Table 3:

Human Studies on the Associations Between Placental Disruption and Phthalate Exposure

Phthalate	Exposure window	Dose/measurement time, sample	Model	Effect on placenta	Conclusions	Reference
MMP, MEP, MBP, MBzP MEHP, MEHHP, MEOHP	Maternal prenatal	0.40–92.07 ng/L/1st trimester, urine 0.32–74.10 ng/L/2nd trimester, urine 0.20–51.99 ng/L/3rd trimester, urine	2,725 pregnant women (1399 boys’ and 1326 girls’ pregnancies)	MBP: + association with placental breadth and surface area MMP, MBP, LMW: - association with length - breadth (1st trimester) MMP, MBP, MEOHP, MEHHP, LMW, HMW: + association with placental thickness (2nd trimester) MBP, MEHP: + association with placental thickness (3rd trimester) MEHP, MEHHP, LMW: increased placental thickness (2nd and 3rd trimesters only in the boys’ pregnancies)	Exposure to phthalates may cause the placenta to become thicker and more circular in the last two gestational trimesters, sexually dimorphic	(Zhu et al., 2018)
MCPP, MBP, MiBP, MBzP, MEP, MCNP, MCOP MEHP, MEHHP, MEOHP, MECPP	Maternal prenatal	0.2–0.6 μg/L/between 23- and 29-weeks’ gestation, urine	473 pregnant women (boys’ pregnancies)	MCNP: - association with placental weight MCNP, MCOP: - association with PFR MBP, DEHP: no association with placental weight	There are possible associations between phthalates exposure and placental weight and PFR	(Philippat et al., 2019)
MEP, MBP, MiBP, MBzP, MEHP, MEHHP, MEOHP, MECPP, MCPP, MCOP, MCNP	Paternal and maternal preconception, and maternal prenatal	2.81 ng/ml (MEHP) to 39.4 ng/ml (MEP)/paternal preconception, urine 2.45 ng/ml (MEHP) to 48.5 ng/ml (MEP)/maternal preconception, urine 2.55 ng/ml (MEHP) to 39.4 ng/ml (ΣDEHP)/maternal prenatal-6-, 21- and 35-weeks’ gestation, urine	132 mothers and 68 fathers (65 couples)	MECPP, ΣDEHP (paternal): - association with placental weight MEP (maternal preconception): inverse association with BW:PW. MEP (prenatal): - association with placental weight DEHP metabolites (prenatal): suggestive association towards a lower BW:PW No differentiation between boys’ and girls’ pregnancies	Paternal and maternal urinary phthalate metabolites may affect placental weight and the BW:PW regardless of fetal sex	(Mustieles et al., 2019)
MEHP, MEOHP, MEHHP, MECPP, MnBP, MiBP, MBzP.	Maternal prenatal	279.8 nm/L (ΣDEHP)/early 3rd trimester, urine	54 placentas	ΣDEHP: + association with lower mRNA expression (PPARγ, AHR, and hCG)	There is an association with lower expression of genes involved in trophoblast differentiation. Results are less consistent for genes that control steroidogenesis pathway	(Adibi et al., 2010)
MnBP, MBzP, MEHP, MEP, MiBP, MEOHP, MEHHP, MECPP, and MCPP	Maternal prenatal	18nM (MEHP) to 1.3 μM (MEP) /34 weeks’ gestation, urine	180 placentas	Lowest quartile of phthalate with differences either lost or reversed over the range of phthalates: + mRNA levels (HSD17B1, CYP19A1, CGA, and PPARγ) (male) MBzP, all quartiles of MnBP, 3rd quartiles of MiBP: + association with the mRNAs above MCPP: association with decreased placental mRNA PPARγ (male) PPARγ: - in large for gestational age cases (male)	Prenatal exposure to phthalates is modestly associated with molecular changes in placental tissue during pregnancy. Associations are stronger in male vs. female placentas, and with MnBP and MiBP	(Adibi et al., 2017)
DIBP, DBP, DEHP	Maternal prenatal	0.08 g/L-4498.53 g/L (DEHP), 0.19 g/L-461.12 g/L (DBP), 0.18 g/L-281.36 g/L (DIBP)/ at delivery, cord blood	207 placentas	LnDIBP, LnDBP, LnDEHP: + association with upregulation of PPARγ protein expression	Phthalates might not only induce PPARγ activation by inducing peroxisome proliferation and binding to PPARγ directly, but also by increasing their protein expression in the placenta	(Huang et al., 2018)
BBP, DMP, DEP, DEHP, DNOP	Maternal prenatal	3.09 μg/L (DMP) to 648.59 μg/L (DEHP) (high exposed group) 3 μg/L (DMP) to 492.76 μg/L (DMP) (low exposed group)/at delivery, cord blood	187 pregnant women (127 from Chenghai-high exposed group and 60 from Haojiang-low exposed group)	MT-1A mRNA: + (low exposed group) FATP1 and HFABP mRNAs: + (high exposed group) DEHP: + association with MT-1A (high exposed group) DNOP: - correlation with MT and MT-2A DEP: + association with FATP1 and HFABP mRNAs DMP: + expression of MT and MT-2A (male and female) DEHP: + correlation with MT and MT-2A (female) DEP: + correlation with HFABP (male) and MT- 1A and FATP1 (female)	Neonatal exposure to phthalates could overexpress the MT isoforms. Different phthalates cause distinct effects, sexually dimorphic	(Li et al., 2016)
MBP, MMP, MEHP, MEOHP, MEHHP	Maternal prenatal	33.2, 9.2, 5.7, 11.4, and 4.6 ng/mL to MBP, MMP MEHP, MEHHP, and MEOHP, respectively/3rd trimester, urine	119 placentas (55 FGR cases and 64 normal controls)	MEHHP, MEOHP, ΣDEHP: + (FGR cases) Placental LINE-1 methylation: + association with fetal birth weight MEHHP, ΣDEHP: - association with placental LINE-1 methylation Every natural-log unit increase of MEHHP and ΣDEHP: inverse association with a birth weight mediated through LINE-1 methylation	There is a link between changes in placental LINE-1 methylation and prenatal phthalate exposure	(Zhao et al., 2015)
23 phthalates	Maternal prenatal	231 ng/ml/1st trimester, urine	49 pregnant women	282 DMRs (245 unique genes) in the early placenta (high phthalate exposure) Gene expression analysis: 39 significant methylation-gene expression correlations (23 unique gene, most inversely correlated −29 out of 39) Pathway molecular analysis: ErbB signaling pathway as the top pathway involved EGFR: present in 18/51 pathways identified	Placental EGFR hypermethylation and decreased expression occur in women with high total phthalate exposure, suggesting that this gene specifically may be a target for endocrine disruption consequences by phthalates exposure	(Grindler et al., 2018)
MnBP, MBzP, MCNP, MCOP, MCPP, MECPP, MEHHP, MEHP, MEOHP, MEP, MiBP	Maternal prenatal	Log (level) ranged between 0.523 (MEOHP) to −0.056 (MCNP)/ 1st trimester, urine	196 pregnant women	Σphthalate, LMW: - H19 methylation Σphthalate, LMW: inverse association with IGF-2 methylation Variation in methylation: no association with changes in allele-specific expression ΣDEHP, HMW: + association with deviation of allele-specific expression of H19 HMW, DEHP: + association with aberrant imprinting of H19 in male newborns	Prenatal exposure to phthalates perturbs methylation of the imprinting genes H19 and IGF2 in the placenta, sexually dimorphic	(LaRocca et al., 2014)
MBP, MMP, MEHP, MEOHP, MEHHP	Maternal prenatal	3.8 ng/mL (MEHP) to 25.7 ng/mL (MPB)/ 3rd trimester, urine	Placenta of 181 mother-newborn pairs (80 FGR newborns, 101 normal newborns)	MEHHP, MEOHP: inverse association with placental IGF2 DNA methylation most evidently in FGR newborns	Changes in placental DNA methylation may represent an underlying biological pathway linking prenatal phthalate exposure and IUGR	(Zhao et al., 2016)
MiBP, MCPP, MCNP, MCOP, MECPP, MEHHP, MEOHP, MBzP, MnBP, MHiBP, MiBP, MEHP, MNP, MMP, MEP MHiNCH, MCOCH	Maternal prenatal	Mean of 158.7 ng/ml (MEP -metabolite with the highest average concentration)/ near delivery date, urine	10 women with uncomplicated dichorionic diamniotic twin pregnancies at term	MEHP, MEHHP, MECPP, MEOHP: + correlation with the lncRNA H19 and the lncRNA IGF2 (both expressed in placental samples) after adjustment for in vitro fertilization and sex MCNP: + correlation with most lncRNAs MHiBP: + correlation with LOC91450 MiBP: + correlation with many lncRNAs LOC91450: + correlation with the greatest number of phthalates Most lncRNAs: = response to phthalates (most relevant upregulations were with MCNP)	There is a link between lncRNA and the genomic imprinting and there are correlations between phthalate exposures and a panel of lncRNAs	(Machtinger et al., 2018)
MnBP, MBzP, MCNP, MCOP, MCPP, MECPP, MEHHP, MEHP, MEOHP, MEP, MiBP	Maternal prenatal	Log (level) ranged between 0.523 (MEOHP) to −0.056 (MCNP)/ 1st trimester, urine	179 pregnant women	Σphthalates: + association with expression of 3 miRNAs (miR-142-3p, miR15a-5p, and miR-185) Gene enrichment analysis: biological processes involved with potential mRNA targets of the 3 miRNAs - regulation of protein serine/threonine kinase activity, cellular response to insulin stimulus, insulin-like growth factor receptor signaling pathway, and positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway	Prenatal phthalate exposure is associated with abnormal miRNA expression in placenta, suggesting a potential molecular target of EDC toxicity	(LaRocca et al., 2016)
MiBP, MCOP, MECCP, MEHHP, MEOHP, MBzP, MHiBP, MEHP, MEP	Maternal prenatal	86.9% (range: 50%–100%))/ near delivery date, urine	10 women with twin pregnancies	MBzP: + association with expression of miR-518e (contained in EVs that are released by the placenta into the maternal circulation)	Prenatal phthalate exposure is associated with abnormal profiles of circulating placenta-derived EV-miRNAs	(Zhong et al., 2019)
MMP, MEP, MBP, MBzP, MEHP, MEHHP, MEOHP	Maternal prenatal	50.092 × 103 ng L−1 (MBP), 13.311 × 103 ng L−1 (MMP), 8.786 × 103 ng L−1 (MEP), 7.380 × 103 ng L−1 (MEOHP) / 1st trimester, urine	2,469 placentas	MBP: + correlation with higher IL-1β, IL-6, and CRP mRNAs expression (male fetuses) and with higher IL-6, CRP, MCP-1, IL-8, IL-10, and CD68 mRNAs expression (female fetuses) MBzP: increased the expression of TNF-α, MCP-1, and CD68 (male fetuses) MEOHP: - correlation with CRP, MCP-1, and CD68 mRNAs (female fetuses)	Maternal phthalate exposure is associated with inflammatory variations in placental tissues, with associations stronger in placentae of male than of female fetuses	(J. Q. Wang et al., 2020)