dominant lethality and skeletal abnormalities in fetal rats. Chromosome aberrations in spermatogonia, DNA alterations in spermatocytes and strand breakage in sperm were specifically notified [142] In vitro experiments documented extensive DNA damage when UO2++ was added to DNA in the presence of an electron donor. Since DNA is particularly dense in sperm-forming cells, such cells may be especially susceptible to UO2++-derived damage. Chromosomal instabilities have also been documented in humans. In 1997 Zaire et al reported finding the increased frequency of sister chromatids exchange in cells of uranium miners [143] Schroder et al. documented chromosomal instability (in the form of increased frequency of dicentric and centric ring chromosomes) among sixteen 1991- Gulf and Balkan war veterans who

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Inorganic Contaminants of Drinking Water: Impact on Pregnancy Outcome and Related Congenital Defects believe they were exposed to Uranium via dust inhalation [144] Mutagenicity of uranium was also observed in residents living near uranium mines also in nonsmokers who resided near uranium mining or milling sites in Texas, but had not worked in the uranium industry. They found that residents living near the uranium mining and milling sites had higher frequencies than controls of aberrant cells, chromosome deletions and chromosomal aberrations. It has reported that the formation of uranium–DNA adducts and mutations in mammalian cells after direct exposure to a depleted uranium compound which suggest that uranium could be chemically genotoxic and mutagenic through the formation of strand breaks and covalent U–DNA adducts. Thus, the health risks for uranium exposure could go beyond those for radiation exposure [145]. Uranium is an embryo toxicant when given orally or subcutaneously to pregnant mice and maternal oxidative stress has been shown to enhance the developmental toxicity [146]. Experimental animal studies strongly support the possibility that uranium is a teratogen. While the detailed pathways by which environmental Uranium can reach and harm reproductive cells are not yet fully elucidated [23]. The epidemiological evidence is consistent with increased risk of birth defects in offspring of persons exposed to Uranium [147]. Domingo et al, demonstrated that both oral and subcutaneous administration of UO2++ to female mice significantly reduces fertility, and induce embryonic and fetal toxicity including reduced growth and malformations. The maternal exposure with uranium mostly induces chemical toxicity, and less radiation toxicity which leads to teratogenicity [148]. The uranium induced chemical toxicity could act at the molecular level (damaging DNA, RNA & protein), at the cellular level, and/or at the organ level, affecting reproductive organs including the testes, placenta, and embryo/fetus. Although it is yet to be evaluated that the uranium can induce teratogenicity, developmental defects and congenital anomalies if the mother during pregnancy consuming drinking water contaminated with uranium. In general, most drinking water sources have radioactive contaminants at levels that are low enough to be considered a public health concern. However, some parts of the world have elevated levels of uranium content in the ground than the recommended average values. For example, the higher uranium content in ground water samples of the Bathinda region of Punjab, India may be attributed to the radioactive rich granitic rock formations of Tusham Hills (Bhiwani) of the neighboring state Haryana, India [149]. Uranium poisoning in Punjab first made news in March 2009, when a South African Board Certified Clinical Metal Toxicologist, Carin Smit, visiting Faridkot city in Punjab, India, instrumental in collecting hair and urine samples (between 2008 and 2009) of 149/53 children respectively, who affected with birth abnormalities including physical deformities, neurological and mental disorders and concluded that uranium toxicity will increase the risk of congenital abnormalities and developmental defects significantly. Inorganic contaminants of drinking water, Induction of Oxidative stress & adverse pregnancy outcomes In healthy individuals, reactive oxygen species, (ROS) and antioxidants maintain a fine balance in the body. Oxidative stress occurs when the ROS and other radical species exceeds the scavenging capacity of antioxidants in the body. Most of the ROS are produced during electron transport chains in the mitochondria endoplasmic reticulum, plasmatic and nuclear membranes. ROS production can be enhanced many fold by exogenous exposures with environmental toxins, including Arsenic, Cadmium, Fluoride, Lead, Mercury, Uranium and other heavy metals. Elimination of ROS is catalyzed by certain cellular enzymes such as superoxide dismutase (SOD), catalase and peroxidase. Antioxidants (including vitamins C and E) and antioxidant cofactors (such as selenium, zinc, and copper) are also capable to dispose off, scavenge and/or suppress ROS formation in the cells. Oxidative stress increases when the ROS generation is increases which leads to oxidative modification of cellular constituents, consequently interfere with cellular metabolism and regulatory pathways [150]. Cellular ROS level and their fine balance of antioxidants are involved in the regulation of physiological activities of the female reproductive system. Physiological ROS levels play an important regulatory role through various signaling pathways in folliculogenesis, oocyte maturation, corpus luteum, uterine function, embryogenesis, embryonic

implantation and feto-placental development. Imbalances between antioxidants and ROS production are considered to be responsible for the initiation or development of patho-physiological processes affecting female reproductive processes. In many literatures oxidative stress has been proposed as causative agent of female sterility, recurrent pregnancy loss and several pregnancy related disorders such as preeclampsia, intra-uterine growth restriction (IUGR) and gestational diabetes. Aerobic metabolism utilizing oxygen is essential for reproductive homeostasis and also associated with generation of ROS including hydroxyl radical, superoxide anion, hydrogen peroxide, and nitric oxide. Cyclic changes in the endometrium are accompanied by changes in the expression and abundance of antioxidants. Superoxide dismutase activity decreased in the late secretory phase while ROS levels increased and ROS triggered the release of prostaglandin F2 [151]. Therefore, any environmentally induced changes in ROS generation in the cells of the endometrium will interfere with normal signaling and physiological pathway. The human embryo undergoes interstitial implantation by invading the maternal decidua at the blastocyst stage [152]. Placentation is initiated when the blastocyst makes contact with the epithelial lining of the uterus shortly after implantation. All of these activities including early placental and embryonic development occurs in a state of low oxygen in histiotroph manner [153]. So, in the early stage of gestation, placenta is poorly protected against oxidative damage, because the antioxidant enzymes (Cu, Zn-SOD and Mn-SOD), are not expressed by the syncytiotrophoblast until approximately 8–9 weeks of gestation. On the other hand, premature perfusion of this space and exposure to elevated levels of oxygen & ROS during the first 10 weeks of development, increases the risk of pregnancy loss [154]. The low oxygen environment during early placental development is essential for normal placental angiogenesis and this angiogenesis is promoted by hypoxia-induced transcriptional and post-transcriptional regulation of angiogenic factors, such as vascular endothelial growth factor and placental growth factor [155,156]. Therefore the increased oxidative stress during the early stage of pregnancy will be harmful for fetal development and may cause abortion and developmental defects. Oxidative stress and teratogenicity: Various factors are responsible for malformations and teratogenicity including environmental exposure with toxic chemicals, which usually induce oxidative stress in the body during pregnancy. A mechanism that has not been well described in teratology is oxidative stress induced mis-regulation of developmental signals leads to dysmorphogenesis. An imbalance between oxidants and anti-oxidants leads to macromolecule damages, such as protein modification, lipid peroxidation, and DNA oxidation, which lead to cell death. This untimely and increased rate of cell death during the differentiation process of fetal development can have serious repercussions on the developing embryo. During early development, one-cell embryo depends on the Krebs cycle for its energy requirement, whereas the blastocyst solely depends on glycolysis and anaerobic pathways. Once the circulatory system is established, there is a higher reliance on oxidative and aerobic metabolism and more ROS are produced by mitochondria. Conversely, more antioxidants are available at this period to counteract and detoxify these reactive oxygen species [157]. Over the course of development, the delicate balance between oxidants and antioxidants can be disrupted by exogenous / environmental agents that simulate ROS production leading to increased oxidative stress and may cause dysmorphogenesis. Many heavy metals like Arsenic, cadmium, uranium and some nonmetal like fluoride are known to induce oxidative stress in human which probably cause oxidative damage to DNA and other cellular macromolecules. ROS impact on embryo implantation and placenta The human embryo undergoes interstitial implantation by invading the maternal decidua at the blastocyst stage [152]. Placentation is initiated when the blastocyst makes contact with the epithelial lining of the uterus shortly after implantation. Early placental and embryonic development occurs in a state of low oxygen in histiotroph manner [158]. The early gestation placenta is poorly protected against oxidative damage, as the antioxidant enzymes Cu, Zn-SOD and Mn-SOD are not expressed by the syncytiotrophoblast until approximately 8–9 weeks of gestation

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Quadri J.A., Alam M.M., Sarwar S., Singh S., Shariff A., Roy T.S. and Das T.K. and premature perfusion of this space during this first 10 weeks of development increases the risk of pregnancy loss [154]. The low oxygen environment during early placental development is essential for normal placental angiogenesis, and this angiogenesis is promoted by hypoxia-induced transcriptional and posttranscriptional regulation of angiogenic factors, as vascular endothelial growth factor and placental growth factor [155]. Therefore, the increased oxidative stress during the early stage of pregnancy will be harmful for fetal development and may cause abortion and development retardation. Conclusion Birth defects are defined as a series of structural, functional and metabolic disorders. Adverse pregnancy outcome from environmental factors may include congenital anomalies, increased risk for miscarriage, preterm delivery, intrauterine growth restriction, and stillbirth. Environmental factors, which have been implicated in adverse pregnancy outcome, include heavy metals and toxic elements. The levels of the contaminants in drinking water are seldom high enough to cause acute health problems in developing countries including India. These contaminants disrupt the endocrine system, reproductive process and interfere with fetal development and can produce infertility, adverse pregnancy outcomes, developmental defects and growth retardation in new born. However, the health effects of chemical contaminants in drinking water are still not well understood. Drinking water, inorganic non-essential toxic contaminants act through reactive oxygen species generation and induction of oxidative stress, molecular injury, lipid peroxidation, genotoxicity, impaired cell signaling and endocrine disruptions. There is an emerging confluence of opinion that suggests that oxidative stress is one of the main underlying mechanisms in the developmental defects and adverse pregnancy outcomes. Recurrent pregnancy loss may be caused by oxidative damage to macromolecules and DNA and ROSinduced signal transduction for various genes are some of the underlying factors leading to recurrent abortion. The available scientific reports are either case reports or epidemiological studies or laboratory animal studies. But all these findings are yet not confirmed in human. There are many unanswered questions about the mechanism of toxicity and related modulating factors of toxicity, which have to be answered yet. These questions include- What are the relative contribution of environmental factors (Drinking water contaminant: arsenic, cadmium, fluoride, mercury, lead and uranium) on pregnancy outcomes, fetal development and related congenital abnormalities? Is the impact of toxicity depends upon the nutritional condition of the patients? Which organ/s is/are more susceptible to particular chemical toxicity and at which stage of pregnancy? Can we limit the frequency and severity of birth defects by drinking water replacement with safe drinking water, better nutrition, and education? Although some congenital defects cannot be prevented fully, but the frequency and severity of birth defects can be minimized by understanding and early detection and prevention of exposure to different types of teratogenic agents. Improvements in the health care, avoidance of certain teratogens, better nutrition, and education can reduce the frequency and phenotypic severity.

[6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26]

Conflict of Interest: None declared

[27] References [1] National Toxicology Program, Tenth Report on carcinogenesis. Department of Health and Human Health Services. Research Triangle Park NC: (2000) III-42-III-44. [2] Institutes of Health The World Bank World Health Organization Population Reference Bureau (2008) Controlling Birth Defects: Reducing the Hidden Toll of Dying and Disabled Children in Low-Income Countries. Disease control priorities project report. www.dcp2.org [3] Nriagu J. (1988) A silent killer of environmental metal poisoning. Environ Pollut, 50(1-2), 139-161. [4] ATSDR (2005) Agency for Toxic Substance and Disease Registry, U.S. Toxicological Profile for Cadmium. Department of Health and Humans Services, Public Health Service, Centers for Disease Control, Atlanta, GA. [5] World Health Organization (2011) Cadmium in Drinking-water: Background

[28] [29] [30] [31] [32] [33] [34] [35]

document for development of WHO Guidelines for Drinking-water Quality. The Ministry of Environment (2005) Review on the occurrence of cadmium and lead in the environment of the Czech Republic. Martelli A., Rousselet E., Dycke C., Bouron A. and Moulis J.-M. (2006) Biochimie, 88, 1807-1814. Satarug S., Baker J.R., Urbenjapol S., Haswell-Elkins M., Reilly P.E. and Williams D.J. (2003) Toxicol Lett, 137(1-2), 65-83. McLaughlin M.J., Whatmuff M., Warne M., Heemsbergen D., Barry G. and Bell M. (2006) Environ Chem, 3(6), 428-432. Berglund M.., Akesson A., Nermell B. and Vahter M. (1994) Environ. Health Perspect, 102(12), 1058-1066. Zalups R.K. and Ahmad S. (2003) Toxicol. Appl. Pharmacol, 186, 163-188. USEPA (2007) Integrated Risk Information System (IRIS) home page.http://www.epa.gov/iris/subst/index.html.U.S.EnvironmentalProtection Agency, Office of Emergency and Remedial Response, Washington, DC. Arsenic in Drinking Water Report (2001) Arsenic in Drinking Water 2001 Update. Washington, DC National Research Council. CERCLA Priority List of Hazardous Substances. (2007. ttp://www.atsdr.cdc.gov/cercla/07list.html. FAO/WHO (2011a) Evaluation of certain contaminants in food. Seventysecond report of the Joint FAO/WHO Expert Committee on Food Additives. Geneva, WHO Technical Report Series, No. 959 Smith A. H., Linga, E. O. and Rahman M. (2000) Bull. World Health Organ, 78, 1093–1103. Rahman A., Vahter M., Ekstrom E. C., Rahman M., Golan Mustafa A. H., Waheed M. A., Yunus M. and Persson L. A. (2007) Am. J. Epidemiol, 165, 1389–1396. Michael F. Hughes, Barbara D. Beck,Yu Chen, Ari S. Lewis, and David J. Thomas.(2011) Toxicological sciences, 123(2), 305–332. von Ehrenstein O. S., Guha Mazumder D. N., Hira-Smith M., Ghosh N., Yuan Y., Windam G., Gosh A., Haque R., Lahir S. and Kalman D. (2006) Am. J. Epidemiol, 163, 662–669. von Ehrenstein O. S., Poddar S., Yuan Y., Mazumder D. G., Eskenazi B., Basu A., Hira-Smith M., Gosh N., Labiri S. and Haque R. (2007) Epidemiology, 18, 44–51. Yorifuji T., Tsuda T. and Grandjean P. (2010) J. Natl. Cancer Inst, 102, 360–361. Hindmarsh J.T. and McCurdy R.F. (1986) CRC Critical Reviews in Clinical Laboratory Sciences, 23, 315–347. Tam G.K., et al. (1982) Bulletin of Environmental Contamination and Toxicology, 28, 669–673. Ishinishi N., et al. (1986) Arsenic. Handbook on the toxicology of metals, 2nd ed. Vol. II. Elsevier, Amsterdam, pp. 43–73. IPCS (2001) Arsenic and arsenic compounds. Geneva, World Health Organization, International Programme on Chemical Safety (Environmental Health Criteria. 224. Golub M.S., Macintosh M.S. and Baumrind N. (1998) J Toxicol Environ Health B Crit Rev, 1(3),199–241. Concha G., Vogler G., Lezcano D., Nermell B. and Vahter M. (1998) Toxicol Sci, 44(2),185–190. Winski S.L. and Carter D.E. (1998) J. Toxicol. Environ. Health, 53, 345– 355. Cullen W. R. and Bentley R. (2005) J. Environ. Monit, 7, 11–15. Kitchin K.T. and Conolly R. (2010) Chem. Res. Toxicol, 23, 327–335. Keyse S.M. and Tyrrell R.M. (1989) Proc.Natl. Acad.Sci.U.S.A, 86, 99–103. Yamanaka K., Hasegawa A., Sawamura R. and Okada S. (1989) Biochem. Biophys. Res. Commun, 165, 43–50. Shi H., Shi X. and Liu K. J. (2004) Mol. Cell. Biochem, 255, 67–78. Del Razo L.M., Quintanilla-Vega B., Brambila-Colombres E., CalderonAvande E. S., Manno M., and Albores A. (2001) Toxicol. Appl. Pharmacol, 177, 132–148. Straub A. C., Clark K. A., Ross M. A., Chandra A. G., Li S., Gao X., Pagano P. J., Stolz D. B. and Barchowsky A. (2008) J. Clin. Invest, 118, 3980–

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347

Inorganic Contaminants of Drinking Water: Impact on Pregnancy Outcome and Related Congenital Defects 3989. [36] Ahmad S., Kitchin K. T. and Cullen W. R. (2000) Arch. Biochem. Biophys, 382, 195–202. [37] Rossman T. G. (2003) Mutat. Res, 533, 37–65. [38] Ponpat I., Panida N., Somchamai W., Krittinee C., William A.S., Chulabhorn M. and Mathuros R. (2012) Environmental Health, 11, 31. [39] Zierler S., et al. (1988) International Journal of Epidemiology, 17, 589–594. [40] Ferm H.V. and Hanlon D.P. (1985) Environmental Research, 37, 425–432. [41] Concha G., Vogler G., Lezeano D., Nermell B., Vahter M. (1998) Toxicol Sci, 44,185–190. [42] Akhtar Ahmad S., Salim Ullah Sayed M.H., Shampa Barua, Manzurul Haque Khan, Faruquee M.H., Abdul Jalil, Abdul Hadi S. (2001) Environmental Health Perspectives, 6, 109. [43] Zhao C. Q., Young M. R., Diwan B. A., Coogan T. P. and Waalkes M. P. (1997) Proc. Natl. Acad. Sci U. S. A, 94, 10907–10912. [44] Chanda S., Dasgupta U. B., Guhamazumder D., Gupta M., Chaudhuri U., Lahiri S., Das S., Ghosh N. and Chatterjee D. (2006) Toxicol. Sci, 89, 431– 437. [45] Organisation for Economic Co-operation and Development (OECD) (1994) [46] Nriagu J. (1988) Environ Pollut, 50(1-2), 139-161. [47] ATSDR (2005) Agency for Toxic Substance and Disease Registry, U.S. Toxicological Profile for Cadmium. [48] Jarup L., Burglund M., Elinder C.G., Nordberg G., Vahter M. (1998) Scand J Work Environ., 24 Suppl 1:1-51. [49] Cadmium in Drinking-water .Background document for development of WHO Guidelines for Drinking-water Quality (2011) © World Health Organization [50] The Ministry of Environment (2005) Review on the occurrence of cadmium and lead in the environment of the Czech Republic report [51] A. Martelli, E. Rousselet, C. Dycke, A. Bouron, J.-M. Moulis. (2006) Biochimie, 88, 1807-1814. [52] National Toxicology Program, Tenth Report on carcinogenesis (2000) Research Triangle Park NC, III-42-III-44. [53] Berglund M., Akesson A., Nermell B. and Vahter M. (1994) Environ Health Perspect, 102(12), 1058–1066. [54] Waalkes M. (2003) Mutation Research, 533, 107-120. [55] Vahter M., Åkesson A., Lidén C., Ceccatelli C., Berglund M. (2006) Environ. Res, 104, 85-9., [56] Lars Järup, Agneta Åkesson (2009) Toxicology and Applied Pharmacology, 238, 201-208. [57] Satarug S, Swaddiwudhipong W, Ruangyuttikarn W, Nishijo M, Ruiz P. (2013) Environmental Health Perspect, 121 (5), 531-536. [58] Cadmium and cadmium compounds. (1993) Eval. Carcinog. Risks Hum, 58, 119-237. [59] Brzóska M.M., Moniuszko-Jakoniuk J. (2001) Food Chem. Toxicol, 39, 967980. [60] Agnieszka SC, Anna S, Maria S, Teresa K, Renata SK, Roman P, Dariusz A, Józef F and Martyna KS. (2000) Toxicology, 145, (2),159–171. [61] Ognjanovic´ BI, Markovic´ SD, Ethordevic´ NZ, Trbojevic´ IS, Stajn AS, et al. (2010) Reprod Toxico, l 29, 191–197. [62] Waalkes M. and Misra R. (1996) FL: CRC Press, 1996, 231-244. [63] Benbrahim-Tallaa L., Waterland R., Dill A., Webber M. and Waalkes M. (2007) Environmental Health Perspectives, 115, 1454-1459. 67. [64] Huang D., Zhang Y., Qi Y., Chen C. and Weihong J. (2008) Toxicology Letters, 179, 43-47. [65] Pius Joseph. (2009) Toxicology and Applied Pharmacology, 238,272- 279. [66] Lohmann R.D., Beyersmann D. (1993) Biochem Biophys Res, 190, 1097– 1103. [67] Muller L. (1986) Toxicology, 40,285-95. [68] Amara S., Abdelmelek H., Garrel C., Guiraud P., Douki T., Ravanat J.L., Favier A., Sakly M., Ben Rhouma K. (2008) J Reprod Dev, 54,129-34. [69] Djukić-Ćosić D., Ćurčić-Jovanović M., Plamenac-Bulat Z., Ninković M., Maličević Z. and Matović V. (2011) Arh Hig Rada Toksikol, 62, 65-76.

[70] Valko M., Morris H. and Cronin M.T.D. (2005) Curr Med Chem, 12,1161208. [71] Valko M., Rhodes C.J., Moncol J., Izakovic M. and Mazur M. (2006) Chem Biol Interact, 160, 1–4. [72] Li J., Yan B., Liu N., Wang Q. and Wang L. (2010) Acta Scientiae Circumstantiae, 30, 2277–2284. (in Chinese) [73] Filipic M., Fatur T. and Vudrag M. (2006) Hum Exp Toxicol, 25, 67–77. [74] Santos F.W., Graca D.L., Zeni G., Rocha J.B., Weis S.N., et al. (2006) Reprod Toxicol, 22, 546–550. [75] Berghella V. (2007) Obstet Gynacol, 110, 904-12. [76] Ikeh-Tawari E.P., Anetor J.I., Charles-davies M.A. (2013) Toxicol Int, 20,108-12. [77] Nishijo M., Nakagawa H., Honda R., Tanebe K., Saito S., Teranishi H., Tawara K. (2002) Occup Environ Med, 59, 394–397. [78] Lafuente A., Cano P., Esquifino A.I. (2003) Biometals, 16, 243–250. [79] Piasek M., Blanusa M., Kostial K. and Laskey J.W. (2001) Reprod Toxicol, 15, 673–681. [80] Magers T., Talbot P., DiCarlantonio G., Knoll M., Demers D., Tsai I., Hoodbhoy T. (1995) Reprod Toxicol, 9, 513–525. [81] Kawai M., Swan K.F., Green A.E., Edwards D.E., Anderson M.B., Henson M.C. (2002) Biol Reprod, 67,178– 183. [82] Shiverick K.T. and Salafia C. (1999) Placenta, 20,265–272. [83] Piasek M., Laskey J.W., Kostial K. and Blanusa M. (2002) Int Arch Occup Environ Health, 75(Suppl), S36– S44. [84] Piasek M, Laskey JW. (1999) J Appl Toxicol, 19,211–217. [85] Falcone T, Little AB. Placental synthesis of steroid hormones. In: Tulchinsky D, Ryan KJ, Eds. (1980) Maternal-Fetal Endocrinology. Philadelphia: W. B. Saunders Company, pp3–16. [86] Huszar G. Biology of the myometrium and cervix. In: Warsham J, Ed. (1983) The Biological Basis of Reproductive and Developmental Medicine. New York: Elsevier Biomedical, pp85–104. [87] Trottier B, Athot J, Ricard AC, Lafond J. (2002) Toxicol Lett, 129,189–197. [88] Egawa M, Yasuda K, Nakajima T, Okada H, Yoshimura T, Yuri T, Yasuhara M, Nakamoto T, Nagata F, Kanzaki H. (2003) Biol Reprod., 68, 2274–2280. [89] Guidelines for drinking-water quality (1999) 2nd ed. Vol. 2. Geneva: W.H.O; World Health Organization. [90] Das TK, Susheela AK, Gupta IP, Dasarathy S, Tandon RK (1994) J Clin Gastroenterol, 18(3),194-9. [91] Dasarathy S, Das TK, Gupta IP, Susheela AK, Tandon RK (1996) J Gastroenterol, 31(3),333-7. [92] Das TK (1991) Effects of excess fluoride ingestion on calcification of bone with reference to Glucocorticoids". PhD thesis Submitted to the All India Institute of Medical Sciences, New Delhi, Effects of fluoride on corticosteroids metabolism and its role in bone mineralization has also been reported). [93] Freni, S.C. (1994) J. Toxicol & Environ. Health, 42, 109-12. [94] Al- Hiyasat, A.S., Elbetieha, A.M. & Darmani, H. (2000) Fluoride, 33, 79-84. [95] Tohyama, E. (1997) Japan Epedem, 7 (3),184. [96] Mamta Kumari et al. (2011) ASIAN J. EXP. BIOL, 2(2). [97] UNICEF Report: State of the world’s children (2008). [98] Yusufji, D. et al. (1973) WHO, 48, 15–22. [99] Susheela, A. K. et al. (1992) Fluoride, 25, 5–22. [100] Gupta, I. P., Das, T. K., Susheela, A. K., Dasarathy, S. and Tandon, R. K. (1992) J. Gastroenterol. Hepatol, 7, 355–359. [101] Das, T. K., Susheela, A. K., Gupta, I. P., Dasarathy, S. and Tandon, R. K. (1994) J. Clin. Gastroenterol, 18, 194–199. [102] Susheela, A. K. and Jain, S. K. (1986) Erythrocyte membrane abnormality and echinocyte formation. Proceedings of the 14th Conference of the International Society for Fluoride Research, Japan, Elsevier Publishing House, Amsterdam, [103] Susheela, A. K., Bhatnagar, M., Vig, K. and Mondal, N. K. (2005) Fluoride, 38, 98–108. [104] A. K. Susheela, N. K. Mondal, Rashmi Gupta, Kamla Ganesh Shashikant

International Journal of Medical and Clinical Research ISSN: 0976-5530 & E-ISSN: 0976-5549, Volume 7, Issue 2, 2016 || Bioinfo Publications ||

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Quadri J.A., Alam M.M., Sarwar S., Singh S., Shariff A., Roy T.S. and Das T.K. Brahmankar, Shammi Bhasin and G. Gupta. (2010) Current science, Vol. 98. [105] Guven A, et al. (2005) Fluoride, 38, 133-138. [106] Wang AG, Chu QL, He WH, Xia T, Liu JL, Zhang M, Nussler AK, Chen XM, Yang KD (2005) Toxicol Lett, 158(2),158-63. [107] Shivashankara AR, Shivarajashankara YM, Bhat PG, Rao SH (2002) Bull Environ Contam Toxicol, 68(4), 612-6. [108] Li Y, Decker S, Yuan ZA, Denbesten PK, Aragon MA, Jordan-Sciutto K, Abrams WR, Huh J, McDonald C, Chen E, MacDougall M, Gibson CW (2005) Arch Oral Biol, 50(8), 681-8. [109] Xu H, Jing L, Li GS (2008) Biol Trace Elem Res, 123(1-3), 91-7. [110] Anuradha CD, Kanno S, Hirano S (2000) Arch Toxicol, 74(4-5), 226-30. [111] Anuradha CD, Kanno S, Hirano S (2001) Free Radic Biol Med, 31(3), 36773. [112] Chlubek D (2003) Fluoride, 36, 217-228. [113] Sullivan K.M. (2009) J. Neurological Sciences, 276, 202. [114] Waugh D.(2013) Report Govt. European Commission and WHO., 282-1-70. [115] Lanphear BP, Matte TD, Rogers J, et al. (1998) Environ Res, 79,51–68. [116] Times of India (Pune) Report Jul 20, 2013. [117] Graziano JH, Popovac D, Factor-Litvak P, et al. (1990) Environ Health Perspect, 89, 95–100. [118] Gulson BL, Mizon KJ, Korsch M.J., Palmer J.M., Donnelly J.B. (2003) Sci Total Environ, 303,79–104. [119] Ahamed M, Mehrotra PK, Kumar P and Siddiqui M.K. (2009) Environ Toxicol Pharmacol, 27(1), 70-4. [120] Saxena G, Flora SJ. (2004) J Biochem Mol Toxicol, 18(4):221-33. [121] Ercal, N., Treratphan, P., Hammond, T.C., Mathews, R.H., Grannemann, N.H. and Spitz, D.R., (1996) Free Rad. Biol. Med., 21, 157-161. [122] Villa, J.C., Davis, P.L. and Acosta, D. (1991) Toxicol. Appl. Pharmacol, 108, 28-35. [123] Pocock SJ, Smith M, Baghurst P. (1994) BMJ, 309,1189–1197. [124] Canfield RL, Henderson CR Jr, Cory-Slechta DA, Cox C, Jusko TA, Lanphear BP. (2003) N Engl J Med, 348,1517–1526. [125] Rice D. (1996) Environ Health Perspect, 104 (suppl 2), 337–351. [126] Chisolm JJ Jr, Kaplan E. (1968) J Pediatr, 73, 942–950. [127] Committee on Environmental Health (2005) Lead Exposure in Children: Prevention, Detection, and Management. Pediatrics, 116;1036. [128] Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. (2012) EXS., 101, 133–164. [129] Agency for Toxic Substances and Disease Registry. (2010) Board Fam Med, 23(6), 797-798. [130] Grandjean P, Weihe P, Burse VW, et al. (2001) Neurotoxicol Teratol, 23,305–317. [131] Debes F, et al. (2006) Neurotoxicol Teratol, 28, 536–547. [132] Food and Drug Administration. (2007) Consumer advisory: An important message for pregnant women and women of childbearing age who may become pregnant about the risks of mercury in fish. Available at: http://vm.cfsan.fda.gov/~dms/admehg.html. [133] Emily O1, Jenny S. Radesky1, Robert O. Wright, David C. Bellinger, Chitra J. Amarasiriwardena, Ken P. Kleinman1, Howard Hu, and Matthew W. (2008) Am J Epidemiol, 15, 167(10), 1171–1181. [134] Berlin M, Rudell B. (1986) Uranium. Handbook on the toxicology of metals, 623–637. [135] Taylor DM and Taylor SK. (1997) Rev Environ Health. 12,147–157. [136] Sullivan MF et al. (1986) Health Physics, 50(2), 223–232. [137] La Touche YD, Willis DL, Dawydiak OI (1987) Health Physics, 53(2), 147– 162. [138] Moss MA (1985) Chronic low level uranium exposure via drinking water — clinical investigations in Nova Scotia. Halifax, Nova Scotia, Dalhousie University (M.Sc. thesis) [139] WHO Guidelines for Drinking-water quality (3rd ed.) (2004) [140] Hartmann HM, Monette A, Avci HL. (2000) Hum Ecol Risk Assess 6, 851– 874.

[141] Domingo JL. (2001) Reprod Toxicol 15, 603–609. [142] Zhu SP, Hu QY, Lun MY. (1994) Chinese Journal of Preventive Medicine, 28 (4), 219-221. [143] Zaire R, Notter M, Riedel W and Thiel E. (1997) Radiation Res, 147, 579584. [144] Schroder H, Heimers A, Frentzel-Beyme R, Schott A, Hoffmann W. (2003) Radiation Prot Dosimetry, 103, 211-220. [145] Diane M.Stearns et al. (2005) cell, 20(6), 417–423. [146] M. Luisa Albina et al. (2003) Exp Biol Med, 228,1072–1077. [147] Rita H, Doug B and Bindu P. (2005) Environmental Health, 4,17. [148] Domingo JL. (2001) Reprod Toxicol 15, 603–609. [149] Harmanjit Singh, Joga Singh, Surinder Singh and B S Bajwa. (2009) Indian J. Phys, 83 (7), 1039-1044. [150] Lushchak VI. (2011) Comp Biochem Physiol C Toxicol Pharmacol, 153, 175-90. [151] Riley JC, Behrman HR. (1991) Proc Soc Exp Biol Med, 198, 781–791. [152] Evans MD, Dizdaroglu M, Cooke MS. (2004) Mutat Res, 567,1-61. [153] Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ. (2000) Am J Pathol, 157, 2111–2122. [154] Hung TH, Burton GJ. (2006) Taiwan J Obstet Gynecol, 3, 189-200. [155] Hansen HM, Longbottom DA, Ley SV. (2006) Chem Commun, 14, (46), 4838-40. [156] Michael P. Murphy. (2009) Biochem. J, 417,1-13. [157] Jergil M, Kultima K, Gustafson A, Dencker L and Stigson M (2009) Toxicol Sci, 108,132-148. [158] Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ. (2000) Am J Pathol, 157, 2111–2122.

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