<table><caption>Table 4. *Cont.*</caption><thead><tr><th>Animal Model</th><th>Chemicals</th><th>Dose Administered</th><th>Exposure Route</th><th>Exposure Duration</th><th>Observation Stage</th><th>Function Studied</th><th>Metabolic Postnatal Outcomes</th><th>Additional Outcomes</th><th>Reference</th></tr></thead><tbody><tr><td>Rat</td><td>DEHP</td><td>1, 10, or 100 mg/kg bw/d</td><td>Oral gavage</td><td>GD9-21</td><td>PND60</td><td>Pancreatic function</td><td>Fasting blood glucose level: DEHP ↑<br/>Serum insulin concentration: DEHP ↓<br/>Glucose and insulin intolerance: DEHP ↑<br/>Body and pancreatic wet weight: DEHP↓<br/>Insulin autocrine action in endocrine pancreas: DEHP ↓ (PND60)<br/>Plasma membrane insulin receptor beta (InsRβ) protein level: DEHP ↓<br/>IRS-2 protein level: DEHP ↓<br/>Endocrine pancreas Akt protein level: DEHP ↓ (PND60)<br/>Islets ex vivo glucose-stimulated insulin secretion: DEHP ↓<br/>Islets GLUT2 cytosolic and plasma membrane GLUT2 protein level: DEHP ↓ (10, 100)<br/>Glucokinase activity: DEHP ↓</td><td>Islets mRNA expression: DEHP ↑ (FoxO1, Atf4, Atf6, Bip, DNMT3a, Cnmt3b, MeCP2, MDB2, mir143, and mir375/10, 100: DNMT1)/↓ (10, 100: GLUT2)<br/>Insulin autocrine action in the endocrine pancreas: DEHP ↓ (PND60)<br/>pInsRβ<sup>Tyr1162-1163</sup> protein level: DEHP ↓<br/>pIRS<sup>Tyr632</sup> protein level: DEHP ↓ (σ/σ: 10, 100)<br/>pIRS<sup>Ser636/639</sup> protein level: DEHP ↑<br/>pAkt<sup>Ser473</sup> and pAkt<sup>Thr308</sup> protein level: DEHP ↓<br/>pAkt<sup>Tyr315/316/312</sup> protein level: DEHP ↓ (10, 100)<br/>Islets protein level: DEHP ↑ (FoxO1)/↓ (MafA, Pdx1, Pax4 and Pax6 and HNF4-α)</td><td>[244]</td></tr></tbody></table>
<table><caption>Table 4. *Cont.*</caption><thead><tr><th>Animal Model</th><th>Chemicals</th><th>Dose Administered</th><th>Exposure Route</th><th>Exposure Duration</th><th>Observation Stage</th><th>Function Studied</th><th>Metabolic Postnatal Outcomes</th><th>Additional Outcomes</th><th>Reference</th></tr></thead><tbody><tr><td>Rat</td><td>DEHP</td><td>600 mg/kg bw/d</td><td>Intragastrically administration</td><td>GD0-PND21</td><td>8 and 14 weeks of age</td><td>Metabolism</td><td>Body and organ weight, body length, food intake, fat pad weight, and ratio: no effect<br>Serum ALAT, TP, ALB, BUN, and creatinine level: ↓ Blood lipids content: no effect<br>Insulin level: DEHP ↑<br>Identification of biomarkers in several metabolic pathways: lipid metabolism pathway, and retinol metabolism pathway</td><td>Serum catalase level: ↓<br>Serum total antioxidant capability, SOD, and malondialdehyde level: no effect<br>T4 level: DEHP ↓<br>Thyroid-stimulating hormone (TSH) level: DEHP ↑<br>T3, free triiodothyronine (FT3), and free thyroxine (FT4) level: no effect<br>Potential biomarker metabolites of DEHP exposure: DEHP ↑ (L-allothreonine, creatinine, uric acid, retinyl ester, and L-palmitoylcarnitine)/↓ (glycocholic acid, LysoPC(18:3))</td><td>[247]</td></tr><tr><td>Rat</td><td>DEHP</td><td>1, 10, or 100 mg/kg bw/d</td><td>Oral gavage</td><td>LD1-21, lactational</td><td>PND22</td><td>Cardiac metabolism/ function</td><td>Fetal bodyweight: DEHP ↓ (PND9-22)<br>Fasting blood glucose level: DEHP ↑ (100)<br>GLUT4 protein: DEHP ↓ (PND22)<br>Phosphorylation GLUT4<sup>ser488</sup>: DEHP ↑ (100)<br>Development of cardiac glucometabolic disorders: DEHP ↑ (σ)</td><td>Heart weight and deoxyglucose uptake: DEHP ↓ (PND22)<br>Glucose oxidation in the cardiac muscle: DEHP ↓ (PND22: 10/PND22: 100)<br>InsRβin in the cardiac muscle: DEHP ↓ (σ)<br>IRS1 protein and phosphorylation of Akt<sup>ser473</sup> in the cardiac muscle: DEHP ↓ (σ: 100)<br>Phosphorylation of IRS1<sup>tyr632</sup> in the cardiac muscle: DEHP ↓ (σ: 10/100)</td><td>[258]</td></tr></tbody></table>
<table><caption>Table 4. *Cont.*</caption><thead><tr><th>Animal Model</th><th>Chemicals</th><th>Dose Administered</th><th>Exposure Route</th><th>Exposure Duration</th><th>Observation Stage</th><th>Function Studied</th><th>Metabolic Postnatal Outcomes</th><th>Additional Outcomes</th><th>Reference</th></tr></thead><tbody><tr><td>Rat</td><td>DEHP</td><td>300 mg/kg bw/d</td><td>Oral gavage</td><td>12 weeks, postnatal (adult)</td><td>adult</td><td>Liver metabolism</td><td>Bodyweight: no effect<br>Liver weight, viscera coefficients, and hepatic cord disorder expansion: DEHP ↑<br>ALAT, TC, and HDL-cholesterol levels: DEHP ↑<br>ASAT, TG, and LDL-cholesterol level: no effect<br>Number of liver differentially expressed genes: DEHP ↑ (130)/↓ (117)<br>Liver-modulated pathways: steroid catabolic process, regulation of intestinal cholesterol absorption, oxidation-reduction process, cholesterol metabolism, primary bile acid biosynthesis, and bile secretion</td><td>Liver malondialdehyde content: DEHP ↑<br>Liver total superoxide dismutase, total antioxidant capacity, and catalase activities: DEHP ↓<br>Liver GSH-px activities: no effect</td><td>[241]</td></tr><tr><td>Rat</td><td>DEHP</td><td>30, 300, or 750 mg/kg bw/d</td><td>Oral gavage</td><td>GD0-PND21</td><td>PND7, 14, and 21</td><td>Thyroid function</td><td>Serum total T3 level: no effect<br>Serum total T4 and TSH level: DEHP ↓ (PND7/PND14/PND21: 300, 750)<br>PND 14 and PND21 mRNA level of genes involved in thyroid development: DEHP ↑ (300: NIS, TTF-1/750: NIS, PAX8, and TTF-1)<br>PND14 protein level of the genes involved in thyroid development: DEHP ↑ (300: NIS/750: NIS, PAX8, and TTF-1)<br>PND21 protein level of the genes involved in thyroid development: DEHP ↑ (30: NIS/300: NIS, PAX8, TTF-1/750: NIS, PAX8, TTF-1)<br>mRNA expression and protein level of thyroid peroxidase (TPO; involved in thyroid function): DEHP ↑ (750)</td><td>PND14 deiodinases (Dio)<br>mRNA expression: DEHP ↑ (30: Dio2/300: Dio1, Dio2/750: Dio1, Dio2)/↓ (Dio3)<br>PND21 deiodinases<br>mRNA expression: DEHP ↑ (Dio1, Dio2)/↓ (Dio3)<br>Ultrastructure damage of the thyroid: DEHP ↑</td><td>[246]</td></tr></tbody></table>
<table><caption>Table 4. *Cont.*</caption><thead><tr><th>Animal Model</th><th>Chemicals</th><th>Dose Administered</th><th>Exposure Route</th><th>Exposure Duration</th><th>Observation Stage</th><th>Function Studied</th><th>Metabolic Postnatal Outcomes</th><th>Additional Outcomes</th><th>Reference</th></tr></thead><tbody><tr><td>Rat</td><td>DEHP</td><td>1, 20, 50, 100, or 300 mg/kg bw/d</td><td>Oral gavage</td><td>GD14-PND0</td><td>GD19, PND3, and 21 and 60</td><td>Metabolism</td><td>PND21 number of adrenal glands differentially expressed genes: DEHP ↑ (100 (67), 300 (175))/↓ (100 (238), 300 (252))<br>PND60 number of adrenal glands differentially expressed genes: DEHP ↑ (100 (213), 300 (331))/↓ (100 (158), 300 (260))<br>PPAR signaling pathway: DEHP ↓<br>Steroid biosynthesis pathway: DEHP ↑ (PND60)<br>PPAR-driven gene expression: DEHP ↓ (PND21-60: Adipoq, Pck1, Ucp1, Fabp4/PND21: Lpl, Rxrg, Pparg, Ppargc1b, Srebf1/PND60: Hmgcr, Hmgcs1)/↑ (PND60: Ppard)<br>Differentially expressed gene involvement: lipid metabolism, adipocyte differentiation, adaptive thermogenesis, and gluconeogenesis<br>Cholesterol biosynthesis pathway: DEHP ↑ (PND60: 100, 300)</td><td>Immune response pathways: DEHP ↑<br>MAPK signaling pathway: DEHP ↑ (PND21: 100/PND60: 100, 300)<br>PND60 PPAR nuclear receptors mRNA levels: DEHP ↑ (100, 300 (Ppard))/↓ (Ppara)<br>PND3 PPAR nuclear receptor mRNA level: DEHP ↓ (Pparg)<br>Expression of genes involved in fatty acid, triacylglycerol, and ketone body metabolism: DEHP ↓ (PND21: 100, 300)</td><td>[259]</td></tr><tr><td>Rat</td><td>DEHP</td><td>0.25, 6.25 mg/kg bw/d</td><td>Oral gavage</td><td>GD0-PND21</td><td>PND0, 2, 15, and 21</td><td>Kidney development and fetal metabolism</td><td>Birth, PND15-21 bodyweight: DEHP ↓ (6.25)<br>Weaning bodyweight: DEHP ↓<br>Absolute kidney weight: DEHP ↓ (♀PND15: 6.25)/↑ (♂PND21: 6.25)<br>Kidney-to-bodyweight ratio: ↓ (♀PND15: 0.25)/↑ (PND21: 6.25/♂PND15: 6.25/♂PND21: 6.25)<br>Creatinine clearance rate: DEHP ↓<br>Serum creatine and blood urea nitrogen level: DEHP ↑ (♀/♂: 6.25)<br>Renal PPARα protein expression: DEHP ↑ (PND0, PND21: 6.25)<br>Renal PPARγ protein expression: DEHP ↑ (PND0, PND21)<br>Serum renin level: DEHP ↑ (0.25)</td><td>Maternal postpartum weight, litter size, and sex ratio: no effect<br>Proportion of cortex in the nephrogenic zone: DEHP ↑<br>Nephron number: DEHP ↓<br>Total glomerular volume: DEHP ↑ (♀PND21: 0.25)/↓ (PND33)<br>Glomerular alterations and tubular damage: DEHP ↑<br>Serum nitric oxide level: DEHP ↓</td><td>[260]</td></tr></tbody></table>
<table><caption>**Table 4. Cont.**</caption><thead><tr><th>Animal Model</th><th>Chemicals</th><th>Dose Administered</th><th>Exposure Route</th><th>Exposure Duration</th><th>Observation Stage</th><th>Function Studied</th><th>Metabolic Postnatal Outcomes</th><th>Additional Outcomes</th><th>Reference</th></tr></thead><tbody><tr><td>Rat</td><td>DBP</td><td>850 mg/kg bw/d</td><td>Oral perfusion</td><td>GD14-18</td><td>PND1, and 18 months of age</td><td>Renal development and fibrosis</td><td>Bodyweight, kidney size, and kidney-to-bodyweight ratio: DBP↓ (PND1)<br>Renal Foxd1, Wnt11, Pax2, and Gdnf mRNA expression: DBP↓ (PND1)<br>Renal Bmp4, Cdh11, Ywhab, and Calm1 mRNA expression: DBP↑ (PND1)<br>Kidney alpha-smooth muscle actin (α-SMA), fibronectin, and TGF-β staining: DBP↑ (18 months)</td><td>Swelling of the glomerular tufts: DBP↑ (18 months)<br>Tubular atrophy and tubular cell compression: DBP↑ (18 months)<br>Widening of intertubular spaces and thickening of the tubular basement membrane: DBP↑ (18 months)<br>Interstitial extracellular matrix accumulation: DBP↑ (18 months)</td><td>[261]</td></tr><tr><td>Rat</td><td>DBP</td><td>850 mg/kg bw/d</td><td>Oral perfusion</td><td>GD12-18</td><td>PND70</td><td>Renal development and fibrosis</td><td>Bodyweight: DBP↓ (♂)<br>Kidney size and kidney-to-bodyweight ratio: DBP↓ (♂)<br>Renal fibrosis, kidney tubular damage, and atrophy: DBP↑ (♂)<br>Kidney interstitial extracellular matrix accumulation: DBP↑ (♂)</td><td>Kidney Fgf10, Fgfr2, and AR protein levels: DBP↓ (♂)<br>Serum testosterone level: DBP↓ (♂)</td><td>[262]</td></tr><tr><td>Rat</td><td>DBP</td><td>850 mg/kg bw/d</td><td>Oral gavage</td><td>GD14-18</td><td>PND1 and 8 weeks of age</td><td>Renal development and fibrosis</td><td>Fetal bodyweight and survival rate: DBP↓<br>Kidney mRNA and protein expression level of RhoA and ROCK1: DBP↑ (PND1)</td><td>Mother and fetal morbidity: no effect<br>Maternal bodyweight gain: DBP↓ (GD14-18)<br>Gestational length: DBP↑</td><td>[263]</td></tr></tbody></table>
<table><caption>Table 4. *Cont.*</caption><thead><tr><th>Animal Model</th><th>Chemicals</th><th>Dose Administered</th><th>Exposure Route</th><th>Exposure Duration</th><th>Observation Stage</th><th>Function Studied</th><th>Metabolic Postnatal Outcomes</th><th>Additional Outcomes</th><th>Reference</th></tr></thead><tbody><tr><td>Rat</td><td>DEHP, DBP</td><td>7, 70, or 700 mg/kg bw/d<br>DEHP—5, 50, or 500 mg/kg bw/d</td><td>Oral gavage</td><td>GD13—PND21</td><td>PND4, 21, 22, 33, 78, 88, and 90</td><td>Metabolism</td><td>Bodyweight from PND16 to 21: DEHP ↑ (700)/DBP ↑ (5)<br>Bodyweight gain from PND29 to 53: DEHP ↑ (σ: 700/σ: 70)<br>Bodyweight: DBP ↑ (σ'PND43: 5)<br>Bodyweight gain from PND57 to 67: DBP ↓ (σ: 50)<br>PND60 bodyweight: DBP ↓ (σ: 50)<br>Adulthood bodyweight, bodyweight gain and mesenteric, retroperitoneal, epididymal, and ovarian fat tissue weight: no effect<br>Fasting plasma glucose concentration: DEHP ↑ (700)/DBP ↑ (500)<br>Plasma cholesterol concentration: DEHP ↑ (σ: 700)/DBP ↑ (σ: 50)<br>Plasma TG level: DBP ↑ (σ: 500)<br>Glucose uptake in response to insulin overload: DEHP ↓ (700)<br>Response to glucose overload: no effect<br>Islets glucose-stimulated insulin secretion: DEHP ↓ (σ: 700)/↑ (σ: 70)</td><td>Dams bodyweight gain and organ weight: no effect<br>Litter size and post-implantation loss: no effect<br>AGI: DEHP ↓ (σ: 700)<br>Age of preputial separation: DEHP ↑ (700)<br>Age of puberty: DEHP ↑ (σ: 700/σ: 70, 700)/DBP ↑ (σ: 500)<br>Number of pups with hypospadias and cryptorchidism: DEHP ↑ (700)<br>Reproductive organs weight: no effect</td><td>[243]</td></tr><tr><td>Mouse</td><td>DEHP, DiNP</td><td>DEHP 25 mg/kg chow/d,<br>DiNP 75 mg/kg chow/d or both</td><td>Oral route (food)</td><td>GD-15 to PND21</td><td>PND21 and 10 months</td><td>Liver metabolism</td><td>Number of DEGs at PND21: DiNP (♀(61))/DEHP + DiNP (♀(1))<br>Number of pathways enriched: DiNP (♀: 12, such as acetyl-CoA/σ: 15, such as alpha-amino acid and organic acid metabolic processes)<br>Number of dysregulated PPAR target gene expressions involved in enriched pathways: DiNP (♀(13)/σ(15))<br>DNA methylation of Cs promoter: DEHP + DiNP ↓ (♀)/↑ (σ')<br>Cs and *Acly* liver expression: DEHP + DiNP ↑ (♀)<br>DNA methylation of *Acly* promoter: DEHP + DiNP ↓ (♀)<br>DNA methylation of *Fasn* promoter and *Fasn* liver expression: DiNP ↑ (♀)<br>Hepatic acylcarnitine levels: DEHP ↑/DiNP ↑/DEHP + DiNP ↑<br>Hepatic acetyl-CoA levels: DEHP + DiNP ↓ (♀: PND21)/↑ (♀: 10 months)</td><td>[237]</td></tr></tbody></table>
<table><caption>**Table 4. Cont.**</caption><thead><tr><th>Animal Model</th><th>Chemicals</th><th>Dose Administered</th><th>Exposure Route</th><th>Exposure Duration</th><th>Observation Stage</th><th>Function Studied</th><th>Metabolic Postnatal Outcomes</th><th>Additional Outcomes</th><th>Reference</th></tr></thead><tbody><tr><td>Rat</td><td>n-BuP</td><td>10, 100, or 500 mg/kg bw/d</td><td>Oral gavage</td><td>GD7-PND22</td><td>PND1, 6, 14, 16, 17, 22, and 80-90</td><td>Fetal development/ Reproduction</td><td>Fetal AGD: n-BuP ↓ (10, 500)<br/>Ovary weights: n-BuP ↓ (PND17: 100/500)<br/>Ventral prostate, prostate, and seminal vesicle weight: n-BuP ↓ (PND90: 500)<br/>Epididymal weight: n-BuP ↑ (PND90: 100)<br/>Epididymal sperm count: n-BuP ↓<br/>Testicular Cyp19a1 expression: n-BuP ↓ (PND16)<br/>Expression level of germ cell, Sertoli cell, and Leydig cell markers: no effect (PND16)<br/>Ventral prostate epithelial area and ratio between epithelium and lumen: n-BuP ↓ (PND22: 100)</td><td>Maternal bodyweight and gestational length: no effect<br/>Litter size, survival rate, and fetal and postnatal bodyweights: no effect<br/>Offspring sexual maturation, and testis and epididymis histological examination: no effect<br/>Number of terminal mammary buds: BP ↑ (PND22: 100/500)<br/>Distance between breast tissue and lymph nodes: BP ↓ (PND22: 100)</td><td>[264]</td></tr><tr><td>Rat</td><td>n-BuP</td><td>850 mg/kg bw/d</td><td>Intragastric administration</td><td>GD14-18</td><td>PND1</td><td>Renal development</td><td>Kidney autophagy marker (LC3B, Beclin-1) staining and expression: n-BuP ↑<br/>Kidney HhIP protein and mRNA expression involved in autophagy and hedgehog regulation: n-BuP ↑<br/>mRNA expression of hedgehog signaling pathway-related gene (Gli1, Ptch1): BP ↓</td><td></td><td>[265]</td></tr></tbody></table>
lipopolysaccharide; LRP-1: LDLR-related protein 1; MafA: MAF bZIP transcription factor A; mc4r: melanocortin type 4 receptor; MDB2: methyl-CpG binding domain protein 2; MeCP2: methyl CpG binding protein 2; MGAT1: alpha-1,3-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase 1; miRNA: microribonucleic acid; MMP7: matrix metallopeptidase 7; mRNA: messenger ribonucleic acid; Mrp3: multidrug resistance-associated protein 3; MSLN: mesothelin; mTOR: mammalian target of rapamycin; MUFAs: monounsaturated fatty acids; NIS: sodium iodide symporter; NP: 4-nonylphenol; nPE1: POMC neuronal enhancer; Npy: neuropeptide Y; OP: 4-tert octylphenol; Pax2: paired box 2; Pax4: paired box 4; Pax6: paired box 6; PAX8: paired box 8; Pck1: phosphoenolpyruvate carboxykinase 1; Pdx1: pancreatic and duodenal homeobox 1; PEPCK: phosphoenolpyruvate carboxykinase; PLS-DA: partial least-squares discriminant analysis; PND: postnatal day; PNPLA2: patatin-like phospholipase domain-containing 2; Pparg: peroxisome proliferator-activated receptor gamma; Ppargc1b: PPARγ coactivator 1; PRKCE: protein kinase C epsilon; Ptch1: patched 1; PUFAs: polyunsaturated fatty acids; RhoA: Ras homolog gene family member A; ROCK1: Rho-associated protein kinase 1; RORγt: retinoic acid-related orphan receptor t; Rxr-β: retinoid X receptor β; Rxrg: retinoid X receptor gamma; pomc: pro-opiomelanocortin; SCD-1: stearoyl-CoA desaturase 1; Slc2a2: solute carrier family 2 member 2; Slc19a2: solute carrier family 19 member 2; SLC44A4: solute carrier family 44 member 4; SMAD7: suppressor of mothers against decapentaplegic 7; SPRY1: sprouty RTK signaling antagonist 1; SR-BI: scavenger receptor class BI; Srebf1: sterol regulatory element-binding transcription factor 1; SREBP-1: sterol regulatory element-binding protein-1; snoRNA: small nucleolar ribonucleic acid; TC: total cholesterol; Tcf21: transcription factor 21; TCS: triclosan; TGs: triglycerides; TIF-1: thyroid transcription factor 1; TP: total protein; Ucp1: uncoupling protein 1; UDPGT: UDP glucuronosyltransferase; WFDC2: WAP four-disulfide core domain 2; Wnt11: Wnt family member 11; Ywhab: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta.
As we can see in Table 4, the experiments relating to maternal oral exposure to phenols, parabens, and/or phthalates during the perinatal period (all or part of gestation and/or lactation) have studied very varied doses of the order of mg/kg with non-monotonic dose-responses and sex-specific metabolic effects in offspring. The observed effects are often transitory around weaning and deserve to be studied later in adulthood.

## 6.2. Effects of PPPs on Cardiometabolic Disorders

### 6.2.1. Epidemiological Data

Most studies examining environmental pollutants have reported associations with increased blood pressure in children. However, the literature reported only putative evidence for the effects of exposure to phenols or phthalates [239]. In human cohorts, the cardiovascular characteristics of the offspring after maternal exposure to PPPs have been poorly examined due to difficulties in assessing blood pressure in infants. Nevertheless, blood pressure was measured in 1277 children aged 6 to 11 years from the European Human Early-Life Exposome (HELIX) cohort. Increases in diastolic blood pressure in infants were observed with prenatal BPA exposure. Interestingly, blood pressure was also measured in 1015 Spanish preadolescents (mean age = 10.4 years), in whom prenatal exposure to BP-3 was associated with higher diastolic blood pressure [174].

Regarding parabens, a decrease in systolic blood pressure in preadolescents was observed with MeP, mainly in boys, and with n-BuP only in girls [174].

Regarding phthalates, prenatal exposure to these compounds was associated with lower systolic blood pressure at ages 4 and 7 in girls, but not boys [191], and with lower cholesterol levels at 8–14 years for both [266]. Vafeiadi et al. also observed a negative association between phthalate metabolite concentrations and systolic/diastolic blood pressure at 4 years in both sexes [198]. Among the few studies examining the association between prenatal phthalate exposure and children’s blood pressure, two studies reported a negative association between ΣDEHP and systolic/diastolic blood pressure [198] in the previously described European HELIX cohort, and between systolic blood pressure and MBzP [267]. Additionally, high- and low-molecular-weight phthalate mixtures were associated with a decreased metabolic score, which included waist circumference, systolic and diastolic blood pressure, triacylglycerol, high-density lipoprotein cholesterol (HDL), and insulin levels [202].

Most studies have highlighted the effects of phenols and phthalates on maternal health, child growth, and cardiometabolic outcomes, but the results are conflicting. Cardiometabolic risks in adulthood need to be confirmed and supported by further rigorous studies [268].

### 6.2.2. Maternal Exposure to PPPs and Cardiovascular Outcomes in Experimental Models

A growing body of evidence suggests that early life exposure to BPA may also have a substantial influence on perinatal and postnatal cardiometabolic programming, contributing to higher cardiometabolic risks in adulthood [249].

In sheep, prenatal BPA exposure (0.5 mg/kg BW/day by injection for the last two-thirds of gestation) had no significant effect on blood pressure or cardiac morphometric measurements in the offspring. However, this exposure increased the atrial natriuretic peptide gene expression in the ventricles and reduced the collagen expression in the right ventricle. When the mothers are overfed, BPA amplifies septal hypertrophy and continues to block left ventricular hypertrophy and blood pressure. Prenatal BPA seems to thwart obesity-induced cardiovascular disorders [251]. The exposure of female Sprague-Dawley rats during the last two-thirds of gestation to a mixture of BPA (0.005 mg/kg bw/day) and a high dose of DEHP (7.5 mg/kg bw/day) produced postnatal outcomes, including increased relative heart weight in adult male offspring [158]. In mice, lifelong maternal exposure to DEHP (30 mg/kg bw through daily oral administration) until weaning had the following effects on 8-week-old offspring: (i) increased blood pressure, (ii) deregulated
aortic eNOS (endothelial nitric oxide synthase) phosphorylation, and (iii) upregulated AT1R (angiotensin I receptor) protein expression (angiotensin II signaling) [236].

Additionally, this perinatal exposure to DEHP was shown to increase adiposity in the offspring with increased bodyweight and WAT- and BAT (white and brown adipose tissue)-to-body-weight ratios, along with impaired hepatic cholesterol metabolism (increased plasma and hepatic cholesterol). Linked to the cardiovascular effects of perinatal exposure to PPPs in offspring, a study in mice highlighted the potential role of DNA methylation in DEHP-induced cardiac effects and emphasized the importance of gender/sex as a biological variable in environmental health studies [253]. Exposure to DEHP (300 mg/kg bw/day) during the last third of gestation, reduced systolic and diastolic systemic arterial blood pressures, and locomotor activity, in PND200 male rats. This exposure to DEHP decreased aldosterone release in these males [259], while aldosterone increased in females. This suggests a sex-specific adrenal response to in utero exposure to DEHP and opens up the possibility of a hypertensive response induced by DEHP in the female offspring [256,257]. However, maternal exposure to a lower dose of DEHP (10 mg/kg bw/d) was shown to induce hypertension and bodyweight gain in male offspring [269]. Another study investigating the effects of maternal DEHP exposure during whole gestation showed impaired renal development in offspring. This led to a nephron deficit, and subsequently elevated blood pressure later in life, by the inhibition of the renin-angiotensin system [260]. Maternal exposure to DBP (850 mg/kg bw/day during GD14-18) induced kidney dysplasia and renal fibrosis in male offspring [261] by an expression of TGF-β1 and the abnormal activation of the epithelial-mesenchymal transition in fibrotic kidneys [270]. This exposure also decreased the testosterone concentration and reduced androgen receptor expression [262]. Maternal exposure to a lower dose of DEHP (10-100 mg/kg bw/d) induced a decreased heart weight and altered cardiac metabolic function in young offspring [258]. Maternal exposure to phthalic acid reduced the bodyweight (bw), heart weight (HW), and HW/bw in offspring, while their heart rates and blood pressures were conversely increased compared to the control group [271]. In the Sprague-Dawley rats, maternal exposure to DBP (850 mg/kg/day orally in the last third of gestation) induced renal fibrosis in the offspring [263,265].

These data highlight the difficulties in establishing a link between PPP exposure (alone or in combination or mixture) and the risk of metabolic and cardiovascular diseases. This is why it is necessary to develop new approaches using a new animal model to assess the long-term effects of exposure to PPPs, including at puberty and in adulthood, and taking into account the sex of the offspring.

### 6.3. Effects of PPPs on Gonadal Functions and Fertility in Cohorts and Animal Models

The gonads are the primary organs of the reproductive system responsible for the production of sex hormones and gametes. Thus, the gonads are particularly susceptible to endocrine disruptors, which are known to interfere with steroid hormone receptors. These include the estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR), causing reproductive dysfunctions. Therefore, this part of the paper will be dedicated to the effect of maternal exposure to BPA, TCS, parabens, and phthalates or a mixture of pollutants on the gonadal functions of male and female offspring in cohorts and/or animal models.

#### 6.3.1. Epidemiological Data

Although difficult to undertake due to the duration of follow-up, the effects of prenatal exposure to PPPs on human reproduction are essential to understand the short-term and long-term effects on offspring [272].

One of the recognized markers of prenatal androgenization widely used and easily accessible is the measurement of anogenital distance [273]. In newborn boys (n = 72), but not in girls, a significant association between high cord blood BPA levels and shortened anoscrotal distance was suggested by Mammadov [274]. Similarly, boys whose mothers
had detectable levels of BPA in their urine at 12–16 weeks of gestation were more likely to have shorter anogenital distance at birth, and at both at 6 and 12 months of age, but not in girls [275].

Related to puberty, the CHAMACOS cohort study reported an association of higher prenatal exposure to BPA with later puberty in girls and earlier puberty in boys [276]. In contrast, maternal urinary concentrations of BPA from three birth cohorts, the INMA (Spain), EDEN (France), and MoBa (Norway), were associated with delayed pubertal development in boys and girls [277]. In the study by Ferguson et al., prenatal exposure to BPA was associated with decreased odds of adrenarche (maturation of adrenal androgen secretion) and puberty in boys between 8 and 14 years of age [278].

To our knowledge, only two studies have investigated the association between the in utero exposure to phenol and reproduction in men in adulthood [279]. In the Western Australian Pregnancy Cohort, maternal BPA exposure at 18 and 34 weeks of gestation was positively associated with their sons' sperm concentration and motility in adulthood (20–22 years), but not for their testicular function [279]. Furthermore, a high exposure to BPA and BP-3 during gestation was characterized by a compensated reduced Leydig cell function in adulthood, with no association with anogenital distance or semen quality [280].

Concerning prenatal TCS exposure, one study has explored its impact on reproductive hormones in cord blood, where TCS was associated with an increase in T and a decrease in E2 concentrations in cord blood among male infants [281]. Earlier puberty has been suggested in girls in all three birth cohorts, the INMA (Spain), EDEN (France), and MoBa (Norway) [277].

Later on, earlier menarche was reported with prenatal TCS exposure in girls from the CHAMACOS cohort, focusing on Latino children [282]. Using the same cohort, earlier breast development, pubic hair development, and menarche were observed with prenatal methylparaben (MeP) exposure in girls, and only earlier menarche with propylparaben. In boys, only genital development was reported associated with prenatal propylparaben exposure [282]. In addition, n-BuP was negatively associated with pubertal onset, adrenarche, and/or gonadarche (earlier gonadal development) in boys in the three European cohorts, the INMA (Spain), EDEN (France), and MoBa (Norway). In contrast, EtP and PrP were negatively associated with gonadarche in boys [277].

The association between prenatal phthalate exposure and gonadal development has been studied. Swan et al. reported an association between the anogenital distance, the incomplete testicular descent, the incomplete virilization, and the prenatal phthalate monoester metabolites exposure [283]. In the TIDES cohort from the USA, first-trimester urinary DEHP metabolite concentrations were associated with increased odds of genital abnormalities, especially due to hydrocele in newborn males [284]. In contrast, in a Canadian pregnancy cohort study, no strong evidence was observed between maternal urinary phthalates in the first trimester and the length or width of the penis at birth [285]. The association of prenatal exposure to phthalates with pubertal timing in boys and girls was investigated using several cohorts. Prenatal exposure to most phthalates was associated with reduced odds of adrenarche (notably with MEHHP, MEOHP, and MBzP) and reduced odds of puberty in association with DEHP metabolites, MBzP, MBP, and MiBP [278].

In the CHAMACOS longitudinal cohort study, it was found that the cx-MiNP, MCOP, and MCPP were associated with the late onset of pubarche (the appearance of pubic hair) and menarche (the first period) mostly among normal-weight girls, whereas MBzP was associated with later thelarche in girls. In boys, all of the phthalate biomarkers were associated with earlier gonadarche and pubarche, but associations with phthalate metabolites were close to the null or positive [276]. Moreover, prenatal urinary MEP concentrations were associated with an earlier onset of pubic hair development only in girls [282].

In the INMA Spanish cohort study, prenatal exposure to DEHP was associated with a higher risk of puberty onset and gonadarche in boys, and a higher risk of adrenarche in girls, at age 7–10 years. In boys, prenatal exposure to DEP, DnBP, and DEHP was also associated
with a higher risk of adrenarche or gonadarche in children with normal weight, and BBzP and DiNCH exposure with lower risk of adrenarche in children with overweight/obesity. In girls, DiBP, DnBP, and DiNCH were associated with a higher risk of gonadarche in children with overweight/obesity [286]. A recent publication from Freire et al. reported that MEHP was associated with delayed gonadarche and adrenarche, respectively, in girls and boys [277].

Interestingly, associations between prenatal exposure to phthalates and peripubertal measures of male reproductive development seem to be dependent on the timing of in utero exposure. In fact, exposure to phthalates during the third trimester was associated with reduced odds of having a Tanner stage higher than one for pubic hair development and higher peripubertal SHBG (sex hormone-binding globulin) levels. Exposure to phthalates during the first- and second-trimester phthalates was not associated with these outcomes. In contrast, only during the first trimester, exposure to DEHP was associated with higher estradiol concentration [287]. The long-term effects on adult reproductive health in male offspring (18–20 years) were also investigated, demonstrating an association between high maternal exposure to some phthalates and an impaired Leydig cell function characterized by lower total and free testosterone/LH ratios [288].

All of these studies suggested that PPPs can affect male and female genital development, puberty, semen quality, and sexual hormones, but the effects can depend on the window of prenatal exposure.

### 6.3.2. Maternal Exposure to PPPs and Gonadal Effects Using Animal Models

* Male Offspring

Most studies that have assessed the risk of perinatal exposure to BPA on male reproductive function have shown abnormal production of sex hormones in adulthood. In rats, daily exposure to 0.025 mg/kg of bodyweight or 0.250 mg/kg bw of BPA during the second half of gestation (GD10-21) reduced circulating testosterone levels (T) and luteinizing hormone (LH). This exposure also increased the levels of follicle-stimulating hormone (FSH) and estradiol (E2) [289]. Similar effects on blood levels of T and E2 are observed when exposure begins at the start of gestation (0.010 mg/kg bw) [290]. However, the opposite effects were observed for these hormones when measured at weaning [290]. Similarly, perinatal exposure (from GD18 to PND5) to 0.5 or 5 mg/kg bw of BPA results in a higher production of T [291]. In addition, exposure to BPA induces a decrease in AR expression and an increase in ER expression [291,292]. As a result, multiple abnormal histological and architectural damages are seen during testicular development. These include interstitial necrosis, germ cell degeneration, decreased tubular and luminal diameter [289,291,293], acrosome and plasma membrane integrity alteration, decreased mitochondrial activity [291], and increased oxidative stress [289]. Additionally, daily exposure to low levels of BPA (in the range of 0.0012 mg/kg bw and 5 mg/kg bw) significantly reduces sperm motility and count [289,291,292]. These outcomes lead to alterations in the fertility of the first male offspring and their subsequent second and third generations. However, this exposure does not affect the transcriptomic and epigenomic profile at the genome scale in sperm [292,293].

Studies conducted using mice or rabbits as a model have revealed similar morphological and hormonal damages in the testis of offspring exposed to BPA [248,294,295]. The observed effects on steroidogenesis are associated with a dysregulation of the steroidogenic enzyme expression. For example, daily exposure to BPA at 500 mg/kg bw from GD8 to PDN14 in mice decreased the expression of *StAR* (Steroidogenic Acute Regulatory Protein) and *Cyp11a* (Cytochrome P450 Family 11 Subfamily A Member 1) [296]. In rabbits, daily exposure to BPA at 50 mg/kg bw from GD15 to birth decreased the expression of *CYP11A1* and *3β-HSD* [297]. However, these effects are associated with different effects on T levels, which are reduced in adult mice and increased in 3-day-old rabbits. In addition, other transcriptomic studies showed that the expression of *Snrnp 40* (U5 small nuclear ribonucleoprotein subunit) was upregulated in the spliceosome pathway and that the expression of *Hnrnpu* (encoding a DNA- and RNA-binding protein) was downregulated.
These expressions suggest that spliceosome blockage may be the cause of abnormal testicular development in male mice exposed to BPA [295]. On the other hand, prenatal BPA exposure upregulated the transcription level at PND21 of testicular *Dnmt1* and inhibited the transcription of testicular *Dnmt3A* and *Dnmt3B*. In addition, the transcriptional level of testicular caspase-7, caspase-9, and bax is increased, and the transcriptional level of bcl-2 is decreased at PND56, leading to apoptosis in the testis [295].

Gestational and postnatal exposure to phthalates also induced adverse effects in male offspring. In rabbits, daily exposure to DBP (400 mg/kg bw) in utero (GD15-29) reduced serum T levels and, consequently, the concentration and quality of ejaculated sperm and the weights of the testes and accessory sex glands. Interestingly, rabbits exposed to DBP developed cryptorchid testes with carcinoma in situ-like cells, malformed foreskin (giving the appearance of feminized external genitalia), hypospadias, hypoplasia and prostate, and agenesis of the bulbourethral gland [298]. In addition, gestational daily exposure (GD10-20) to DEHP equivalent to a human daily intake (0.0024–0.003 mg/kg of bw/day) in mice reduced the anogenital distance, seminal vesicle weight, expression of testicular steroidogenic enzymes (*Star*, *Cyp17a1*, *Hsd17b12*, *Hsd3b1*, and *Hsd3b6*), and sperm count. However, this exposure did not affect either the testicular morphology or fertility performances [299]. It was previously assumed that the effect of DEHP on T production and steroidogenic enzyme expression was strain-dependent in rats [300]. However, Hannas and al. reported very minor differences in the testicular and epididimal phenotype between the Sprague-Dawley and Wistar rat strains [301].

Over the years, the use of animal models to understand the effects of maternal exposure to PPPs during pregnancy on the offspring phenotype has provided evidence that this exposure caused genital abnormalities in both male and female offspring. These studies were conducted by exposing animals to single compounds. However, on a daily basis, humans are exposed to dozens or even hundreds of chemical combinations through inhalation, skin contact, and ingestion. Consequently, the number of studies using mixtures of toxic substances is increasing. For example, an epidemiological study including 194 pregnant women (European EDC-MixRisk project (http://edcmixrisk.ki.se, accessed on 12 September 2024) reported a correlation between the levels of a mixture of phthalates (33% MBP, 16% MBzP, 21% MEHP, and 30% MiNP) in urine collected during the first trimester and the anogenital distance from their newborn boys. Repouskou et al. conducted an experimental study exposing mice throughout gestation to 0, 0.26, 2.6, and 13 mg/kg bw of this phthalate mixture [302]. As expected, they observed adverse effects on the male offspring reproductive system. These effects included a shorter anogenital distance, abnormal testicular development with thinner and disorganized seminiferous tubules, atypical germ cells, and low sperm production. At higher doses of this mixture, these effects were associated with increased circulating T and E2, and the increased expression of steroidogenic enzymes. Additionally, Hannas et al. tested a mixture of nine phthalates (DEHP, di-iso-heptyl phthalate, di-iso-butyl phthalate (DiBP), di-butyl phthalate (DBP), benzyl-butyl phthalate (BBP), di-cyclohexyl phthalate (DCHP), di-heptyl phthalate, di-hexyl phthalate (DnHP), and di-pentyl phthalate). They demonstrated that an administration of 650 mg/kg/day of this mixture from GD14 to GD18 reduced fetal T production in a dose-dependent manner [301]. Additionally, pregnant rats exposed to a combination of only two phthalates (DBP and DEHP; 500 mg/kg bw) within the same time window reduced fetal T production and decreased the expression of the steroidogenic enzymes *Star* and *Cyp11a* [303]. In this study, exposed male offspring were more likely to develop external and internal reproductive malformations, such as a shorter anogenital distance, hypospadias, external feminization (a higher number of nipples), testicular and epididymal malformations, and agenesis of the seminal vesicle and vas deferent. Interestingly, the mixture of different active molecules also interfered with normal sexual differentiation. Maternal and postnatal exposure to a combination of phthalates with genistein, polychlorinated biphenyls, or BPA also resulted in the low production of T, impaired seminiferous tubule development, and the reduction in testicular weight, sperm count, and sperm viability [304–306].
* Female Offspring

As for the male offspring, the harmful effects on female reproductive functions are induced by gestational or perinatal exposure to BPA, phthalates, or a mixture of pollutants. However, a limited number of studies focusing on female reproductive health have been published in the past five years.

In mice, gestational exposure to BPA (2.5, 5, 10, 20, and 40 mg/kg bw/day from GD0.5 to GD17.5) advanced puberty, induced atrophy of the ovary at adulthood, and female offspring were more likely to abort [307]. At higher doses, BPA (50, 500, and 2500 mg/kg bw) caused ovarian damage by increasing vacuole formation and decreasing the number of corpus granules [290,296]. In rats, prolonged exposure to BPA through drinking water (1 µg/mL or 10 µg/mL BPA from GD6 to PND21) caused similar damage to female sexual differentiation, such as advanced puberty and endometrial malformation [296,308]. Multiple hypotheses of the BPA action mechanism have been suggested. BPA has been shown to exert its effect by binding to the ER and mimicking the weak effect of estrogen. Interestingly, serum levels of E2, and ovarian ERa and ERb, were reduced in female offspring exposed in utero upon reaching adulthood. On the other hand, a decrease in the ovarian expression of Dnmt1, Dnmt3A, Dnmt3B, and Bcl2, and an increase in the relative expression of caspase-9, caspase-7, and bax, were seen in female offspring exposed to BPA [290,296,307]. Moreover, the activation of inflammation and abnormal autophagy via the TLR4/NF-κB and mTOR signaling pathways have been reported in the ovary and in the uterine tissue of exposed female offspring [308]. Altogether, these observations suggest that the exposure to BPA leads to the dysregulation of estrogen levels, altered DNA methylation, and the activation of inflammation and apoptosis in the ovaries of females of the next generation.

In females, the effects of maternal exposure to DEHP have negative effects on oocyte growth, meiotic maturation, and ovarian function [309]. Specifically, in first-generation ovarian primordial germ cells (GD12.5) and first- and second-generation oocytes (PND21), maternal exposure to DEHP (0.040 mg/kg bw/day, from GD0 to birth) decreases the methylation of CpG sites in the maternal imprinted gene *Igf2r* (insulin-like growth factor 2 receptor) and in the paternal imprinted gene *Peg3* (*paternally expressed gene 3*) [310]. Additionally, Pocar et al. showed that a longer exposure to a higher level of DEHP (0.05 or 5 mg/kg bw/day, from GD0 to PND21) decreased the expression of *Cyp19a1* and *Cyp17a1*, and blocked the process of meiosis II in most oocytes after superovulation in adult female offspring [311]. More recently, Repouskou et al. reported a cumulative effect of a mixture of phthalates. Pregnant mice exposed to a mixture of four phthalate monoesters (33% MBP, 16% MBzP, 21% MEHP, and 30% MiNP at 0, 0.26, 2.6, and 13 mg/kg bw/day from GD0 to birth) reduced the number of preantral follicles (primary and secondary), increased follicular atresia, and reduced the *Cyp19a1* expression in the ovaries of female offspring [302].

Altogether these studies conducted in animal models demonstrated that PPPs can affect gonadal development, puberty, steroidogenic enzymes, sexual hormones, semen, and oocyte quality.

7. Conclusions

Despite the implementation of regulations aimed at banning certain PPPs or reducing their concentrations in consumer products, the general population, including pregnant women, continues to be exposed daily to these pollutants. The objective of this review was to compile the current knowledge on the effects of prenatal exposure to these molecules on fetoplacental development and offspring health in the context of the developmental origins of health and disease concept (DOHaD).

Due to a short half-life, these molecules are rapidly eliminated in the urine in the form of one or more metabolites. Maternal urine sampling appears relevant for biomonitoring the exposure to these molecules. Worth noting, while spot urine samples are of interest in large populations for describing exposure, their use in etiologic studies is limited. Given the
reported high intra-individual variability in urinary concentrations of some phenols and phthalates, these snapshot assessments imperfectly reflect the average exposure over a long period, such as pregnancy. This leads to measurement errors and estimated effects biased toward zero. As shown in a simulation study, for a compound with a high intra-individual variability, such as BPA (intraclass correlation coefficients of around 0.2), the bias in effect estimates can be as high as 80%. The collection of repeated urine samples in the period of interest is, therefore, necessary to properly assess the exposure to PPPs and their effects on human health [312]. Unfortunately, this approach is not always applied to cohorts due to logistical constraints. Additionally, preconception maternal exposure levels are rarely known, as expectant mothers are recruited into cohorts once their pregnancies have been established.

During gestation, PPPs from the maternal bloodstream are able to cross the placental barrier in a native form or as metabolites and reach the fetal circulation, thereby contributing to direct exposure to the fetus. In humans, depending on the compound, positive or negative associations have been observed with placental weight or newborn weight and size, with, in some cases, sex-specific effects. Some studies have also found associations with DNA methylation, but generally without exploring the link between these methylation patterns and gene expression or any biological significance.

In vitro and in vivo studies were used to investigate the individual effects of PPPs on placental function. In vitro, depending on their concentration, according to a non-monotonic dose-response relationship, i.e., a U-shaped curve, phenols may or may not affect the proliferation of placental trophoblast cells and their hormone production. On the other hand, with monotonic dose-response curves, i.e., progressive effects depending on their concentrations, phthalates show effects on the lipid content, hCG secretion, and cell fusion through PPARγ. The in vitro approach makes it possible to test several concentrations of PPPs, alone or in a mixture, and to decipher their mechanism of action, but it does not take into account the sub-chronic effects or the complexity of the different cell types that make up the placenta. It is, therefore, essential to complement these studies with in vivo models.

The use of different animal models made it possible to evaluate the effects of sub-chronic exposure, to test several concentrations, and to target different periods of gestation. BPA appears to affect the placental structure, the expression of hormone receptors, and the genes involved in DNA methylation, as well as the DNA methylation levels, while TCS affects the expression of nutrient transporters and hormones. Phthalate-related alterations have been reported in placental morphology, hormone production, vascularization, histopathology, and gene/protein expression [131]. It should be noted, however, that the effects of pollutants on placental function are never evaluated in a cocktail, and that the exposure time only partially covers the preconception and/or gestation periods. Furthermore, sex-specific effects are rarely taken into account in these studies.

In a DOHaD context, it is also important to take into account the effects of prenatal exposure on the postnatal phenotype to assess population risks and, if necessary, adapt the PPP regulations. In human cohorts, depending on the children's sex, positive or negative associations have been established between prenatal exposure to PPPs and children's BMI, blood pressure, gonadal function, or age at puberty. However, the phenotyping of offspring is sometimes limited in terms of exploratory physiological tests for obvious ethical reasons, and, given the intergenerational duration, postnatal monitoring is currently limited to puberty. It is, therefore, essential to establish the postnatal phenotype of the offspring reaching adulthood, and even transgenerationally, by generating animal models exposed to PPPs at different doses and exposure durations so to complement the data from human cohorts.

Depending on the level of in utero exposure, and on the age and sex of the offspring, bisphenols and phthalates have been shown to affect bodyweight, carbohydrate homeostasis, insulin sensitivity, and thyroid hormones in offspring. These pollutants also have cardiovascular effects. Bisphenols can lead to ventricular hypertrophy, while phthalates
affect blood pressure, with the phenotypes depending on the sex. As PPPs are endocrine disruptors, these molecules disrupt gonad development, the age of puberty, sex hormone concentrations, and the quality of sperm and oocytes.

Future challenges will be to define a pollutant mix based on data from human cohorts, including fetoplacental biometric data and postnatal phenotyping data representative of the maternal exposome. The next challenge will be to study the effects of maternal exposure by the ingestion of this mixture of PPPs in an animal model mimicking human maternal exposure. In particular, this challenge needs to explore the effects on the development and fetoplacental growth, as well as on the postnatal phenotype, especially the cardiometabolic status and gonadal function, whilst taking into account the sex of the offspring. The question of the animal model is crucial. It is important to choose a model whose placenta is close to that of the human placenta.

Currently, rodent models are the most widely used. However, their placenta is made up of three layers of trophoblastic cells and is therefore more distant from the human placenta than that of lagomorphs [313]. This makes lagomorphs an interesting model to explore. Additionally, the establishment of placental epigenetic signatures seems to be a relevant issue to link to the postnatal phenotype, and thus to predict the health trajectory of the offspring. These data could then be extrapolated to follow-up cohorts to assess the potential phenotypic risks for children exposed in utero to PPPs. By doing so, preventive measures can be put in place to limit the exposure to PPPs, and regulations could be revised, if necessary.

**Author Contributions:** Conceptualization, D.R.-R., V.G., C.P. and A.C.-T.; writing—original draft, D.R.-R., J.B., M.O., N.J., V.G., N.M., M.-N.D., N.P.-H., M.-J.F.-S., H.J., C.P. and A.C.-T. Writing—review and editing, A.C.-T. and D.R.-R., Funding acquisition, A.C.-T. All authors have read, improved, and approved the final version of the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Agence Nationale de la Recherche, ANR MEMORI grant number ANR-21-CE34-0022. J.B. was also supported by a grant from INRAE, Human Nutrition Department. N.J. was supported by a grant from a doctorate school.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflicts of interest.

**Abbreviations**

AR: androgen receptor; AT1R: angiotensin 1 receptor; ATM: ataxia telangiectasia mutated; BAT: brown adipose tissue; BBP: benzyl butyl phthalate; Bcl-2: B cell lymphoma 2; 11beta-HSD2: 11-beta-hydroxysteroid dehydrogenase 2; BMI: body mass index; BMPP: bis (4-methyl-2-pentyl) phthalate; n-BuP: n-butylparaben; BP-1: benzophenone-1; BP-3: benzophenone-3; BP-8: benzophenone-8; BPA: bisphenol A; BPAF: bisphenol AF; BPAP: bisphenol AP; BPB: bisphenol B; BPC: bisphenol C; BPE: bisphenol E; BPF: bisphenol F; BPFL: bisphenol FL; BPM: bisphenol M; BPP: bisphenol P; BPS: bisphenol S; BPZ: bisphenol Z; bw: bodyweight; BzP: benzylparaben; CCL2: C-C motif chemokine ligand 2; CL: blood clearance; CRE: CBP-responsive element; CREB: cAMP-responsive element-binding protein; CRH: corticotrophin-releasing hormone; $C_{SS}$: steady-state plasma concentration; CTR1: SLC31A1 for solute carrier family 31, member 1; cx-MiNP: mono(carboxy-iso-nonyl) phthalate; DBEP: bis (2-n-butoxyethyl) phthalate; DBP: di-n-butyl phthalate; DCHP: dicyclohexyl phthalate; 2,4-DCP: 2,4-dichlorophenol; 2,5-DCP: 5-dichlorophenol; DEEP: bis (2-ethoxyethyl) phthalate; DEHP: di-(2-ethylhexyl) phthalate; DEP: diethyl phthalate; DnHP: di-n-hexyl phthalate; DI: daily PPP intake; DiBP: diisobutyl phthalate; DiDP: di-isodecyl phthalate; DiNCH: di-iso-nonyl-cyclohexane-1,2-dicarboxylate; DiNP: di-isononyl phthalate; DMEP: bis(2-methoxyethyl) phthalate; DMP: di-methyl phthalate; DnBP: di-n-butyl phthalate; DNMT1: DNA (cytosine-5)-methyltransferase 1; DnOP: di-n-
octyl phthalate; DNP: dinonyl phthalate; DPP: di-amyl phthalate; E2: estrogen; ECHA: European Chemicals Agency; EDCs: endocrine-disrupting chemicals; EFSA: European Food Safety Authority; EGF: epidermal growth factor; eNOS: endothelial nitric oxide synthase; EtP: ethylparaben; ER: estrogen receptor; ERE: estrogen response element; F: bioavailability; FPR: birthweight-to-placental-weight ratio; FSH: follicle-stimulating hormone; Fue: urinary excretion factors; GCNF: *Germ cell* nuclear factor; GLUT-1: glucose transporter 1; GWs: gestational weeks; hCG: human chorionic gonadotropin; HEPH: hephestin; HIF-1α: hypoxia-inducible factor 1-α; HMW: high-molecular-weight phthalates; HeP: heptylparaben; Hsp70: heat shock protein 70; 5-HT: serotonin; ICR: imprinting control region; IGF-1 or -2: insulin-like growth factor; IGF-2R: insulin-like growth factor-2 receptor; IGFBPs: IGF-binding proteins; IL: interleukin; i-BuPB: iso-butylparaben; i-PrPB: iso-propylparaben; LH: *luteinizing hormone*; LMW: low-molecular-weight phthalates; LXR: liver X receptor; MBP: mono-n-butyl phthalate; MBzP: monobenzyl phthalate; MCIOP: mono(4-methyl-7-carboxyheptyl) phthalate; MCMHP: mono-2-carboxy-methyl hexyl phthalate; MCOP: mono-carboxy-iso-octyl phthalate; MCPP: mono(3-carboxypropyl) phthalate; MECPP: mono(2-ethyl-5-carboxy-pentyl) phthalate; MECPTP: mono(2-ethyl-5-carboxy-pentyl) terephthalate; MEHHP: mono(2-ethyl-5-hydroxyhexyl) phthalate; MEHP: mono(2-ethyl-hexyl) phthalate; MEOHP: mono(2-ethyl-5-oxohexyl) phthalate; MEP: mono-ethyl phthalate; MiBP: mono-iso-butyl phthalate; MiDP: mono-iso-decyl phthalate; MiNP: monoiso-nonyl phthalate; MMP-9 or 2: matrix metalloproteinase; MMP: monomethyl phthalate; MeP: methylparaben; mTOR: mammalian target of rapamycin; MW: molecular weight; NF-κB: nuclear factor κ-light-chain-enhancer of activated B cells; NIS: sodium iodide symporter; NP: 4-nonylphenol; NRF-2: erythroid 2-related factor 2; OP: 4-tert octylphenol; PAX8: paired box 8; PE: polyethylene; Peg3: paternally expressed gene 3; PET: polyethylene terephthalate; PFR: placental-to-birthweight ratio; PHBA: para-hydroxybenzoic acid; PMCA1: plasma membrane calcium ATPase; PND: postnatal day; PrP: propylparaben; PPAR: peroxisome proliferator-activated receptors; PPPs: combination of phenols, parabens, and phthalates; PR: progesterone receptor; PVA: polyvinyl acetate; PVC: polyvinyl chloride; Rb: retinoblastoma; REACH: registration, evaluation, authorization, and restriction of chemicals; RORγ: retinoid Z receptor; SF-1: steroidogenic factor-1; SNAT-1 or 4: sodium-coupled neutral amino acid transporters; SRD5A2: steroid 5α-reductase 2; SULT1E1: estrogen sulfotransferase 1E1; T: testosterone; T4: thyroxine; TBAARS: thiobarbituric acid-reactive substances; TBBPA: tetrabromobisphenol A; TCS: triclosan; TET1: Tet methylcytosine dioxygenase 1; TGF-β: transforming growth factor β; THB: 2,3,4-trihydroxybenzophenone; TLR4: Toll-like receptor 4; TIMP-3: tissue inhibitor of metalloproteinase 3; TKs: toxicokinetics; TPO: thyroid peroxidase; TSH: thyroid-stimulating hormone; TTF-1: thyroid transcription factor 1; UE: molar urinary excretion of the measured compound; UGT1A1: UDP-glucuronosyltransferase 1A1; UV<sub>norm</sub>: daily excreted urinary volume; Vss: steady-state volume of distribution; WAT: white adipose tissue; WC: waist circumference.

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