Placental concentrations of xenoestrogenic organochlorine pesticides and polychlorinated biphenyls and assessment of their xenoestrogenicity in the PA-MAMI mother-child cohort.

BACKGROUND: Organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCB), they have contributed to the exposure of women to persistent organic pollutants (POPs). These compounds can cross the placental barrier and interfere with the hormonal system of newborns. AIM: To determine concentrations of OCPs and PCBs and their xenoestrogenic activity in placentas of women from the PA-MAMI cohort of Panama. METHODS: Thirty-nine placenta samples from women in the Azuero peninsula (Panama) were analyzed. Five OCPs [p-p'-dichlorodiphenyldichloroethylene (p-p'-DDE), beta-hexachlorohexane (ß-HCH), γ-hexachlorohexane (lindane), hexachlorobenzene (HCB) and mirex] and three PCB congeners (PCB-138, PCB-153 and PCB-180) were quantified in placenta extracts. The xenoestrogenic activity of extracts was assessed with the E-Screen bioassay to estimate the total effective xenoestrogen burden (TEXB). RESULTS: All placental samples were positive for at least three POP residues and >70% for at least six. The frequencies of quantified OCPs ranged from 100% for p,p'-DDE and HCB to 30.8% for ß-HCH. The highest median concentration was for lindane (380.0 pg/g placenta), followed by p,p'-DDE (280.0 pg/g placenta), and HCB (90.0 pg/g placenta). Exposure to p,p'-DDE was associated with greater meat consumption, suggesting that animal fat is a major source of exposure to DDT metabolites. The frequency of detected PCBs ranged between 70 and 90%; the highest median concentration was for PCB 138 (17.0 pg/g placenta), followed by PCB 153 (16.0 pg/g placenta). All placentas were positive in the estrogenicity bioassay with a median TEXB-α of 0.91 pM Eeq/g of placenta. Exposure to lindane was positively associated with the xenoestrogenicity of TEXB- α, whereas this association was negative in the case of exposure to PCB 153. CONCLUSIONS: To our best knowledge, this study contributes the first evidence on the presence of POPs and xenoestrogenic burden in placentas from Latin-American women. Given concerns about the consequences of prenatal exposure to these compounds on children's health, preventive measures are highly recommended to eliminate or minimize the risk of OCP exposure during pregnancy.

Cell cycle, apoptosis, cell differentiation, and lipid metabolism gene expression in endometriotic tissue and exposure to parabens and benzophenones.

AIM: To describe the expression profile in endometriotic tissue of genes involved in four signaling pathways related to the development and progression of endometriosis (cell cycle, apoptosis, cell differentiation and lipid metabolism) and to explore its relationship with the women exposure to chemicals with hormonal activity released from cosmetics and personal care products (PCPs). METHODS: This cross-sectional study, encompassed within the EndEA study, comprised a subsample of 33 women with endometriosis. Expression levels of 13 genes (BMI1, CCNB1, CDK1, BAX, BCL2L1, FOXO3, SPP1, HOXA10, PDGFRA, SOX2, APOE, PLCG1 and PLCG2) in endometriotic tissue and urinary concentrations of 4 paraben (PB) and 3 benzophenone (BP) congeners were quantified. Bivariate linear and logistic regression analyses were performed to explore the associations between exposure and gene expression levels. RESULTS: A total of 8 out 13 genes (61.5 %) were expressed in >75 % of the samples. Exposure to congeners of PBs and/or BPs was associated with the overexpression of CDK1 gene (whose protein drives cells through G2 phase and mitosis), HOXA10 and PDGFRA genes (whose proteins favor pluripotent cell differentiation to endometrial cells), and APOE (whose protein regulates the transport and metabolism of cholesterol, triglycerides and phospholipids in multiple tissues) and PLCG2 genes (whose protein creates 1D-myo-inositol 1,4,5-trisphosphate and diacylglycerol, two important second messengers). CONCLUSIONS: Our findings suggest that women exposure to cosmetic and PCP-released chemicals might be associated with the promotion of cell cycle and cell differentiation as well as with lipid metabolism disruption in endometriotic tissue, three crucial signaling pathways in the development and progression of endometriosis. However, further studies should be accomplished to confirm these preliminary data.

Biomonitoring bisphenols, parabens, and benzophenones in breast milk from a human milk bank in Southern Spain.

BACKGROUND: Human breast milk is considered the optimal source of nutrition for infants. Milk from breast milk banks offers an alternative to infant formulas for vulnerable hospitalized neonates most likely to benefit from exclusive human milk feeding. However, breast milk can also be a source of exposure to environmental contaminants, including endocrine-disrupting chemicals (EDCs). AIM: To evaluate concentrations of phenolic EDCs, including bisphenols, parabens (PBs), and benzophenones (BPs), in samples from a human milk bank in Granada, Southern Spain and to explore sociodemographic, reproductive, and lifestyle factors related to their concentrations in the milk. METHODS: Concentrations of three bisphenols [bisphenol A (BPA), bisphenol F (BPF), and bisphenol S (BPS)], four PBs [methyl- (MeP), ethyl- (EtP), propyl- (n-PrP), and butyl-paraben (n-BuP)], and six BPs [BP-1, BP-2, BP-3, BP-6, BP-8, and 4-hydroxy-BP] were determined in milk samples from 83 donors. Information on potential explanatory variables was gathered using the milk bank donor form and an ad hoc questionnaire. Multiple linear and logistic regression models were fitted. RESULTS: Detectable concentrations were found of at least one of the analyzed compounds in all donor breast milk samples and at least five compounds in one-fifth of them. The most frequently detected compounds were MeP (90.5%), BP-3 (75.0%), EtP (51.2%), n-PrP (46.4%), and BPA (41.7%). Median concentrations ranged between <0.10 ng/mL (n-PrP, n-BuP, BP-1) and 0.59 ng/mL (BP-3). No sample contained detectable concentrations of BPF, BPS, or most BPs (BP-2, BP-6, BP-8, and 4- hydroxy-BP). Breast milk phenol concentrations were associated with parity, the utilization of deodorants, mouthwash, skin care products, and cosmetics, and the intake of nutritional supplements. CONCLUSIONS: Results reveal the widespread presence of BPA, PBs, and BP-3 in donor breast milk samples, highlighting the need for preventive measures to enhance the benefits of breast milk from milk banks and from breastfeeding women in general.

Concentrations of bisphenols, parabens, and benzophenones in human breast milk: A systematic review and meta-analysis.

BACKGROUND: Breast milk is the main source of nutrition for infants but may be responsible for their exposure to environmental chemicals, including endocrine-disrupting chemicals. AIM: To review available evidence on the presence and concentrations of bisphenols, parabens (PBs), and benzophenones (BPs) in human milk and to explore factors related to exposure levels. METHODS: A systematic review was carried out using Medline, Web of Science, and Scopus databases, conducting a comprehensive search of peer-reviewed original articles published during the period 2000-2020, including epidemiological and methodological studies. Inclusion criteria were met by 50 studies, which were compiled by calculating weighted detection frequencies and arithmetic mean concentrations of the chemicals. Their risk of bias was assessed using the ROBINS-I checklist. RESULTS: Among the 50 reviewed studies, concentrations of bisphenols were assessed by 37 (74.0%), PBs by 21 (42.0%), and BPs by 10 (20.0%). Weighted detection frequencies were 63.6% for bisphenol-A (BPA), 27.9-63.4% for PBs, and 39.5% for benzophenone-3 (BP-3). Weighted mean concentrations were 1.4 ng/mL for BPA, 0.2-14.2 ng/mL for PBs, and 24.4 ng/mL for BP-3. Mean concentrations ranged among studies from 0.1 to 3.9 ng/mL for BPA, 0.1 to 1063.6 ng/mL for PBs, and 0.5 to 72.4 ng/mL for BP-3. The highest concentrations of BPA and PBs were reported in samples from Asia (versus America and Europe). Higher BPA and lower methyl-paraben concentrations were observed in samples collected after 2010. Elevated concentrations of these chemicals were associated with socio-demographic and lifestyle factors in eight studies (16.0%). Two epidemiological studies showed moderate/serious risk of bias. CONCLUSIONS: This systematic review contributes the first overview of the widespread presence and concentrations of bisphenols, PBs, and BPs in human breast milk, revealing geographical and temporal variations. The methodological heterogeneity of published studies underscores the need for well-conducted studies to assess the magnitude of exposure to these chemicals from human milk.

Cosmetic and personal care product use, urinary levels of parabens and benzophenones, and risk of endometriosis: results from the EndEA study.

AIM: To explore the relationship of urinary concentrations of different congeners of benzophenones and parabens with the utilization of cosmetics and personal care products (PCPs) and their impact on the risk of endometriosis, and to evaluate the influence of oxidative stress on associations found. METHODS: This case-control study comprised a subsample of 124 women (35 cases; 89 controls). Endometriosis was confirmed (cases) or ruled out (controls) by laparoscopy, with visual inspection of the pelvis and biopsy of suspected lesions (histological diagnosis). Urinary concentrations of benzophenone-1 (BP-1), benzophenone-3 (BP-3), 4-hydroxibenzophenone (4-OH-BP), methyl- (MeP), ethyl- (EtP), propyl- (PrP), and butyl-paraben (BuP), and biomarkers of oxidative stress [lipid peroxidation (TBARS) and total antioxidant power (TAP)] were quantified. Information was gathered on the frequency of use of cosmetics and PCPs. Associations between the frequency of cosmetics/PCP use, urinary concentrations of benzophenones and parabens, oxidative stress, and endometriosis risk were explored in logistic and linear multivariable regression analyses. RESULTS: The frequency of utilization of certain cosmetics and PCPs was significantly associated with urinary concentrations of benzophenones and parabens. After adjustment for potential confounders, the risk of endometriosis was increased in women in the second versus first terciles of MeP (OR = 5.63; p-value<0.001), BP-1 (OR = 5.12; p-value = 0.011), BP-3 (OR = 4.98; p-value = 0.008), and Æ©BPs (OR = 3.34; p-value = 0.032). A close-to-significant relationship was observed between TBARS concentrations and increased endometriosis risk (OR = 1.60, p-value = 0.070) and an inverse association between TAP concentrations and this risk (OR = 0.15; p-value = 0.048). Oxidative stress results did not modify associations observed between benzophenone/paraben exposure and endometriosis risk. CONCLUSIONS: Our findings indicate that the frequency of cosmetics and PCP utilization is a strong predictor of exposure to certain benzophenone and paraben congeners. These compounds may increase the risk of endometriosis in an oxidative stress-independent manner. Further studies are warranted to corroborate these findings.

Serum levels of non-persistent environmental pollutants and risk of incident hypertension in a sub-cohort from the EPIC study.

BACKGROUND: The prevalence of arterial hypertension (AHT), a well-known risk factor for cardiovascular disease, has considerably increased over last decades. Non-persistent environmental pollutants (npEPs) are a group of ubiquitous chemicals, widely used in consumer products such as food packaging and cosmetics, which have been identified as endocrine disrupting chemicals and obesogens. The aim of this study was to assess the potential associations of serum levels of three groups of npEPs with the risk of incident AHT. METHODS: Cohort study within a sub-cohort of Granada EPIC-Spain center (n = 670). We quantified serum concentrations of three groups of npEPs, i.e., bisphenol A (BPA), four parabens: methylparaben (MP), ethylparaben (EP), propylparaben (PP) and butylparaben (BP), and two benzophenones: benzophenone 1 (BP1), benzophenone 3 (BP3), in samples collected at recruitment. Statistical analyses were performed by means of Cox Proportional Hazard Models. RESULTS: Median follow-up time was 23 years. BPA and MP were found in >80% of the study population. Individuals within the 4th PP quartile (0.53-9.24 ng/ml) showed a statistically significant increased risk of AHT (HR = 1.40, p = 0.015). No associations were found for the rest of pollutants. CONCLUSIONS: Overall, we evidenced no associations of most npEPs with AHT risk, with the exception of an increased risk in the highest PP percentiles. Considering the limitations of using one spot serum sample for exposure characterization, further research on the potential contribution of npEPs on the development of AHT risk is warranted.

Historical exposure to non-persistent environmental pollutants and risk of type 2 diabetes in a Spanish sub-cohort from the European Prospective Investigation into Cancer and Nutrition study.

BACKGROUND: Environmental factors are believed to account for a substantial burden of type 2 diabetes mellitus (T2DM). Non-persistent environmental pollutants (npEPs) are a group of widely-used chemicals identified as endocrine/metabolic disrupting chemicals and obesogens. The aim of this study was to analyse the potential associations of serum levels of three groups of npEPs with the risk of incident T2DM. METHODS: This is a longitudinal study within a sub-sample of Granada EPIC-Spain cohort (n = 670). We quantified serum concentrations of 7 npEPs: four parabens (Methylparaben (MP) ethylparaben (EP), propylparaben (PP) and butilparaben (BP); two benzophenones: Benzophenone 1 (BP1), Benzophenone 3 (BP3); and Bisphenol A (BPA). Exposure was assessed by means of chemical analyses of serum samples collected at recruitment, and information on potential confounders was gathered by using validated questionnaires at baseline. Follow-up was performed by review of patients' clinical records. Cox Proportional Hazards Models were used for the statistical analyses. RESULTS: Median follow-up time was 23 years. There were 182 (27%) incident T2DM diagnoses in our sub-cohort. MP was the most frequently detected npEP, 88.42% samples above the limit of detection, and BP showed the lowest percentage of detection (19.21%). Those individuals within the fourth PP quartile (0.53-9.24 ng/ml) showed a statistically significant increased risk of T2DM (HR = 1.668 p = 0.012), while BP1 concentrations showed an inverse non-significant trend with the risk. CONCLUSIONS: We evidenced a potential contribution of npEP exposure on T2DM, but no clear trend was observed. However, limitations in relation to exposure estimation might influence our findings and further research is warranted to confirm our results.

Menstrual blood concentrations of parabens and benzophenones and related factors in a sample of Spanish women: An exploratory study.

AIM: To evaluate concentrations of parabens (PBs) and benzophenones (BzPs) in menstrual blood and explore related sociodemographic/lifestyle factors, and to compare between menstrual and peripheral blood concentrations in a subset of samples. MATERIAL AND METHODS: Concentrations of 4 PBs [methyl- (MeP), ethyl- (EtP), propyl- (PrP) and butyl-paraben (BuP)] and 6 BzPs [BzP-1, BzP-2, BzP-3, BzP-6, BzP-8 and 4-OH-BzP] were determined in menstrual blood from 57 women and in both menstrual and peripheral blood samples from 12 women, all healthy Spanish women of reproductive age. Socio-demographic characteristics and lifestyle habits [diet and use of cosmetics and personal care products (PCPs)] were gathered using an online questionnaire. Spearman correlation analysis was performed to examine the relationship between menstrual and peripheral blood concentrations, while multivariable linear regression was used to identify potential explanatory variables for menstrual PB and BzP concentrations. RESULTS: Globally, all menstrual blood samples had detectable levels of ≥3 compounds, and 52.6% of the samples contained ≥6 compounds. MeP, PrP, and BzP-3 were the most frequently detected compounds (detection frequencies >90.0%), with median concentrations of 1.41, 0.63, and 1.70 ng/mL of menstrual blood, respectively. Age, the use of PCPs, and consumption of some food items (meat, pasta, cheese, or dairy products) were related to the menstrual blood concentrations of some PBs/BzPs. Serum:menstrual blood ratios of PBs/BzPs ranged from 1.7 to 3.6, with no inter-matrix correlations. CONCLUSIONS: This study reveals, to our knowledge for the first time, the widespread presence of several PBs and BzPs in intimate contact with gynecological tissues, although their concentrations in menstrual blood were not correlated with those in peripheral blood from the same women. These results shed light on the information provided by the menstrual blood as a potential matrix for characterizing exposure to PBs and BzPs, whose consequences for women's reproductive health need to be addressed.

Environmental phenols and parabens in adipose tissue from hospitalized adults in Southern Spain.

Urinary concentrations of non-persistent environmental pollutants (npEPs) are widely assessed in biomonitoring studies under the assumption that they are metabolised and eliminated in urine. However, some of these chemicals are moderately lipophilic, and their presence in other biological matrices should also be evaluated to estimate mid/long-term exposure to npEPs and its impact on human health. The present study aims to explore concentrations and potential determinants of npEPs in adipose tissue from a hospital-based adult cohort (GraMo cohort, Southern Spain). Concentrations of bisphenol-A (BPA), benzophenone-3 (BP-3), triclosan (TCS), three chlorophenols (2,4-DCP, 2,5-DCP and 2,4,5-TCP) and two phenylphenols (2-PP and 4-PP), triclocarban (TCCB) and parabens [methyl- (MeP), ethyl- (EtP), propyl- (n-PrP and i-PrP), butyl- (n-BuP and i-BuP) and benzyl-paraben (BzP)] were analysed in adipose tissue samples from a subcohort of 144 participants. Spearman correlation tests were performed, followed by stepwise multivariable linear regression analyses to assess determinants of the exposure. Detection frequencies and median concentrations were: BPA (86.8%, 0.54 ng/g tissue), BP-3 (79.2%, 0.60 ng/g tissue), TCS (45.8%,

QuEChERS and ultra-high performance liquid chromatography-tandem mass spectrometry method for the determination of parabens and ultraviolet filters in human milk samples.

Concerns are growing about human exposure to endocrine disrupting chemicals (EDCs), especially during developmental stages. Parabens (PBs) and ultraviolet filters (UVFs) are prevalent EDCs widely used as additives in cosmetics and personal care products (PCPs). The objective of this study was to develop a method to determine four PBs and ten UVFs in human milk using QuEChERS treatment and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Multivariate strategies were applied to optimize experimental parameters. Limits of quantification ranged from 0.1 to 0.2 ng mL-1 and inter-day variability (evaluated as relative standard deviation) from 6% to 13%. The method was validated using matrix-matched standard calibration followed by a recovery assay with spiked samples. Recovery percentages ranged from 87% to 112%. The method was satisfactorily applied to assess target compounds in human milk samples from 15 donors. This analytical procedure can provide information on newborn exposure to these EDCs.

Determination of personal care products -benzophenones and parabens- in human menstrual blood.

Benzophenones and parabens are synthetic chemicals used in many personal care products, foods and pharmaceuticals. Benzophenones are used to protect the skin and materials from the adverse effects of UV-radiation, and parabens are used as preservatives. Despite their widespread occurrence and proven endocrine disrupting activity, relatively little is known about human exposure to these compounds. In the present work, an analytical method based on sample treatment using dispersive liquid-liquid microextraction (DLLME) for the extraction of six benzophenones (benzophenone-1, -2, -3, -6, -8 and 4-hydroxybenzophenone) and four parabens (methyl-, ethyl-, propyl- and butyl- paraben) from human menstrual blood samples, followed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis, is proposed and validated. The method was validated using matrix-matched standard calibration followed by a recovery assay with spiked samples. The limits of detection ranged from 0.1 to 0.3ngmL-1, with recoveries of 93.8% to 108.9%, and precision (evaluated as relative standard deviation) lower than 14% for all selected compounds. This method was successfully applied for the determination of the target compounds in 25 samples of human menstrual blood. Methylparaben and benzophenone-3 were the most frequently detected compounds (96%).

Serum and adipose tissue as matrices for assessment of exposure to persistent organic pollutants in breast cancer patients.

The aim of this study was to assess differences between two biological matrices (serum and breast adipose tissue) in the evaluation of persistent organic pollutant (POP) exposure in breast cancer patients. The study population consisted of 103 women undergoing surgery for newly diagnosed breast carcinoma in a public hospital in Granada, Southern Spain. Independent variables were gathered from questionnaires and clinical records. POP concentrations were quantified in breast adipose tissue and serum samples. Spearman correlation tests were performed between pairs of POP concentrations and stepwise multivariable linear regression analyses were conducted to assess predictors of concentrations in the two matrices. p,p'- Dichlorodiphenyldichloroethylene (p,p'-DDE) showed the the highest median concentration in both matrices (194.34 and 173.84 ng/g lipid in adipose tissue and serum, respectively). Median wet-basis adipose tissue:serum ratios ranged from 109.34 to 651.62, while lipid-basis ratios ranged from 0.88 to 4.34. In general, we found significant positive correlation coefficients between pairs of POPs in adipose tissue and in serum, which were always higher in adipose tissue. We found positive and statistically significant correlations between serum and adipose tissue concentrations of p,p'-DDE and hexachlorobenzene (HCB) but not of polychlorinated biphenyls (PCBs). Age was positively associated with most POPs in adipose tissue and serum, while the body mass index was positively associated with adipose tissue HCB concentrations and negatively associated with serum PCB-153 and PCB-138 concentrations. Recent weight loss was inversely associated with POP residues in adipose tissue and positively associated with POP residues in serum. Serum HCB and PCB-180 concentrations were lower in patients who had received preoperative chemotherapy. According to our results, serum and adipose tissue POP concentrations in breast cancer patients may be differentially affected by external predictors. Taken together, these findings indicate the need to take account of the individual POP(s) under study and the biological matrix used when relating internal POP exposure to breast cancer disease and to make a careful selection of covariates for adjusting the model.