Exposure to Synthetic Endocrine-Disrupting Chemicals in Relation to Maternal and Fetal Sex Steroid Hormones: A Scoping Review

Purpose of Review Many synthetic endocrine-disrupting chemicals (EDCs) are ubiquitous in the environment and highly detected among pregnant people. These chemicals may disrupt maternal and/or fetal sex steroid hormones, which are critical to pregnancy maintenance and fetal development. Here, we review the epidemiological literature examining prenatal exposure to common synthetic EDCs in relation to maternal and fetal sex steroid hormones. Recent Findings We performed a literature search using PubMed, SCOPUS, and Embase, ultimately identifying 29 articles for full review. Phenols, parabens, and persistent organic pollutants generally showed inverse associations with androgens, estrogens, and progesterone. Phthalates and per-and polyfluoroalkyl substances tended to be inversely associated with progesterone, while evidence regarding androgens and estrogens was mixed. Inconsistent, but noteworthy, differences by fetal sex and timing of exposure/outcome were observed. Summary Overall, the literature suggests EDCs may disrupt maternal and fetal sex steroid activity, though findings are mixed. Given the pervasive, high-volume production of these synthetic chemicals and the critical functions sex steroid hormones play during gestation, additional research is warranted. Supplementary Information The online version contains supplementary material available at 10.1007/s40572-024-00455-6.


Introduction
During pregnancy, the endocrine system supports pregnancy maintenance and fetal development.Sex steroid hormones, including estrogens, progesterone, and androgens, are important to the development of essential systems and functions (e.g., growth, reproduction), but may also be vulnerable to disruption by exogenous exposures [1].During pregnancy, estrogens serve key functions such as increasing blood flow to the uterus, stimulating tissue and uterine growth, and promoting the development of fetal organs [2][3][4].In early pregnancy, most estrogen is produced by maternal organs (e.g., ovaries, adipose tissue), however as pregnancy progresses, the placenta takes over as the primary producer [4].Similar to estrogens, progesterone is predominately produced by the placenta during pregnancy [4].Progesterone prevents premature uterine contractions and modulates the mother's immune response [4,5].In comparison to estrogens and progesterone, androgen activity in pregnancy has been less extensively studied.Key androgens include total testosterone (TT) and free testosterone (fT), which may derive from the ovaries and adrenal gland [6].Additionally, testosterone is aromatized into estrogen by aromatase, which is highly expressed in the placenta [6].
Androgens may play a role in sexual differentiation [7].
Several epidemiological studies have linked altered sex steroid concentrations in maternal circulation or cord blood to pregnancy complications, as well as child outcomes including growth and neurodevelopment [8][9][10].
These epidemiological studies are supported by toxicological studies indicating adverse outcomes associated with sex steroid hormone manipulation [11][12][13].Ultimately, the disruption of sex steroid hormone pathways during pregnancy may have important implications for maternal and child health and has been the subject of a growing scientific literature [14].
In the modern world, a major source of endocrine disruption is through exposure to synthetic endocrine disrupting chemicals (EDCs)-compounds that interfere with the body's hormone activity [15].Over 1,000 chemicals have proven or suspected endocrine disrupting properties, many of which are widely found in pharmaceuticals, agricultural products, food, drinking water, and consumer goods [16].As a result, many EDCs are widely found in the environment and have high levels of detection in humans, including pregnant people [17][18][19].As the production of chemicals increases, it is vital to understand their impact on health, particularly during pregnancy.Recognizing the central role of hormone activity in maternal-fetal health, the objective of this review was to summarize the current epidemiologic literature on prenatal exposure to synthetic chemicals in relation to maternal and fetal sex steroid hormones.The classes of synthetic chemicals included in this review were chosen based on their designation as common EDCs by the Endocrine Society and included phenols, parabens, phthalates, poly-and perfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), flame retardants, pesticides, and dioxins [15].

Search Strategy
We performed a scoping review to evaluate the current epidemiological literature examining prenatal synthetic EDCs in relation to sex steroid hormones in pregnant people and their fetuses.This review was conducted according to the PRISMA Extension for Scoping Reviews.The PRIS-MAScR checklist is provided in Supplemental Table 1.A protocol for this review was registered in PROPSPERO (ID CRD42023440353).Studies were identified through searches in PubMed, SCOPUS, and Embase.Major concepts for searching were synthetic chemicals and maternal and fetal sex steroid hormones.A medical librarian consulted on the initial search strategy.Search terms and strategies are shown in Supplemental Table 2.

Study Screening and Selection
We reviewed original epidemiologic studies in pregnant people relating maternal exposure to one or more EDCs of interest (i.e., phenols, parabens, phthalates, PFAS, PCBs, flame retardants, pesticides, and dioxins) to any of the outcomes (maternal or fetal sex steroid hormones: testosterone, free testosterone, estrone, estriol, estradiol, and progesterone).Following our search, articles were exported and duplicates were removed in Rayyan.Next, we screened the article titles and abstracts for relevance in Rayyan, which enabled the screenings to be independent and blinded.Each title and abstract were reviewed independently by two reviewers to determine whether the full text should be reviewed.Both reviewers examined the full text and made an independent determination about whether it should be included.Any discrepancies were resolved through discussion, including with additional co-authors as needed.We retrieved the full-text version of the remaining articles and assessed eligibility.Study inclusion criteria were based on our PECO statement (Table 1) and were as follows: [1] published in English; [2] human participants; [3] publication dates from January 1st, 2000 to July 5th, 2023 (the date when the initial search was performed); [4] any race, ethnicity, socioeconomic status, or geographical location; [5] primary research studies; [6] examined maternal exposure to a synthetic chemical (phenols, parabens, phthalates, PFAS, PCBs, flame retardants, pesticides, or dioxins) in relation to maternal or fetal sex steroid hormones (testosterone, free testosterone, estrone, estriol, estradiol, or progesterone).Searches were limited to after the year 2000 in an effort to highlight the most current literature.Studies were excluded if they did not meet these criteria, if the synthetic chemical exposure was examined in a fetal (rather than maternal) biomarker (e.g., cord blood and amniotic fluid), or if the exposure or outcome was measured in a non-preferred matrix.Preferred maternal chemical matrices are as follows: phenols-urine; parabens-urine; phthalates-urine; PFAS-blood; PCBS-blood; flame retardants (polybrominated diphenyl ethers)-blood; organophosphate pesticides-urine; organochlorine pesticides-blood; dioxins-blood.Acceptable hormone matrices included maternal serum, maternal plasma, maternal urine, cord plasma, cord serum, or cord blood.Primary searchers were run in PubMed, SCOPUS, and Embase on July 5, 2023.The search was rerun in PubMed on January 15, 2024 to capture additional papers that had been published since the original search was completed.Following screening, data charting was done independently by one reviewer.For quality assurance and consistency, each table was reviewed by a second author, after which all tables were edited for consistency by the first author as needed.For each study, we extracted the study sample and location, study design, exposure measures and assay, exposure source and timing, outcome measures and assay, outcome source and timing, and main findings.This information is presented in Tables 2 and  3, which examine non-persistent and persistent chemical exposures, respectively.Compounds that were the focus of five or more papers (e.g., phthalates, PFAS), were discussed in a discrete sub-section.Parabens and phenols were discussed together, as parabens are considered phenolic compounds [20].The remaining chemical classes with limited literature (< 5 studies), were synthesized within chemical class for discussion.These included PCBs, flame retardants, pesticides, and dioxins.A critical appraisal of the evidence -0.13, -0.03); DETP and T (β:−0.08ng/mL,95%CI:-0.14,-0.01); DAPS and T (β:−0.10ng/mL,95%CI:-0.17,-0.03); DMP and T/E2 (β:−0.06,95%CI: -0.10, -0.01); DETP and T/E2 (β:−0.07,95%CI:-0.13,-0.01) -In participants carrying males, significant association between DETP and T/E2 (β:-0.09,95%CI:-0.17,-0.00) -Significant inverse associations in participants carrying females included: DMP (β:−0.05pg/mL,95%CI: -0.07, -0.02), DEP (β:−0.06pg/mL,95%CI: -0.09, -0.02), DETP (β:−0.04pg/mL,95%CI:-0.08,-0.00), and DAPS (β:−0.07pg/mL,95%CI: -0.(continued) a BH-FDR of 0.1 was considered significant) [35].Finally, a New York cohort (n = 139) reported a non-significant inverse association between ΣBisphenols and progesterone (%Δ:-4.8;95%CI:-10.4,1.1) [36].

Estrone (E1):
In 851 Chinese pregnancies, in each trimester, participants in the highest BPA quartile had lower E1 compared to those in the lowest quartile, with some differences noted by trimester and fetal sex [40].

Summary of Search Results
Searches across the three databases yielded a total of 3,505 articles.After duplicate removal, 2,511 papers remained for screening.The title and abstract screening process resulted in the exclusion of 2,474 articles, with 37 moving forward to full-text review.After full-text review, 28 articles were selected for narrative review.The search rerun resulted in the identification of 24 new papers.Following screening, one paper met the inclusion criteria, resulting in a final count of 29 papers to be reviewed (Fig. 1).Five studies were excluded for using a non-preferred maternal matrix.These studies measured phenols and parabens in plasma or serum, phthalates in plasma, and sex steroids in hair [21][22][23][24][25].There were 9 articles on phenols, 9 on phthalates, 8 on PFAS, 4 on parabens, 3 on PCBs, 3 on pesticides, 2 on dioxins, and 1 on flame retardants.The included studies represent 19 pregnancy cohorts from geographically diverse areas including the United States, China, South Africa, and Germany.Study sizes varied from 56 participants to 879 participants.Across studies, median concentrations of chemicals varied for some compounds, but were relatively similar for others.For example, median perfluorooctanoic acid (PFOA) ranged from 0.59-42.83ng/mL,while median Bisphenol A (BPA) ranged from 0.68-4.0ng/mL[19,[26][27][28][29][30][31][32].

Parabens & Phenols
Nine studies investigated paraben and phenol concentrations in relation to maternal and/or fetal sex steroid hormones (Table 2).
Progesterone.Preliminary analyses from the PROTECT cohort, which recruited pregnant people in Puerto Rico (n = 106), showed non-significant inverse associations between phenols and parabens (methylparaben ) and progesterone at multiple timepoints across pregnancy [33].A larger PROTECT study expanded upon this preliminary analysis (n = 602) and similarly observed no significant associations in mixed models [34].By contrast, a smaller cohort from Michigan (MMIP; n = 56) reported a positive association between butylparaben (BuPB) and cord plasma progesterone (β:0.35nmol/L,Benjamini-Hochberg false discovery rate (BH-FDR):0.096;(continued) 0.38) [40].Banker et al. [35] reported that negative associations between E3 and BPA and 2,4-DCP were strongest in participants with a high BMI carrying female fetuses [35].Lastly, no associations between phenols and E3 were observed in PROTECT [34].

Phthalates
To our knowledge, to date, nine publications have reported on maternal urinary phthalate exposure in relation to maternal or cord sex steroids (Table 2).

PFAS
Eight publications have examined gestational PFAS in relation to sex steroid hormones, with mixed results (Table 3).
In the German Duisburg cohort, late pregnancy PCBs, categorized as non ortho (non-o-PCBs), mono ortho PCBs (mono-o-PCB), and Σ 6 PCB (PCB 28,52,101,138,153,180) were studied in relation to cord serum E2 and T [49].Amongst all births, non-o-PCBs were inversely associated with T (means ratio:0.85,95%CI:0.75,0.96) and E2 (means ratio:0.83,95%CI:0.73,0.95).Results were similar but weaker for mono-o-PCB exposure.In sex stratified analyses, mono-o-PCB and Σ 6 PCB were inversely related to cord serum T in female, but not male, infants and inversely related to E2 in both sexes.These results differ from the Hokkaido Study, where in general, positive trends between PCBs and E2 were observed, while results were null for T [50].That study also reported sex-specific associations including that non-ortho PCBs (Q4 vs. Q1) were significantly associated with lower T/E2 (p = 0.007) among males only.
One theoretical explanation for inconsistent associations across studies is temporal trends in chemical exposure, however the majority of studies recruited participants within the same years (2010-2017).A few older cohorts recruited earlier (from 1999 to 2005), and although one might expect the older cohorts to have higher levels of chemicals like PFAS, as PFAS levels have fallen over the past decades, no notable temporal trends were observed.For example, the Hokkaido Study recruited between 2002 and 2005 and had median PFOS and PFOA concentrations of 5.0ng/mL and 1.4ng/ mL, respectively [26,27].The remaining cohorts recruited from 2010 to 2019 and had median PFOS and PFOA ranging from 2.5-9.17ng/mL and 0.59-42.83ng/mL,respectively, suggesting some studies were conducted in highly exposed populations, while others are likely more representative of the general population [19,[28][29][30][31][32].The lack of temporal trend may be in part due to geographical and sociodemographic differences across the cohorts.
Several studies across chemical classes showed that maternal synthetic EDC exposure was inversely associated with progesterone.The epidemiological literature suggests that low levels of progesterone, particularly early in pregnancy, are associated with increased risk of hypertensive disorders of pregnancy and reduced birthweight [53][54][55].Phenols, parabens, PCBS, and pesticides were generally associated with lower androgen and estrogen concentrations.Some research suggests that alterations in androgens and estrogens concentrations are associated with pregnancy and child outcomes including low birth weight, preterm birth, and child behavior, however these studies tend to observe adverse outcomes in association with higher steroid concentrations [56,57].More research is needed to understand the impact of lower maternal androgen and estrogen concentrations on pregnancy and fetal health.However, there is some suggestion that low levels of estrogens are associated with preeclampsia [58,59].
The current body of literature on maternal synthetic chemical exposure and sex steroid hormones has several notable strengths.First, while some samples were very small (n < 50), most were considerably larger, which is important given the need to additionally examine moderation by fetal sex.Overall, many pregnancy cohorts have pursued questions regarding EDCs and sex steroid hormones, resulting in geographically diverse samples from the United States and Puerto Rico in addition to international samples from countries including China, Denmark, France, Germany, Japan, Slovakia, South Africa, and Taiwan.Limitations and gaps are also noted.Few studies employed mixtures analyses, which more accurately reflect the real-life simultaneous exposure to multiple chemicals.Additionally, establishing consistency across studies is challenging given the many variable factors including the timing of chemical with progesterone or E2 were observed.In contrast to the null findings in the Hokkaido cohort, amongst FETOTOX participants, hexachlorbenzen (HCB) was associated with lower first trimester E2 (β:-264.2pmol/l,95%CI:-445.2,-83.2) and E1 (β:-147.0pmol/l,95% CI:-286.4,-7.5); no additional associations between OCPs and hormones were evident [31].
Dioxins.Results of the two studies on dioxins and maternal and fetal sex steroid hormones are inconsistent (Table 3).Seventeen maternal polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) congeners were examined in relation to cord serum T and E2 in Duisberg cohort participants (n = 104) [49].Although no associations with T were observed in the full cohort, amongst female infants, PCDD/ Fs were inversely associated with cord serum T (means ratio:0.69,95%CI:0.53,0.90).E2 was inversely related to PCDD/Fs amongst the whole cohort (means ratio:0.73,95%CI:0.60,0.87) and in both sexes, individually.The Sapporo Cohort of Hokkaido Study examined maternal dioxinlike compounds (7 PCDDs, and 10 PCDFs) from mid and late pregnancy in 183 mother-child pairs in relation to cord blood hormones, reporting null results overall [50].In models stratified by fetal sex, in males, beta estimates trended negative while in females they trended positive, suggesting sex steroid disruption by dioxins may occur in a fetal sex dependent manner.

Discussion
In this scoping review, we examined maternal exposure to synthetic chemicals in relation to maternal and fetal sex steroid hormones.The vast majority of studies considered maternal exposure to phthalates and phenols, while other chemicals with endocrine-disrupting potential such as dioxins and pesticides have been considered less often in relation to sex steroids in the epidemiological literature from the examined time period.Generally, studies examining maternal exposure to phenols and parabens showed inverse associations with progesterone, testosterone, and estrogens, with some inconsistencies when stratified by fetal sex (Table 4).Most studies assessing exposure to phthalates and PFAS in relation to progesterone similarly suggested inverse associations, whereas there was less consistency regarding the direction and magnitude of the associations with androgens and estrogens.Lastly, within the remaining chemical classes, in relation to androgens and estrogens, studies examining PCBs generally found inverse associations, studies of pesticide exposure typically found null or inverse associations, and the two dioxin studies observed inverse associations, with some conflicting results when examining by fetal sex.as these classes have been given limited attention in the literature.Conversely, phenols, parabens, phthalates, and PFAS have a richer body of primary evidence, warranting consideration for systematic reviews.

Conclusion
Overall, the epidemiological research shows that exposures to common synthetic chemicals are associated with sex steroid hormones during pregnancy.However, many of the findings are mixed, with differences in the direction of the estimate, differences by fetal sex, and differences by timing of hormone measurement.As these synthetic chemical classes become more prominent in the environment and in consumer goods, it is important to continue monitoring their impact on the health of pregnant people and their offspring.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended and hormone assessment, examination of sex differences, metabolites and hormones measured, assays used, and modeling approaches.We encourage repeat measures of EDCs and sex steroids in each trimester, which will enable the examination of trimester-specific associations and associations across pregnancy.This may aid in the identification of critical windows of exposure.Further, consistent examination of sex differences is important, as there is evidence that many environmental chemicals impact male and female fetuses differently [19,35,46].Some hormones have received less attention thus far.For example, free testosterone was examined infrequently despite its importance as the biologically active fraction of testosterone [60].Lastly, select studies examined correlations and these unadjusted results should be viewed with caution.There are also limitations to our scoping review process.A critical assessment of the papers was not performed, and therefore the potential biases of each paper was not considered.Further, our search was limited to studies published from January 1st, 2000 to July 5th, 2023 and in English, potentially excluding relevant literature.However, to the best of our knowledge, very little literature was published on this topic prior to 2000.
We offer recommendations as this literature continues to grow.Future studies can extend current research by examining maternal/fetal sex steroid hormones as mediators on the pathway between synthetic chemical exposures and child outcomes.Zhang et al. [41] provide an example of that approach by examining sex steroid hormones as mediators in the association between maternal triclosan exposure and offspring outcomes including ponderal index and head circumference [41].Further, future research can examine critical periods of exposure to determine if disruption at specific points during pregnancy (e.g., early vs. late) has different implications for maternal and fetal health.Repeat measures of exposure across pregnancy, but also within trimester, is particularly important for the non-persistent chemicals, which tend to show low stability over time [61].For persistent chemicals, future studies might consider associations by parity given the potential for "shedding" of persistent organic pollutants (POPs) through birth and breastfeeding [62,63].To date, this literature has relied primarily upon single pollutant models that evaluate each chemical separately.Consistent with general advances in environmental epidemiology, future studies should additionally incorporate analytic approaches to evaluate joint exposure to multiple synthetic chemicals within and across classes ("mixtures") in relation to maternal hormone profiles.The analysis of additional sex steroid hormones (e.g., dehydroepiandrosterone and dihydrotestosterone) will enrich our understanding of this topic and the mechanisms by which EDCs disrupt steroidogenic pathways.More primary research is specifically required for dioxins, pesticides, and flame retardants, AbbreviationsBEP = benzylparaben; BPA = bisphenol A; BPAF = bisphenol AF; BPA-g = BPA-glucuronide; BPAP = bisphenol AP; BPB = bisphenol B; BPF = bisphenol F; BPP = bisphenol P; [MPB] and propylparaben [PPB]) and phenols (BPA, triclosan [TCS], benzophenone-3 [BP-3], 2,4-dichlorophenol [2,4-DCP], and 2,5-dichlorophenol [2,5-DCP] Abbreviations br-PFHxS = perfluorohexanesulfonic acid and its branched isomer; br-PFOS = perfluorooctanesulfonic acid and its branched isomer; CG-NICI-MS = gas chromatography/neg-

Fig. 1
Fig. 1 Flow chart of study selection

Table 2
Summary of epidemiological studies examining the relationship of maternal non-persistent chemical exposures with maternal and/or fetal sex steroid hormones

Table 3
Summary of epidemiological studies examining the relationship of maternal persistent chemical exposures with maternal and/or fetal sex steroid hormones

Table 4
Overall trends of associations between maternal exposure to synthetic chemicals (by class) and sex steroid hormones Androgens Estrogens Progesterone No. of papers Direction of assoc.No. of papers Direction of assoc.No. of papers Direction of assoc.