Fetal–Maternal Exposure to Endocrine Disruptors: Correlation with Diet Intake and Pregnancy Outcomes

Endocrine-disrupting chemicals (EDCs) are exogenous substances able to mimic or to interfere with the endocrine system, thus altering key biological processes such as organ development, reproduction, immunity, metabolism and behavior. High concentrations of EDCs are found in several everyday products including plastic bottles and food containers and they could be easily absorbed by dietary intake. In recent years, considerable interest has been raised regarding the biological effects of EDCs, particularly Bisphenol A (BPA) and phthalates, on human pregnancy and fetal development. Several evidence obtained on in vitro and animal models as well as by epidemiologic and population studies strongly indicated that endocrine disruptors could negatively impact fetal and placental health by interfering with the embryonic developing epigenome, thus establishing disease paths into adulthood. Moreover, EDCs could cause and/or contribute to the onset of severe gestational conditions as Preeclampsia (PE), Fetal Growth Restriction (FGR) and gestational diabetes in pregnancy, as well as obesity, diabetes and cardiovascular complications in reproductive age. Therefore, despite contrasting data being present in the literature, endocrine disruptors must be considered as a therapeutic target. Future actions aimed at reducing or eliminating EDC exposure during the perinatal period are mandatory to guarantee pregnancy success and preserve fetal and adult health.


Introduction
Natural and man-made chemicals may mimic or interfere with the endocrine system, a complex communication network among the nervous system and key biological functions such as reproduction, immunity, metabolism and behavior [1]. These compounds-known as endocrine-disrupting chemicals (EDCs)-are found in pesticides, metals and in several everyday products, including plastic bottles and food containers, detergents, flame retardants, toys and cosmetics [2]. Due to their extreme diffusion in everyday life, EDCs became object of intense investigation by the medical-scientific community, mainly to clarify their role as risk factors and/or pathogenic triggers. Pregnancy is the most sensitive clinical environment, where two lives, the mother and the developing embryo, could be simultaneously affected by EDC activity. There are contrasting data in the literature about the immediate and long-term effects of maternal and fetal EDC exposure. durability. Among them, the most commonly employed additive is di (2-ethylhexyl) phthalate (DEHP). Low-molecular-weight phthalates, like diethyl phthalate (DEP), are mainly used in personal care products and cosmetics, but they could be also found in pesticides and in food packaging [21]. Exposure to DEHP is reflected by the presence of its metabolites in urine, such as mono (2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate, mono (2-ethyl-5-carboxypentyl) phthalate and mono (2-ethyl-5-oxohexyl) phthalate, whereas the main urinary metabolite of DEP is mono-ethyl phthalate (MEP). Remarkably, the bioactivity of phthalate metabolites is superior to that of the original substance [16].

Exposure to EDCs and Fertility
Human reproduction and pregnancy success depend on both female and male reproductive health and EDCs, as BPA and phthalates could affect fertility of both genders.
The ovaries are responsible for female gametogenesis and endocrine functions during reproductive life. It has been demonstrated that prenatal BPA exposure inhibited germ cell nest breakdown in F1 generation ovaries in mice, decreased the numbers of primordial, primary, preantral and total healthy follicles at post-natal day 21 and decreased estradiol levels in female rats dosed for 1 year [46,47]. Hu and colleagues reported that sexually mature CD-1 mice treated by 5 consecutive BPA concentration gradients (1, 10, 100, 1, and 10 mg/kg) for 28 days initiated the excessive premature activation of primordial ovarian follicles via the PTEN/PI3K/AKT signaling pathway by downregulating PTEN expression in vivo [48]. In a previous prospective cohort study, the association between urinary BPA concentration and ovarian response among women undergoing in vitro fertilization (IVF) was investigated. BPA was detected in the majority of IVF women and its urinary concentrations (ranging from <0.4 to 25.5 mg/L) were inversely associated with number of retrieved oocytes per cycle and peak levels of serum estradiol [49]. Moreover, a recent study on 700 Chinese couples attempting pregnancy revealed that women with the highest urinary BPA concentration (>2.33 ng/mL) had a 30% reduction in fecundability and a 64% increase in the odds of infertility [33].
Phthalates were shown to disrupt female fertility by altering oocytes development and maturation. Data are available from animal models. Adult CD-1 mice orally daily dosed with DEHP (20-750 mg/kg/day) for 10 and 30 days showed a decreased percentage of primordial follicles and an increased percentage of primary follicles, thus reducing reproductive lifespan. The mechanism by which DEHP accelerates primordial follicle recruitment is likely via over-activation of the phosphatidylinositol 3-kinase (PI3K) signaling, a pathway that regulates primordial follicle survival, quiescence and recruitment. DEHP exposure increased ovarian mRNA levels of 3-phosphoinositide-dependent protein kinase-1 (Pdpk1), mammalian target of rapamycin complex 1 (Mtorc1), factors that drive primordial follicle recruitment, and decreased Phosphatase and tensin homolog (Pten) and Tuberous sclerosis 1 (Tsc1) mRNA levels, promoters of primordial follicle quiescence [50]. Prenatal DEHP exposure (0-40 µg/kg/day) significantly reduced percentage of methylated CpG sites in Insulin-like growth factor 2 receptor (Igf2r) and Paternally expressed gene 3 (Peg3) differentially methylated regions (DMRs) in fetal primordial germ cells and in the oocytes of the F1 mice. These DEHP-induced oocytes DNA methylation alterations were inherited by the F2 mice, indicating that DEHP effects on oocyte development are heritable [51]. MEHP, the active toxicant DEHP metabolite, significantly reduced mouse oocyte viability at concentrations of 250 and 500 µM by promoting oxidative stress. Overexpression of Cu-Zn superoxide dismutase (Sod1) and decreased expression of mitochondrial respiratory chain protein (Nd1) were identified as possible molecular mechanism leading to these MEHP-induced alterations in oocyte viability [52].
In males, EDCs exposure was associated with declined semen quality, increased sperm DNA damage, alterations in testis morphology and endocrine function [20,[53][54][55]. Mantzouki and colleagues demonstrated that very high concentrations of plasma BPA (>3 ng/mL) were associated with azoospermia in humans [56]. A cross-sectional study performed on 215 healthy young university students (18-23 years old) revealed a significant positive association between urinary BPA concentrations (2.8 (0.16-11.5) ng/mL) and serum LH levels as well as a significant and inverse association with sperm concentration and the total sperm count, thus concluding that BPA exposure may be associated with a reduction in Leydig cell capacity and decreased sperm counts in young men [57]. In accordance, other studies demonstrated that urinary BPA levels (median 1.87 µg/L) were associated with decreased sperm concentration and mobility, reduced semen quality, decreased antioxidant levels, reduced sperm DNA integrity and increased percentage of immature sperm [58,59].
Even phthalates could negatively impact on male fertility. DEHP exposure (750 mg/kg/day) in male CD-1 mice induced lower serum testosterone levels, accompanied by higher serum estradiol and LH levels. Moreover, histological mice evaluations showed that male mice prenatally exposed to DEHP were characterized by increased germ cell apoptosis, and the degeneration of seminiferous tubules, oligozoospermia, asthenozoospermia, and teratozoospermia, leading to premature reproductive senescence [60]. Yuan and colleagues described that DBP exposure (500 mg/kg) significantly decreased sperm count in F1 through F3 generations. Specifically, they found global DNA hypomethylation along with the hypomethylation of follistatin-like 3 (Fstl3) promoter, known modulator of Sertoli cell number and spermatogenesis [61]. Recent evidence suggested that embryonic exposure to DEHP (500 mg/kg body weight/day) could disrupt testicular germ cell organization and spermatogonia stem cell function in a transgenerational manner. Specifically, DEHP treatment of pregnant CD1 outbred mice at Embryonic Day 7 (E7) to E14 lead to disrupted testicular germ cell association, decreased sperm count and motility in F1 to F4 offspring [62].
Therefore, EDCs as BPA and phthalates could have severe detrimental effects on human reproduction, impairing both female and male fertility before pregnancy onset and causing gametes anomalies during fetal development that could be inherited by the following generations.

Exposure to EDCs during the Reproductive Age and Development of Obesity, Diabetes and Cardiometabolic Abnormalities
The reproductive age is a critical phase in the life of a woman, as the development of certain pathological conditions during this phase may influence the outcomes of future pregnancies. The presence of obesity [63], diabetes [64][65][66] and cardiometabolic abnormalities [67,68], during pregnancy has been associated with an increased risk of adverse maternal and fetal outcomes, including gestational hypertension, preeclampsia, gestational diabetes, caesarean section, congenital malformations, shoulder dystocia, perinatal death, preterm birth and large for gestational age at birth. A pregnancy free of such comorbidities is, thus, the best situation to preserve the health of both mother and child.
Nevertheless, the prevalence of obesity, diabetes and metabolic syndrome continuing to increase worldwide [69]. Unhealthy dietary habits and a sedentary lifestyle are considered the big two causes of such an increment, but there is a growing body of evidence suggesting a possible relationship between exposure to EDC and cardiometabolic health [25]. It must be said that almost all epidemiologic evidence on this issue comes from large cross-sectional studies and some cohort studies including women of all ages, whereas the evidence of an association between the exposure to EDC during the reproductive age and the risk of developing obesity, diabetes and cardiometabolic abnormalities is limited to few, generally small, cross-sectional studies [70][71][72][73].
At this stage, it is clear that it is not possible to draw conclusions on the relationship between exposure to EDC during reproductive age and the risk of developing pathological conditions potentially affecting pregnancy outcome. However, given the effect that obesity and metabolic complications can have on the health of both mother and child, it is urgent to conduct epidemiological studies specifically designed for this issue.

EDCs and Fetal Programming
The Developmental Origins of Health and Disease theory (DOHaD) introduced the concept that maternal diet, environmental insults and lifestyle could significantly impact on fetal-placental, development, thus establishing disease paths into adulthood [74,75]. In this context, endocrine disruptors may play a leading role in fetal programming. It was previously reported that the placenta is not such an effective barrier against EDCs and that pregnant women's exposure was associated with EDCs' entrance in the fetal circulation [76][77][78]. Importantly, the developing fetus might be more sensitive to EDCs than the adult [76] explaining why endocrine disruptors could adversely affect fetal development with a particular impact on reproductive and hormonal systems. Epigenetic influences were implicated as mediators of the relationship between EDCs, environmental insults and health status, while BPA and phthalates were indicated as sources of epigenetic disruption [79].
Epigenetics defines heritable phenotype changes that involve alterations in gene expression and not in DNA sequence. Epigenetic mechanisms include DNA methylation, acetylation, genomic imprinting, as well as the expression of microRNAs (miRNAs) and non-coding RNAs. These modifications usually have an inhibitory effect on gene expression since they modulate DNA accessibility to transcription factors and regulatory proteins by altering chromatin structure and/or by the recruitment of histone modifiers. Early fetal development is particularly vulnerable to epigenetic insults since it is characterized by a high DNA synthesis rate and because the complex machinery modulating DNA methylation and chromatin organization is established at this time [80].
Studies investigating EDCs' impact on fetal-placental epigenetics in early human pregnancy are few due to the difficulties of collecting samples during the first trimester of pregnancy. Therefore, most of the data available came from in-vitro and animal studies.
Data obtained on human fetal liver biopsies revealed that even low BPA doses could significantly influence in-utero epigenetic regulation of xenobiotic metabolizing enzymes (XMEs), pivotal for compounds metabolism and excretion. In particular, they described increased methylation at COMT and SULT2A1 promoters related to higher BPA levels, anomalies that could alter disease susceptibility later in life [81].
A recent cohort study reported the negative association among first-trimester maternal exposure to BPA and phthalates and term cord blood methylation of imprinted (H19, IGF2) and non-imprinted (PPARA, ESR1) genes and LINE-1 repetitive elements [82], epigenetic targets associated with growth, development and metabolism. Of note, a sex-stratified analysis for DNA methylation revealed that these EDC-induced effects were female-specific [82], confirming the epigenetics-related sexually dimorphic effects of EDC exposure during prenatal development previously demonstrated in several animal models [83]. A similar designed study was performed on 296 newborns from the CHAMACOS Mexican-American longitudinal birth cohort. They specifically focused on fetal phthalates metabolites' exposure during pregnancy, assessed on maternal urines, and their association with imprinted genes DNA methylation quantified on cord blood samples at term. Interestingly, this investigation demonstrated a significant positive association between phthalate metabolites concentration and the methylation of Maternally Expressed 3 (MEG3) gene, known for its role in early growth, tumorigenesis and metabolic processes [84].
Moreover, early life EDC exposure could affect obesity epigenetic programming through endocrine disruptors' ability to bind nuclear receptors as the Peroxisome Proliferator-Activated Receptor (PPAR)γ, master regulator of adipogenesis modulating the expression of metabolic genes during differentiation [85]. EDC-induced obesogenic effects are also accompanied by altered methylation of PPARγ or PPARγ target genes [85]. Indeed, the relative expression of PPARγ-induced genes during early development determines whether mesenchymal stem cells differentiate into osteocytes or adipocytes, thus influencing body fat accumulation [86].
Another EDC target with important consequences for epigenetic regulation is the Estrogen Receptor (ERα) [76,87]. ERα is a transcription factor whose activation triggers estrogen-responsive elements present on the promoter region of the histone-lysine N-methyltransferase enzyme EZH2, key player in gene silencing. It was recently reported that BPA and other estrogenic EDCs, by activating Estrogen Receptors and ERs coregulators Mixed Lineage Leukemia histone methylases (MLL2 and MLL3) and histone acetyltransferase CBP/P300, increase the expression of EZH2 [88], thus potentially affecting global epigenetic regulation, even during in-utero development.
Even the placenta is directly affected by EDC activity. Studies conducted in mice demonstrated that BPA intrauterine exposure markedly altered the placental methylation of imprinted genes [89] affecting placental loss-of-imprinting and decreasing both global and CpG-specific DNA methylation [90]. Furthermore, it was reported in the HTR8/SVneo human cytotrophoblast cell line that BPA exposure negatively affected cytotrophoblast invasion through the hypermethylation and downregulation of the WNT2 gene via DNA (cytosine-5)-methyltransferase 1 (DNMT1), with a negative correlation confirmed also in BPA-induced preeclamptic-like mouse placentae [91]. The BPA-substitute BPS was reported to alter the placental expression of the efflux transporter P-glycoprotein (P-gp), one of the main regulators of fetal exposure to xenobiotics encoded by the ABCB1 gene. Using CRL-1584 human trophoblast cell lines, Speidel and colleagues demonstrated that acute exposure to BPS (0.5 nM) induced a significant haplotype-dependent decrease in ABCB1 promoter activity, while chronic BPS exposure (0.3 nM) induced a significant haplotype-dependent promoter activity increase, thus dramatically impacting on P-gp levels and fetal exposure to xenobiotics coming from the maternal circulation [92]. Moreover, prenatal exposure to BPS (5 mg/kg/d) in C57BL/6 N mice was described to increase the susceptibility to high-fat-diet-induced adipogenesis in F1 male adult mice via the upregulation of PPAR-γ and its target genes [93]. Finally, the epidermal growth factor receptor (EGFR) was identified as a key mediator of phthalates effects on early placental function among a group of 39 first-trimester placental genes with altered methylation after high phthalate exposure [94].
Indeed, different EDCs types such as BPA and phthalates have specific gene targets and their actions could be influenced by fetal sex. Importantly, so-called safer alternatives to BPA as BPS could have detrimental effects on fetal programming too. These data open new perspectives into the understanding of EDCs' influence on the prenatal development of adult health susceptibilities and pregnancy-related disorders.

EDCs and Placenta-Related Conditions
Beside impacting on epigenetic switches and fetal programming, BPA and phthalates could directly alter pregnancy physiology, undermining its success. As reported for EDC-induced epigenetic modifications, most of the mechanistic data present in the literature about endocrine disrupting chemicals and human pregnancy disorders derive from animal and in vitro data.
Starting from the very beginning of gestation, EDCs were recognized as potent perturbators of human Chorionic Gonadotropin (hCG) production and secretion [95]. hCG is a hormone specifically produced by the syncytiotrophoblast whose major functions are crucial for pregnancy establishment as it induces ovulation, maintenance of the corpus luteum and progesterone production during the first 9 weeks of gestation [95]. In vitro studies on trophoblast cell lines and human chorionic villous explants demonstrated that very low BPA concentrations increased hCG secretion and reduced extravillous trophoblast migration and invasion [96,97], early modifications typical of severe pregnancy-related syndromes such as Preeclampsia (PE).
PE is a major cause of mortality and morbidity worldwide, complicating 3 to 8% of all pregnancies and characterized by maternal hypertension and multiorgan damage. It originates during early gestation and, despite its etiopathogenesis remaining unclear, it is widely accepted that a placental/systemic vascular dysfunction characterized by an imbalance between pro-and anti-angiogenic factors such as placental growth factor (PlGF) and soluble fms-tyrosine kinase (sFlt)−1 underlie PE onset.
In a recent population-based prospective cohort study including 1233 women, a positive association was reported between increased first-trimester urine high molecular weight phthalates metabolites and a higher sFlt-1/PlGF ratio, parameter used for PE screening [98]. However, the authors did not find consistent associations among early pregnancy EDCs metabolite concentrations and maternal prenatal blood pressure, placental hemodynamic outcomes or gestational hypertensive disorders [98]. In line with these results, it was previously shown that maternal urine BPA and DEHP metabolites are associated with an increased maternal plasma sFlt-1/PlGF ratio, where BPA specifically induced sFlt-1 increase, while DEHP accounted for PlGF decrease [99].
Among the proposed mechanisms by which EDCs could lead to PE, the disruption of normal placental development plays a major role. A pregnant mouse model exposed to a BPA minimum effective dose of 4 µmol/L developed preeclampsia-like features such as hypertension, abnormal circulating and placental sFlt-1/PlGF levels and kidney damage [91]. The BPA-induced PE phenotype was accompanied by decreased trophoblast invasion, increased expression of metalloproteinases inhibitors TIMP-1/2 and DNA methylation transferase-1 (DNMT-1) and decreased expression of metalloproteinases MMP-2/9, β-catenin and WNT-2, key cell fate regulator. Of note, the BPA-related reduced expression of WNT-2 was correlated with increased DNA methylation in its promoter region [91].
Preeclampsia is often associated with Fetal Growth Restriction (FGR) defined as failure of the fetus to achieve its genetically determined growth potential [100]. DEHP exposure during pregnancy (50-200 mg/Kg) was demonstrated to induce FGR by disrupting placental thyroid hormone receptor (THR) signaling in mice [101]. The DEHP-FGR mice were also characterized by the down-regulation of THR downstream genes such as Vegf, Pgf, Igf1 and Igf2, pivotal for placental angiogenesis [101]. Other EDCs, such as fenvalerate, a widely used type II pyrethoid pesticide, were reported to induce FGR by impairing THRs pathways [102]. Specifically, maternal fenvalerate exposure down-regulated TRalpha1 and TRbeta1 placental expression and it repressed the nuclear translocation of placental TRbeta1 in mice [102]. These results are in agreement with increasing evidence demonstrating the important role of thyroid hormone receptor signaling in the preservation of placental function and fetal development [103,104].
Even BPA exposure was linked to FGR development. In a recent work, a considered safe dose of BPA (50 µg/kg BPA/day) was administered to pregnant mice during the implantation window (day 1 to 7 of gestation), thus inducing defective remodeling of maternal spiral arteries by placental trophoblast with consequent intrauterine growth restriction [105].
The deleterious EDCs effects on physiological pregnancy development were also demonstrated in in vitro human placental models and population studies, even though contrasting data are present in the literature. MEHP inhibited trophoblast invasion by activating the PPARγ pathway in human HTR-8/SVneo extravillous trophoblast cell lines, mechanisms associated with early pregnancy loss [106]. A prospective birth cohort investigation performed on 788 mother-child pairs in the third trimester in Korea concluded that BPA exposure was negatively associated with intrauterine linear growth and affected by maternal glutathione transferases polymorphisms [107], while previous studies reported no association between exposure to BPA and birth weight [108].
In conclusion, despite controversial evidence in epidemiologic, in vitro and animal studies, there is a general consensus on the harmful effects of EDC exposure during fetal life. Several molecular mechanisms have been proposed to explain the role of BPA and phthalates in the onset of severe pregnancy-related conditions such as PE and FGR, suggesting as a main outcome an aberrant placental development. Most of the differences in the literature results and interpretations are probably due to an extreme variability in EDC types and concentrations used, time of administration, for animal or in vitro models, or sampling windows for human gestation studies.

EDCs and Gestational Diabetes
It is well known that even during a healthy pregnancy, the release of numerous placental hormones promotes insulin-resistance, which is addressed through a compensatory insulin secretion by the pancreatic β-cells [109]. Gestational diabetes (GDM) occurs when pregnant women have dysfunctional β-cells, unable to balance the increased requirements of insulin [110].
Excessive weight gain during pregnancy is a risk factor for GDM. Some recent studies suggest a possible link between the gestational exposure to EDCs and weight gain in pregnancy. In a population-based prospective cohort study among 1213 pregnant women, each log unit increase in early pregnancy BPA and di-n-octylphthalate urine concentrations were associated with lower mid-to late pregnancy gestational weight gain (−132 g/log unit increase [95% CI −231, −34] and −176 g/log unit increase [95% CI −324, −29]) [111]. Differently, in the LIFECODES pregnancy cohort, 347 pregnant women were recruited, and the 1 st -trimester urinary phthalate metabolite concentrations were related to early gestational weight gain (median time period: 7.4 gestational weeks). The association between MEP and gestational weight gain followed a U-shape with increasing gestational weight gain in the second quartile compared to the lowest one (difference 1.3 kg, 95% CI: 0.3-2.4). Differently, the dose-response association between DEHP and gestational weight gain was described by an inverse U-shape [112].
In a Chinese cohort prospective study including 620 pregnant women, plasma glucose at 2 h in the 75-g OGTT was 0.36 mmol/L lower (95% CI −0.73, 0.01) for women with urine BPA in the high versus the low tertile, and for each log unit increase, the odds of GDM was reduced by 27% (OR 0.73, 95% CI 0.56, 0.97) [113]. On the contrary, in a small case-control study, no evidence of association between BPA exposure and GDM diagnosis across increasing tertiles of BPA exposure was found [114]. No statistically significant associations were observed between first-trimester urinary BPA concentration with diagnosis of impaired glucose tolerance (IFG) or GDM even in the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort study [115]. The latter study also failed to find an association between urinary concentration of phthalates metabolites and risk of IFG and GDM [115]. Contrary, in the LIFECODES pregnancy cohort, second-trimester MEP exposure was associated with increased odds of IGT (OR 7.18, 95% CI 1.97, 26.15). DEHP concentration was inversely associated with IGT (OR 0.25, 95% CI 0.08, 0.85). In both cases, the confidence intervals were very wide, suggesting low accuracy of the risk estimates [116]. In "The Infant Development and Environment Study" (TIDES), which included 705 pregnant women, the averaged first and third trimester urinary MEP concentration was associated with increased odd of GDM (OR 1.61, 95% CI 1.10, 2.36), whereas first-trimester urinary mono-(3-carboxypropyl) phthalate (MCPP) concentration was inversely associated (OR 0.64 95% CI 0.43, 0.96). Only the averaged first-and third-trimester urinary mono-n-butylphthalate (MNBP) concentration was associated with the risk of IGT (OR 1.32, 95% CI 1.00, 1.75) [117]. In a small cross-sectional study, women with the highest urinary concentrations of mono-iso-butyl phthalate (MIBP) and mono-benzyl phthalate (MBZP) had lower blood glucose levels at the time of GDM diagnosis compared to women with lower urinary concentrations of such phthalates metabolites [118].
In conclusion, the limited evidence and conflicting results do not allow a definitive conclusion. The discrepancies in the literature results are presumably due to the different time windows considered for the exposure assessment, the use of a single-spot urine sampling to assess exposure, the different criteria used to diagnose GDM, and not considering pre-gestational exposure.

Guidelines to Reduce Dietary Exposure to EDCs
Although there is an urgent need to have data on the association between the level of EDCs in reproductive age and pregnancy outcomes, it is well known that dietary exposure is relevant. There can be substantial variability in phthalate concentrations within food groups based on the region of food production, processing practices, presence and type of packaging and lipid content [119,120]. Recent reviews of the food monitoring and epidemiology data revealed that foods of animal origin are major sources of phthalates, partially because they are slightly lipophilic and can bioaccumulate in fat-containing foods [10,121]. Poultry, some dairy products (cream) and fats are routinely contaminated with higher concentrations of phthalates than other foods [121]. Detectable concentrations of phthalates and BPA are in seafood products, especially if frozen or canned [10], and consuming them ≥1-3 times/week making it a major source of BPA during pregnancy [122]. By contrast, milk, yogurt and eggs were found to contain low concentrations of phthalates as a whole [121]. Concerning vegetable foods, fruit and vegetables products in jars contain high concentrations of phthalates, while fresh fruits and vegetables, pasta, noodles, rice are associated with lower exposures [10].

Perfluorinated Compounds (PFCs): PFOS and PFOA
According to the EFSA Panel on Contaminants in the Food Chain, some foods (especially seafood) are an important source of exposure to PFCs. Moreover, PFOA has been used in the past in the production of non-stick coatings. Currently, Italian manufacturers of cookware coatings do not use products with PFOA. Therefore, consumers have to turn their attention to products coming from non-European countries, especially those without the CE mark [123].

Di(2-Ethylhexyl)-Phthalate (DEHP)
Food contact materials (film, blister packaging, screw caps, bottles, trays and transport packaging) are the main dietary sources of DEHP. However, DEHP use in Europe has dramatically dropped; for some usages, such as flooring and food contact film, European manufacturers have almost completely substituted and phased-out DEHP [123].

Polycyclic Aromatic Hydrocarbons (PAHs)
PAHs are a group of compounds that are formed from combustion processes, both industrial and household. Nutrition plays a key role in the prevention of exposure: PAHs form at high temperatures within overheated parts of foods, especially with some cooking methods, such as grilling or charring, smoking, or barbecuing [123].

BPA
As mentioned above, BPA is a chemical «building block» for the manufacture of polycarbonate plastic used in food contact materials and epoxy resins (lining protective of most cans and food recipients). Canned foods and beverages are the main source of dietary exposure for all age groups, and consumers may be exposed to either the residual monomer that migrates from cans to beverages and foods, or the products that result from polymer hydrolysis [123]. Table 2 summarizes the practical arrangements for food selection, cooking and storage elaborated by the National Institute of Health [123] and integrated with other recent epidemiological findings [122][123][124][125] to reduce dietary exposure to EDCs during reproductive age and the risk of developing pathological conditions that may compromise a future pregnancy. Table 2. Guidelines to reduce dietary exposure to EDCs.

1.
Prefer fresh seasonal food, especially fish, fruits and vegetables;

2.
Reduce the consumption of canned fish or frozen seafood to once a week; 3. Buy your tomato sauce and legumes in glass jars;

4.
Purchase beverages in plastic or glass bottles. Prefer tap water if possible: visit the website of your municipality to learn more about its characteristics;

5.
Avoid ready-made food as "heat-and-go" cups or instant soups;

6.
Prefer pizza or sandwich without boxes or wrappers but displayed freshly at the counter;

7.
Reduce the use of popcorn bags for microwave cooking, choosing stovetop alternatives;

8.
Replace a plastic coffee maker using a French press or ceramic drip;

9.
Avoid plastic tea bags and purchase tea from manufacturers who can certify that their tea bags do not contain EDCs. It is preferable to opt for loose tea; 10. Avoid the consumption of partially charred/burned foods, removing burned parts (i.e., meat or pizza).; 11. Limit smoked foods to once a month. 20. Use grease-proof paper or film for food packaging (e.g., cling film) only following the manufacturer's instructions. Read the product's label; 21. When choosing home materials, limit the use of soft PVC containing DEHP. Prefer BPA-and phthalates-free products.

Concluding Remarks
Endocrine-disrupting chemicals represent a health threat that should not be underestimated, especially when dealing with human pregnancy. Pregnant women can be easily exposed to a large number of EDCs by dietary intake. Because of their biochemical features, EDCs pass the placental barrier and reach the developing fetus, causing aberrant genetic/epigenetic regulation with sex-specific modifications and contributing to the onset of placenta-and pregnancy-related disorders. The medical-scientific community has still a lot of work to do in order to clarify the pathways involved in EDCs' effects on pregnancy physiology. The main limitation that explains the contrasting results present in the literature is the high variability in experimental conditions and models used to investigate EDC activity in the perinatal period. Therefore, a great effort must be made by researchers in the field to set up common protocols and guidelines in order to improve data reliability.
Author Contributions: A.R. conceived the review, determined the general design and structure of the article, wrote the article (with specific application to the sections regarding "EDCs", "Exposure to EDCs and Fertility", "EDCs and Fetal Programming ", "EDCs and placenta-related conditions" and Concluding remarks), reviewed and edited the article; A.M.N. wrote the article (with specific contribution to the "Introduction" section), reviewed and edited the article; L.M. reviewed and edited the article; R.D.A. wrote the article (with specific application to the sections regarding "Guidelines to reduce dietary exposure to Eds"), reviewed and edited the article; S.B. determined the general design of the article, reviewed and edited the article; A.L. determined the general design and structure of the article, wrote the article (with specific application to the sections regarding "Exposure to BPA and phthalates", "Exposure to EDCs during the Reproductive Age and Development of Obesity, Diabetes and Cardiometabolic Abnormalities ", "EDCs and gestational diabetes") reviewed and edited the article; All the authors gave a significant intellectual contribution to the article. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest:
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.