Effect of cadmium exposure during and after pregnancy of female

ABSTRACT Cadmium is a common environmental pollutant and used for industrial purposes all over the world. Cadmium exposure causes a variety of public health issues, mainly reproductive health. The present review discusses the information related to female reproductive health, including during and after pregnancy and its outcomes. Cadmium alters steroidogenesis, delays puberty, causes pregnancy loss of reproductive hormones, disturbs the menstrual cycle, causes premature births, and reduces birth weights in females. Besides that, their offspring are affected differently by prenatal mother exposure to cadmium, with more female offspring being distressed. During lactation period, nursing babies fed with milk containing cadmium causes disparity in brain physiology, reflex changes and physical immaturity. Together, these reviews highpoint the need for more studies into the consequences of cadmium exposure on reproductive health.


Introduction
Cadmium is a heavy metal with no known biological advantages to the human body [1].However, it possesses a major public health issue, especially harmful to the reproductive system [2], because of its ability to interfere with hormonal action, that is why it is also called endocrine disruptor [3].Cadmium is commonly found in minerals alongside copper (Cu), zinc (Zn), and lead (Pb) [4].Cadmium is widely used in numerous industrial processes, such as preservatives, color pigments, stabilizers in polyvinyl chloride products, neutron absorbers in nuclear power plants, and nickel-cadmium batteries.The major pathways of cadmium exposure include inhalation of cadmiumcontaining smoke and dust, accidental ingestion through contaminated hands and food, and passive/ active cigarette smoking [5].Cadmium enters the blood stream and binds to proteins such as metallothionein and albumin, then transported to liver, and then gastrointestinal tract (GIT) system.Cadmium causes hepatocyte necrosis, apoptosis and interruption of autophagy flux in the liver [6].Following that, some of the cadmium that has already been absorbed via biliary tract discharge as cadmium-glutathione conjugates are then broken down into cadmium-cysteine complexes.Then, cadmium is able to re-enter the small intestine [7].Cadmium's second main target organ is the kidney, where it accumulates over time and causes tubulus cell necrosis, after that it excretes though urine and faeces [4].Previously reported that, a disease called itai-itai occurred in Japan as a consequence of industrial cadmium waste discharge into a river.Residents of the river tributaries who used contaminated water undergone severe back and joint pain [8].It was discovered that pneumonia and gastrointestinal diseases contributed to an increased mortality risk in itai-itai ailing patients.Renal disease is a significant risk factor for mortality in itai-itai patients and patients with renal tubular dysfunction [9].Cadmium can affect lung function and increase lung cancer risk [10].In addition, chronic low-level environmental cadmium exposure in industrialized countries adversely affects bones and kidneys in the general population [11,12].
The body burden of heavy metals in females, particularly those with iron deficiency, is usually higher than in males because iron deficiency up-regulates the duodenal iron transporter, resulting in increased absorption of dietary heavy metals by the intestines [13].The female reproductive system is extremely vulnerable to cadmium damage.Ingestion of plant foods and other chemical compounds, including cadmium, can affect or enhance the functioning of the female reproductive system, especially the uterus.This could be due to their direct action on the uterus or their effect on the hypothalamic-pituitary-gonadal axis, which can either inhibit or improve certain important biochemical processes [14].Cholesterol is the basic precursor to the female sex hormones progesterone and estrogen.
Cadmium has been shown to interrupt the rates of steroidogenesis in the ovaries and placenta, preventing the secretion of female sex hormones and therefore negatively affecting normal reproduction [15].Cadmium decreases progesterone production by inhibiting the expression of the steroidogenic acute regulatory protein StAR and the cytochrome P450 cholesterol side-chain enzyme P450scc.The StAR protein modulates intra-mitochondrial cholesterol transport [16], whereas the P450scc is a mitochondrial membrane enzyme responsible for converting cholesterol to pregnenolone, the first step in the steroidogenic pathway in mammalian tissues.Cadmium also accrues in the granulosa cells of the ovary, causing a significant decrease in gonadotropins and interrupting the activities of steroidogenic enzymes [17].Cadmium also disrupts follicle maturation, follicle arrangement, and corpus luteum degradation, as well as increasing the number of atresia follicles [18].Moderate and high doses of Cadmium affect steroid synthesis in female reproductive organs [19].Even though cadmium effectively binds to estrogen and androgen receptors because low-dose cadmium exposure has powerful estrogen-and androgen-like activities [20].Cadmium, like estradiol, can rapidly activate extracellular signal-regulated kinases 1 and 2 as well as Ak strain transforming pathways [21,22].Cadmium toxic effects have long been an issue of public health among women reproduction, and its negative effects on the reproductive system cannot be overstated.This review is written to provide an update on the potential adverse effects of cadmium during and after pregnancy of female.

Cadmium exposure causes the increased length of menstruation and hormonal impairment
A growing body of evidence suggests that cadmium, a non-essential heavy metal, may be linked to a variety of negative reproductive health outcomes in women [23].Hormonal changes are important biological signals that make a contribution to the etiology of cancer, heart disease, and other diseases [24][25][26].The relationship between blood metal levels and hormone levels is measured at clinically significant time periods in the menstrual cycle.Blood cadmium levels have been shown to associate with female reproductive hormones [8].Cadmium is one of the contaminants in cigarettes that have been linked to estrogenic influences, despite the fact that smoking has been linked to anti-estrogenic effects, such as a reduction in risk of earlier age at menopause and endometrial cancer [27][28][29].In rats, cadmium has been linked to the early vaginal opening, increased uterine weight, and increased mammary gland development [30]; decreased gonadotropin binding and altered steroidogenic enzyme activity in rat granulosa cells [15,31]; irregular menstrual cycles in young women [32]; endometriosis [33,34].According to earlier research, it is unknown why cadmium is connected to higher estradiol hormone levels in the early follicular phase; however, the connection could be due to cigarette smoke rather than cadmium exposure.In 2004 epidemiological research, smoking is linked to higher estradiol hormone levels [35] and limited overall menstrual cycle duration [36,37] and shorter follicular phase length [38].On the other hand, the lack of relationship when smokers are excluded may be due to the elimination of persons with the highest blood cadmium levels, which may have a threshold effect.Regarding cycle length, the found relation between cadmium and increased cycle length got greater when the study was confined to never-smokers, indicating that cadmium and cigarette smoke may have separate and opposing impacts on the menstrual cycle length.Previous research has found that the average menstrual cycle length of 22 females was 25 days, and that of 17 females was 35 days.To ensure that females were compared at the same physiological time point, hormone levels were estimated on clinically significant days of the menstrual cycle and then normalized to a 28-day cycle.Progesterone and luteinizing hormone levels decreased in 15% (n = 39) and 14% (n = 35) of the study participants, respectively.A potential negative correlation between higher mercury levels and lower luteinizing hormone levels may have gone undetected because females who lost their luteinizing hormone levels also had slightly higher mercury levels.Blood metal levels that reflect current metal exposure are very accurately measured.Within 16 days of the study cycle, when follicles are developing and exposure can result in steroid genesis and cycle length for the following cycle, the majority of participants had their metal levels measured.If exposure is not measured during a crucial exposure window, studies may be limited.Considering that the hypothalamicpituitary-ovarian axis develops during this time, animal studies suggest that lead and cadmium exposure during pregnancy or childhood may be a sensitive exposure window [39,40].Alternately, metal levels should be measured in a surrogate matrix such as bone (lead), hair (mercury), or urine (cadmium) if cumulative metal exposure is more pertinent to the outcome of interest.

Cadmium exposure causes pregnancy loss
The most serious complication of early pregnancy is spontaneous abortion, which is a major reproductive health issue.However, this could be due to a variety of cytogenetic, immunological, or endocrinological factors [41].The role of environmental toxins cannot be marked down.Toxicity may impair ovarian function in the female reproductive system [42].
High level of cadmium in the placenta causes increased expression of the Metallothionein gene family.Metallothionein is a cysteine-rich protein that serves as a protective barrier, preventing toxic metals from passing through the placenta.Cadmium has the ability to displace zinc in the fetus.Zinc is a trace element that is necessary for normal fetal growth and development.To protect the developing fetus, metallothionein maintains the cadmium, but cadmium reduces the fetus's zinc bioavailability [43], affecting cellular division and differentiation.In low birth weight babies, cadmium concentration is very high, while zinc levels are very low [40].Cadmium can also reduce leptin hormone synthesis, increase corticosterone concentration, and interrupt progesterone production in the placenta [44,45].Another studies included in the present meta-analysis found a significant difference in blood cadmium levels between case and control groups, which may indicate that recent cadmium exposure is more likely to be associated with embryo toxicity and spontaneous abortions than total-body cadmium burden [46].One-third of all conceptions and 10-15% of clinically confirmed the pregnancies contribute through pregnancy loss, or miscarriage.Cadmium may affect pregnancy loss through endocrine pathways or by boosting oxidative stress, which has been linked to poor reproductive health [47].While controls (female without a history of recognized pregnancy loss) had lower mean blood cadmium levels of 0.25 g/L, female with a self-reported history of recurrent (defined as three or more) pregnancy losses had mean blood cadmium levels of.46g/L (p0.05) [48].To clarify a potential link between cadmium and pregnancy loss, additional prospective studies at environmentally relevant levels of cadmium exposure are required because there is a serious shortage of human data.

Cadmium exposure is small for gestational age
A number of other studies found a negative correlation between maternal cadmium exposure and child weight [49,50], indicating that cadmium exposure is a major public health concern.In addition to occupational and environmental exposures, smoking also exposes pregnant women to hazardous substances.None of the contributors in this research had a history of smoking and occupational exposure.Therefore, cadmium exposure in these subjects comes mainly from environmental exposure.Several adverse reproductive outcomes have been reported from maternal exposure to cadmium, including premature birth and low birth weight.However, most studies have focused on the association between maternal blood or placental cadmium levels and pregnancy outcomes.In fact, the placenta is a barrier that protects the fetus from toxic metals such as lead, cadmium, and mercury [51][52][53].These metals, especially cadmium, accumulate in the human placenta [53][54][55].In fact, cord blood cadmium represents the absolute amount of cadmium that reaches the fetus via the placenta.Therefore, we analyzed the effect of cord blood cadmium on pregnancy outcomes and subsequent child development.Many genetic and environmental factors influence pregnancy outcomes and child development.We included in the analysis variables that we could measure, such as maternal age, body weight, gestational week, maternal educational status, time of delivery, method, feeding mode, kindergarten age, US EST, and annual income per capita, to study the effects of cadmium exposure during pregnancy on the infant.Everybody is aware that no level of lead exposure seems to be 'safe' and that even the 'low' levels of lead exposure that children are already experiencing are linked to neurodevelopmental impairments [56].In addition to postnatal exposure, prenatal lead exposure can also affect the development of a baby's IQ level.A study from Yugoslavia found that increases in maternal blood lead concentrations in the second trimester (12-20 weeks) were significantly associated with a decrease in IQ at 3-7 years, regardless of postpartum exposure patterns [57].At the time of prenatal blood lead conditions, the Ohio State Research Center in Ohio, regardless of subsequent blood lead tests, 6 to 28 days of blood lead in the body represents an important health monitoring and structural factor [58].Therefore, in a blood-borne study evaluating the effects of cadmium exposure on control reports and PB reports, monitoring the effect of BMI on blood from developing children showed it to be high, while short, without body length.Cord blood cadmium levels remained an independent factor affecting fetal development even after potential confounding variables were eliminated.Nishijo et al. and others According to some reports, cadmium exposure has no significant effect on embryo development [59].The variety of biological samples used in their investigation (cadmium in maternal urine) may cause these inconsistent results.
We also examined the long-term effects of cadmium exposure during pregnancy on anthropometric results and subsequent IQ development of offspring.Children aged 4.5 years in the high cadmium group had significantly lower height and overall Wechsler preschool and primary scales of intelligence (WPPSI-RIQ) scores than those in the low cadmium group.When relevant confounders were taken into account, associations of this type remained unchanged.Lead has been the subject of the majority of studies on the adverse effects of low prenatal exposure to heavy metals on later IQ development.Children without overt lead-related symptoms experience negative consequences of low-level lead exposure on their behavior and intellectual performance, according to Needleman et al. [60].Many, but not all, later investigations have found that asymptomatic children are negatively affected by low-level lead exposure in terms of function [61].However, to our knowledge, there are few reports on how prenatal cadmium exposure affects future IQ growth.Our latest findings -which are fundamental explorations and contribute to a better understanding of the harmful effects of cadmiumconcern the adverse consequences of embryonic cadmium exposure on offspring development.However, it is clear that several additional societal, family and genetic variables may affect pregnancy and fetal development, and these factors should be considered in future research on the harmful effects of prenatal cadmium exposure on development.

Cadmium exposure causes low birth weight, length and decreased head circumference
One of the best indicators of a successful pregnancy is the birth weight of the newborn, which also serves as a predictive indicator of neonatal mortality and morbidity [62].The average weight of a full-term baby (between 35 and 40 weeks at delivery) is between 2,812 and 4,173 g.Low birth weight babies are those who weigh less than 2,500 g and are more likely to have health problems as a newborn and adults.Birth weight is influenced by various factors, including the mother's nutritional status [63], exposure to toxic pollutants such as cadmium, hunger and the deficiency of some important trace elements such as zinc, iron and copper (Cu) [4].Cadmium is a heavy metal that seriously harms the quality of human life.The physiological role of cadmium in the human body has not yet been identified [64].Cadmium exposure occurs when people consume foods containing the metal, which is found in trace amounts in all foods (highest concentrations are found in shellfish, liver, and kidney meat), smoke cigarettes or inhale cigarette smoke, breathe polluted office air, drink contaminated water, or live near industrial facilities that release cadmium into the air [65].The lungs are more effective in absorbing cadmium than the gastrointestinal tract [65,66].Zinc is an essential trace mineral required for many basic body processes, including the development of the immune system, reproduction, and healthy skin and bones.Zinc affects pregnancy outcomes and is important for healthy fetal development [66].Low birth weight neonates are associated with maternal zinc deficiency during pregnancy.With ligands for sulfur, nitrogen, and oxygen, cadmium and Zn (both class II-B transition elements) share the same electronic configuration and valence and therefore have comparable geochemical and environmental characteristics [67].
They are about the same size when ionized and have an oxidation state of +2.Therefore, cadmium can replace zinc in many biological systems.The lack of Zn observed in most cadmium processing systems has led to the description of cadmium as an antimetabolite of Zn [68].Zinc-binding proteins, especially those containing zinc finger protein structures, are responsible for the expression of cadmium toxicity in vivo [69].According to animal studies, maternal iron deficiency during pregnancy can cause lower birth weight and chronic hypertension in children.Humans often experience iron deficiency during pregnancy, which has been linked to poor birth outcomes, including low birth weight [70].Iron deficiency can also make it easier for divalent metals, including lead, cadmium, aluminium, and manganese, to enter the body [71].A small amount of the trace element selenium (Se) is necessary, but excessive amounts can be harmful.It is important for the development and reproduction of animals and stops the formation of free radicals.It is important to minimize the biological hazards caused by cadmium [72].Human fetuses, newborns and children require copper for proper growth and development as well as for hematopoiesis.According to studies, mothers who are underweight during pregnancy can give birth to babies with low birth weight [73].Investigating the potential consequences of cadmium on the occurrence of spontaneous molecular processes is instructive given the increasing role of the metal in disrupting many biological and molecular systems, including genome instability or destruction.Determining the potential impact on the recovery of macronutrients such as zinc, copper and selenium is the aim of this study, which also seeks to examine the impact of cadmium on maternal and infant health (newborn birth weight).Zinc, in particular, plays an important role in the molecular reproductive process but has not received sufficient attention in reproductive studies.

Effect of cadmium exposure after pregnancy during lactation period
Studies conducted on nursing babies fed with breast milk containing cadmium during lactation have shown altered brain physiology, reflex changes, physical immaturity, a delay in neuromotor development, and hyperactivity [74].Lactating mothers exposed to cadmium during lactation transferred the heavy metal to their offspring through breastfeeding.Therefore, this plan confirmed the effect seen in the offspring due to the cadmium in milk.In addition, neurological effects in nursing pups are reported at low Cd doses (4.8, 0.9 and 1.2 mg Cd/kg b.w., respectively), including increased motor activity [75], serotonergic system disturbances, increased motor activity, and memory impairment [76].After 17 days of cadmium exposure, the motor activity increased and memory affected, and after 19 days of cadmium exposure the serotonergic system is disturbed.Interestingly, neurological effects are observed in offspring at 100 days after birth at a low dose (1.2 mg Cd/kg b.w.), which was given for 7 days.This finding suggests that Cd exposure only during lactation is sufficient to cause changes in neuronal functions.Furthermore, after 10-17 days of cadmium exposure, the biochemical effects in the offspring have been reviewed and results indicate alteration in brain fatty acid metabolism [77] and oxidative stress increased and evaluated by malondialdehyde determination in plasma and erythrocytes [78].Slyuzova et al. determined that cadmium effects in plasma and erythrocytes are obvious in lactation exposure than in pregnancy, and above observations indicate that only lactation cadmium exposure can induce effects on the offspring.Besides that, 300 mg/L cadmium concentration in drinking water given to Wistar rats the morphological changes are observed in sucking baby's mouth [79][80][81] and a decline in the weights of the female offspring's body, kidney, and spleen [82] and also cadmium accumulate in kidney of nursing babies and cause nephrotoxic syndrome [83].These effects seen in the lactation exposure system conclusively show that mother passes cadmium to their offspring through breast milk.

Conclusion
With regard to the various reproductive health consequences, cadmium is observed as a reproductive toxin in females, with the strongest body of evidence of cadmium exposure and reproductive health impairment.This study focused on the hazards related to cadmium effects on female reproductive systems, cadmium toxicity causing variations of steroidogenesis process, delayed puberty and menarche, pregnancy loss, menstrual cycle and reproductive hormone disorders, premature birth, and low birth weights as well as the studies on nursing babies fed with breast milk containing cadmium during lactation period (Figure 1).Together, these reviews highpoint the need for more studies into the consequences of cadmium exposure on reproductive health.

Figure 1 .
Figure 1.Shows one possible pathway for cadmium exposure and reproductive health impairment.