Birth Outcomes in DES Children and Grandchildren: A Multigenerational National Cohort Study on Informative Families.

OBJECTIVE: Diethylstilbestrol (DES), a potent synthetic nonsteroidal estrogen belonging to the family of endocrine disrupting chemicals (EDCs), can cross the placenta and may cause permanent adverse health effects in the exposed mothers, their children (exposed in utero), and also their grandchildren through germline contribution to the zygote. This study evaluated pregnancy duration and birthweight (BW) variations in the children and grandchildren born before, during, and after maternal DES treatment in the same informative families, to rule out genetic, endocrine, and environmental factors. DESIGN AND SETTING: Nationwide retrospective observational study on 529 families of DES-treated women registered at the HHORAGES-France Association. The inclusion criteria were: (i) women with at least three pregnancies and three viable children among whom the first was not exposed in utero to DES, followed by one or more children with fetal exposure to DES, and then by one or more children born after DES treatment; (ii) women with at least one pre-DES or post-DES grandchild and one DES grandchild; (iii) confirmed data on total DES dose. Women with severe pathologies or whose illness status, habitat, lifestyle habits, profession, treatment changed between pregnancies, and all mothers who reported pregnancy-related problems, were excluded. RESULTS: In all, 74 women met all criteria. The preterm birth (PTB) rate was 2.7% in pre-DES, 14.9% in DES, and 10.8% in post-DES children (Cochran-Armitage test for trend, p = 0.0095). The mean BW was higher in DES than pre-DES full-term neonates (≥37 weeks of gestation) (p = 0.007). In grandchildren, BW was not different, whereas the PTB and low BW rates were slightly increased in children of DES women. CONCLUSIONS: These data within the same informative families show the DES impact on BW and PTB in DES and post-DES children and grandchildren. In particular, mean BW was higher in DES than pre-DES full-term neonates. This result may be in opposition to previous data from American cohorts, which reported lower BW in DES children, but is consistent with animal study. Our retrospective observational study highlights a multigenerational and likely transgenerational effect of this EDC in humans.

The Influence of Zearalenone on Selected Hemostatic Parameters in Sexually Immature Gilts.

Vascular toxicity induced by xenobiotics is associated with dysfunctions or damage to endothelial cells, changes in vascular permeability or dysregulation of the vascular redox state. The aim of this study was to determine whether per os administration of zearalenone (ZEN) influences selected hemostatic parameters in prepubertal gilts. This study was performed on female gilts divided into a control group which received placebo and an experimental group which received ZEN at a dose of 5.0 µg·kg-1 b.w. × day-1. On days 14, 28 and 42, blood samples were collected from the animals for analyses of hematological, coagulation and fibrinolysis parameters, nitric oxide, von Willebrand factor antigen content and catalase activity. The results demonstrated that the treatment of gilts with ZEN at a dose below no observable adverse effect level did not affect the primary hemostasis and the blood coagulation cascade. However, ZEN could have temporarily affected the selected indicators of endothelial cell function (increase of von Willebrand factor, decrease of nitric oxide levels) and the oxidative status plasma (decrease of catalase activity) of the exposed gilts. In summary, these results suggest that the adaptive response to ZEN-exposure can induce a transient imbalance in the vascular system by acting on vascular endothelial cells.

The Effects of Zearalenone on the Localization and Expression of Reproductive Hormones in the Ovaries of Weaned Gilts.

This study aims to investigate the effects of zearalenone (ZEA) on the localizations and expressions of follicle stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR), gonadotropin releasing hormone (GnRH) and gonadotropin releasing hormone receptor (GnRHR) in the ovaries of weaned gilts. Twenty 42-day-old weaned gilts were randomly allocated into two groups, and treated with a control diet and a ZEA-contaminated diet (ZEA 1.04 mg/kg), respectively. After 7-day adjustment, gilts were fed individually for 35 days and euthanized for blood and ovarian samples collection before morning feeding on the 36th day. Serum hormones of E2, PRG, FSH, LH and GnRH were determined using radioimmunoassay kits. The ovaries were collected for relative mRNA and protein expression, and immunohistochemical analysis of FSHR, LHR, GnRH and GnRHR. The results revealed that ZEA exposure significantly increased the final vulva area (p < 0.05), significantly elevated the serum concentrations of estradiol, follicle stimulating hormone and GnRH (p < 0.05), and markedly up-regulated the mRNA and protein expressions of FSHR, LHR, GnRH and GnRHR (p < 0.05). Besides, the results of immunohistochemistry showed that the immunoreactive substances of ovarian FSHR, LHR, GnRH and GnRHR in the gilts fed the ZEA-contaminated diet were stronger than the gilts fed the control diet. Our findings indicated that dietary ZEA (1.04 mg/kg) could cause follicular proliferation by interfering with the localization and expression of FSHR, LHR, GnRH and GnRHR, and then affect the follicular development of weaned gilts.

Evidence of intergenerational transmission of diethylstilbestrol health effects: hindsight and insight.

This review summarizes key findings from the US National Cancer Institute (NCI) diethylstilbestrol (DES) Combined Cohort Study with a focus on the results of the NCI Third Generation Study, a cohort of DES-exposed and -unexposed granddaughters. Findings to date from the Third Generation Study are discussed in the context of other research efforts and case reports, suggesting an intergenerational heritability of DES-related effects. The DES story serves as a model for the influence of endocrine disrupting chemicals on human health. It also serves as a warning of the special hazards of pregnancy exposures, and more broadly, of the potential for invisible health consequences arising from new or changing exposures.

Multigenerational endometriosis : consequence of fetal exposure to diethylstilbestrol ?

BACKGROUND: Endometriosis, which affects 10-15 % of women of reproductive age, is an estrogen-driven condition influenced by environmental and genetic factors. Exposition to estrogen-like endocrine-disrupting chemicals (EDCs) has been reported to contribute to the fetal origin of this disease. CASE PRESENTATION: We report here an informative family in which all prenatally DES-exposed daughters and subsequent granddaughters presented endometriosis, whereas the unexposed first daughter and her progeny presented no gynecological disorders. Moreover, the only post-pubertal great-granddaughter, who presents chronic dysmenorrhea that remains resistant to conventional therapy, is at risk of developing endometriosis. The mother (I-2) was prescribed DES (30 mg/day for 3 months) to inhibit lactation after each delivery. CONCLUSIONS: Although a direct causal link between the grandmother's treatment with DES and the development of endometriosis in possibly three exposed generations remains speculative, this report strengthens the suspicion that fetal exposition to DES contributes to the pathogenesis of adult diseases, such as endometriosis. It also highlights a multigenerational and likely transgenerational effect of EDCs.

The heritable legacy of diethylstilbestrol: a bellwether for endocrine disruption in humans.

Millions of women and their fetuses were exposed to the toxic pregnancy drug diethylstilbestrol (DES) from the 1940s into the 1970s, a time when the medical profession had little knowledge about potential developmental consequences of fetal drug exposures. Pathological consequences of DES exposure to the pregnant mothers and their offspring are well documented, but now generational research is finding that the grandchildren of women given DES in pregnancy are also at risk. This commentary summarizes presentations on this subject from the Beyond Genes panel "Heritable Impacts of Diethylstilbestrol (DES)."

The effect of plastic bottled water consumption on outcomes of ICSI cycles undertaken for unexplained infertility.

RESEARCH QUESTION: Do bisphenol A (BPA) levels in maternal urine, serum and follicular fluid affect embryo quality and intracytoplasmic sperm hinjection (ICSI) cycle outcomes in women with unexplained infertility? DESIGN: Prospective study conducted between 1 April 2019 and 30 September 2019. The study cohort consisted of 82 women aged between 23 and 33 years who underwent intracytoplasmic sperm injection owing to unexplained infertility and provided urine, blood and follicular fluid samples on the day of oocyte retrieval. Consumption of drinking water from plastic carboys or bottles at home were considered as chronic BPA exposure. Demographic features and IVF outcomes of the patients were collected. RESULTS: Among the 82 women with unexplained infertility, clinical pregnancy was achieved in 22 (26.8%) patients after the IVF and embryo transfer cycle. The patients who consumed tap water had statistically significantly lower BPA values in three body fluids compared with patients who consumed plastic bottled water (all P < 0.001). Women who had grade 1 embryos transferred had lower serum BPA values than women who had grade 2 embryos transferred (10.8 ± 5.2 versus 26.9 ± 22 ng/ml, P = 0.003). Serum and follicular fluid BPA levels were statistically significantly higher in women who failed to achieve clinical pregnancy (P < 0.001, P = 0.006, respectively) and obtain a live birth (both P = 0.007). CONCLUSIONS: A negative relationship was found between serum and follicular fluid BPA levels and embryo quality, clinical pregnancy and live birth in these women. In addition, the BPA levels of women who consume tap water at home were lower than those who use plastic bottled water.

Obesity alters the ovarian proteomic response to zearalenone exposure†.

Zearalenone (ZEN), a nonsteroidal estrogenic mycotoxin, is detrimental to female reproduction. Altered chemical biotransformation, depleted primordial follicles and a blunted genotoxicant response have been discovered in obese female ovaries, thus, this study investigated the hypothesis that obesity would enhance ovarian sensitivity to ZEN exposure. Seven-week-old female wild-type nonagouti KK.Cg-a/a mice (lean) and agouti lethal yellow KK.Cg-Ay/J mice (obese) received food and water ad libitum, and either saline or ZEN (40 µg/kg) per os for 15 days. Body and organ weights, and estrous cyclicity were recorded, and ovaries collected posteuthanasia for protein analysis. Body and liver weights were increased (P < 0.05) in the obese mice, but obesity did not affect (P > 0.05) heart, kidney, spleen, uterus, or ovary weight and there was no impact (P > 0.05) of ZEN exposure on body or organ weight in lean or obese mice. Obese mice had shorter proestrus (P < 0.05) and a tendency (P = 0.055) for longer metestrus/diestrus. ZEN exposure in obese mice increased estrus but shortened metestrus/diestrus length. Neither obesity nor ZEN exposure impacted (P > 0.05) circulating progesterone, or ovarian abundance of EPHX1, GSTP1, CYP2E1, ATM, BRCA1, DNMT1, HDAC1, H4K16ac, or H3K9me3. Lean mice exposed to ZEN had a minor increase in γH2AX abundance (P < 0.05). In lean and obese mice, LC-MS/MS identified alterations to proteins involved in chemical metabolism, DNA repair and reproduction. These data identify ZEN-induced adverse ovarian modes of action and suggest that obesity is additive to ZEN-induced ovotoxicity.

Bisphenol A at a human exposed level can promote epithelial-mesenchymal transition in papillary thyroid carcinoma harbouring BRAFV600E mutation.

Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, alters the function of endocrine system and enhances the susceptibility to tumorigenesis in several hormone-dependent tumours as thyroid carcinoma. About 50% of papillary thyroid cancers (PTC), the most common type of thyroid malignancy, harbours the BRAFV600E mutation. This study aimed to investigate a potential combined effect of BPA exposure and BRAFV600E mutation on epithelial-mesenchymal transition (EMT) in PTC. Firstly, the level of BPA in plasma, the evaluation of BRAFV600E mutation and the level of EMT-related proteins in PTC samples were individually determined. Additionally, the migration, invasion, colony formation capacity and the expression of EMT-related proteins after exposure to BPA were precisely analysed in vitro thyroid cells genetically modified by the introduction of BRAFV600E mutation. Moreover, ERK-Cox2 signalling pathway was also introduced to explore the possible mechanism in PTC development. As expected, whether the clinical investigation or cultured thyroid cells demonstrated that BPA at a concentration compatible with human exposed levels (10-7  M) synergized with the BRAFV600E mutation promoted EMT via the activation of ERK-Cox2 signalling pathway. Our findings offer some evidence that BPA as an environmental risk factor can facilitate the progression of PTC harbouring BRAFV600E mutation.

Prenatal diethylstilbestrol exposure and risk of diabetes, gallbladder disease, and pancreatic disorders and malignancies.

Prenatal diethylstilbestrol (DES) exposure is associated with increased risk of hormonally mediated cancers and other medical conditions. We evaluated the association between DES and risk of pancreatic cancer and pancreatic disorders, type 2 diabetes, and gallbladder disease, which may be involved with this malignancy. Our analyses used follow-up data from the US National Cancer Institute DES Combined Cohort Study. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age, sex, cohort, body mass index, smoking, and alcohol for the association between prenatal DES exposure and type 2 diabetes, gallbladder disease (mainly cholelithiasis), pancreatic disorders (mainly pancreatitis), and pancreatic cancer among 5667 exposed and 3315 unexposed individuals followed from 1990 to 2017. Standardized incidence rate (SIR) ratios for pancreatic cancer were based on age-, race-, and calendar year-specific general population cancer incidence rates. In women and men combined, the hazards for total pancreatic disorders and pancreatitis were greater in the prenatally DES exposed than the unexposed (HR = 11, 95% CI 2.6-51 and HR = 7.0, 95% CI 1.5-33, respectively). DES was not associated overall with gallbladder disease (HR = 1.2, 95% CI 0.88-1.5) or diabetes (HR = 1.1, 95% CI 0.9-1.2). In women, but not in men, DES exposure was associated with increased risk of pancreatic cancer compared with the unexposed (HR: 4.1, 95% CI 0.84-20) or general population (SIR: 1.9, 95% CI 1.0-3.2). Prenatal DES exposure may increase the risk of pancreatic disorders, including pancreatitis in women and men. The data suggested elevated pancreatic cancer risk in DES-exposed women, but not in exposed men.

SIX1 cooperates with RUNX1 and SMAD4 in cell fate commitment of Müllerian duct epithelium.

During female mammal reproductive tract development, epithelial cells of the lower Müllerian duct are committed to become stratified squamous epithelium of the vagina and ectocervix, when the expression of ΔNp63 transcription factor is induced by mesenchymal cells. The absence of ΔNp63 expression leads to adenosis, the putative precursor of vaginal adenocarcinoma. Our previous studies with genetically engineered mouse models have established that fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), bone morphogenetic protein (BMP)/SMAD, and activin A/runt-related transcription factor 1 (RUNX1) signaling pathways are independently required for ΔNp63 expression in Müllerian duct epithelium (MDE). Here, we report that sine oculis homeobox homolog 1 (SIX1) plays a critical role in the activation of ΔNp63 locus in MDE as a downstream transcription factor of mesenchymal signals. In the developing mouse reproductive tract, SIX1 expression was restricted to MDE within the future cervix and vagina. SIX1 expression was totally absent in SMAD4 null MDE and was reduced in RUNX1 null and FGFR2 null MDE, indicating that SIX1 is under the control of vaginal mesenchymal factors: BMP4, activin A and FGF7/10. Furthermore, Six1, Runx1, and Smad4 gene-dose-dependently activated ΔNp63 expression in MDE within the vaginal fornix. Using a mouse model of diethylstilbestrol (DES)-associated vaginal adenosis, we found DES action through epithelial estrogen receptor α (ESR1) inhibits activation of ΔNp63 locus in MDE by transcriptionally repressing SIX1 and RUNX1 in the vaginal fornix.

Effects of Prenatal Exposure to a Low-Dose of Bisphenol A on Sex Differences in Emotional Behavior and Central Alpha2-Adrenergic Receptor Binding.

Prenatal exposure to bisphenol A (BPA) influences the development of sex differences neurologically and behaviorally across many species of vertebrates. These effects are a consequence of BPA's estrogenic activity and its ability to act as an endocrine disrupter even, at very low doses. When exposure to BPA occurs during critical periods of development, it can interfere with the normal activity of sex steroids, impacting the fate of neurons, neural connectivity and the development of brain regions sensitive to steroid activity. Among the most sensitive behavioral targets of BPA action are behaviors that are characterized by a sexual dimorphism, especially emotion and anxiety related behaviors, such as the amount of time spent investigating a novel environment, locomotive activity and arousal. Moreover, in some species of rodents, BPA exposure affected males' sexual behaviors. Interestingly, these behaviors are at least in part modulated by the catecholaminergic system, which has been reported to be a target of BPA action. In the present study we investigated the influence of prenatal exposure of mice to a very low single dose of BPA on emotional and sexual behaviors and on the density and binding characteristics of alpha2 adrenergic receptors. Alpha2 adrenergic receptors are widespread in the central nervous system and they can act as autoreceptors, inhibiting the release of noradrenaline and other neurotransmitters from presynaptic terminals. BPA exposure disrupted sex differences in behavioral responses to a novel environment, but did not affect male mice sexual behavior. Importantly, BPA exposure caused a change in the binding affinity of alpha2 adrenergic receptors in the locus coeruleus and medial preoptic area (mPOA) and it eliminated the sexual dimorphism in the density of the receptors in the mPOA.

Effect of bisphenol-A (BPA) on placental biomarkers for inflammation, neurodevelopment and oxidative stress.

Background Bisphenol-A (BPA) is a widespread pollutant whose effects on pregnant women are poorly understood. Therefore, we investigated the effects of BPA on basal and bacteria-stimulated production of proinflammatory cytokines [interleukin (IL)-1ß, tumor necrosis factor-α (TNF-α) and IL-6], anti-inflammatory mediators [soluble glycoprotein 130 (sgp) 130, heme oxidase-1 (HO-1) and IL-10] and biomarkers for neurodevelopment [brain-derived neurotrophic factor (BDNF)], and oxidative stress [8-isoprostane (8-IsoP)] by the placenta. Methods Placental explant cultures were treated with BPA (0-10,000 nM) in the presence or absence of 107 colony-forming unit (CFU)/mL heat-killed Escherichia coli for 24 h. Biomarker concentrations in conditioned medium were quantified by the enzyme-linked immunosorbent assay (ELISA). Results Under basal conditions, IL-1ß and IL-6 production was enhanced by BPA in a dose-dependent manner. Sgp130, a soluble receptor that reduces IL-6 bioactivity, was suppressed by BPA at 1000-10,000 nM. BPA also enhanced BDNF production at 1000 and 10,000 nM, and 8-IsoP expression at 10 and 100 nM. For bacteria-treated cultures, BPA increased IL-6 production at 100 nM and reduced sgp130 at 1000 nM but had no effect on IL-1ß, TNF-α, BDNF, HO-1, 8-IsoP or IL-10 production. Conclusion BPA may increase placental inflammation by promoting IL-1ß and IL-6 but inhibiting sgp130. It may also disrupt oxidative balance and neurodevelopment by increasing 8-IsoP and BDNF production.

Simultaneous analysis of bisphenol A fractions in maternal and fetal compartments in early second trimester of pregnancy.

Background Bisphenol A (BPA) is an estrogenic, endocrine-disrupting compound widely used in the industry. It is also a ubiquitous environmental pollutant. Its presence was confirmed in human fetuses, which results from maternal exposure during pregnancy. The mechanisms behind maternal-fetal transfer, and relationships between pregnant women and fetal exposures remain unclear. The aim of this study was to assess the impact of maternal exposure to BPA on the exposure of the fetus. Methods Maternal plasma and amniotic fluid samples were collected from 52 pregnant women undergoing amniocentesis for prenatal diagnosis of chromosomal abnormalities. BPA was measured by gas chromatography-mass spectrometry (GC-MS). The permeability factor - a ratio of fetal-to-maternal BPA concentration - was used as a measure delineating the transplacental transfer of BPA. Results The median concentration of maternal plasma BPA was 8 times higher than the total BPA concentration in the amniotic fluid (8.69 ng/mL, range: 4.3 ng/mL-55.3 ng/mL vs. median 1.03 ng/mL, range: 0.3 ng/mL-10.1 ng/mL). There was no direct relationship between the levels of BPA in maternal plasma and amniotic fluid levels. The permeability factor, in turn, negatively correlated with fetal development (birth weight) (R = -0.54, P < 0.001). Conclusion Our results suggest that the risk of fetal BPA exposure depends on placental BPA permeability rather than the levels of maternal BPA plasma concentration and support general recommendations to become aware and avoid BPA-containing products.

The protective effects of modified palygorskite on the broilers fed a purified zearalenone-contaminated diet.

This study was conducted to evaluate the protective effects of dietary modified palygorskite (Pal) supplementation on broiler chickens fed a purified zearalenone (ZEN)-contaminated diet. A total of 144 1-day-old male chicks were allocated to one of the 3 treatments, with each treatment being composed of 6 replicates of 8 birds each. The birds were fed with a control diet (Control group), the ZEN-contaminated diet (2.0 mg ZEN/kg diet), and the ZEN-contaminated diet supplemented with 1.0 g/kg diet of modified Pal for 42 d, respectively. Compared with control group, feeding ZEN-contaminated diet reduced weight gain and feed conversion efficiency of broilers during the finisher and overall experimental period (P < 0.05), while the values of these parameters in broilers fed the diet contaminated with ZEN increased after modified Pal administration (P < 0.05). ZEN challenge increased the 21-d serum aspartate aminotransferase and 42-d serum alanine aminotransferase activities, 42-d relative liver weight, and ZEN residues in the liver at both 21 and 42 d and kidney at 42 d (P < 0.05). In contrast, birds fed the ZEN-contaminated diet that was supplemented with modified Pal exhibited lower serum alanine aminotransferase activity at 42 d, relative liver weight at 42 d, and hepatic and renal ZEN accumulation at both 21 and 42 d (P < 0.05), when compared with their counterparts fed the contaminated diet. ZEN contamination decreased superoxide dismutase activity in the serum at 21 d, kidney at 42 d, and liver at both 21 and 42 d, respectively (P < 0.05). The hepatic and renal malondialdehyde accumulation at 42 d increased, while renal glutathione level at 42 d decreased, when feeding broilers with the ZEN-contaminated diet (P < 0.05). Dietary modified Pal supplementation reduced hepatic malondialdehyde accumulation, whereas increased renal superoxide dismutase activity in broilers fed a ZEN-contaminated diet at 42 d (P < 0.05). This finding suggested that dietary modified Pal administration could promote growth performance, reduce hepatonephric ZEN residues, and improve liver function and antioxidant status of broiler chickens receiving a ZEN-contaminated diet.

Pregnancy drugs, fetal germline epigenome, and risks for next-generation pathology: A call to action.

Drugs taken during pregnancy can affect three generations at once: the gestating woman (F0), her exposed fetus (F1), and the fetal germ cells that confer heritable information for the grandchildren (F2). Unfortunately, despite growing evidence for connections between F0 drug exposures and F2 pathology, current approaches to risk assessment overlook this important dimension of risk. In this commentary, we argue that the unique molecular vulnerabilities of the fetal germline, particularly with regard to global epigenomic reprogramming, combined with empirical evidence for F2 effects of F1 in utero drug and other exposures, should change the way we consider potential long-term consequences of pregnancy drugs and alter toxicology's standard somatic paradigm. Specifically, we (1) suggest that pregnancy drugs common in the postwar decades should be investigated as potential contributors to the "missing heritability" of many pathologies now surging in prevalence; (2) call for inclusion of fetal germline risks in pregnancy drug safety assessment; and (3) highlight the need for intensified research to ascertain generational impacts of diethylstilbestrol, a vanguard question of human germline toxicity. Only by fully addressing this important dimension of transplacental exposure can we responsibly evaluate safety of drug exposures during pregnancy and convey the full scope of risks, while also retrospectively comprehending the generational legacy of recent history's unprecedented glut of evolutionarily novel intrauterine exposures. Environ. Mol. Mutagen. 60:445-454, 2019. © 2019 Wiley Periodicals, Inc.

Association of Bisphenol A and Its Substitutes, Bisphenol F and Bisphenol S, with Obesity in United States Children and Adolescents.

BACKGROUND: Bisphenol F (BPF) and bisphenol S (BPS) are increasingly used as substitutes for bisphenol A (BPA), an environmental obesogen. However, health effects of BPF and BPS remain unclear. In this study, we evaluated the associations of BPA, BPF, and BPS with obesity in children and adolescents. METHODS: We used data from the U.S. National Health and Nutrition Examination Survey 2013 to 2014, a nationally representative study. We included 745 participants aged 6 to 17 years old. General obesity was defined based on the 2000 Centers for Disease Control and Prevention body mass index-for-age growth charts for the United States. Abdominal obesity was defined as waist-to-height ratio ≥0.5. RESULTS: After adjustment for demographic, socioeconomic and lifestyle factors, and urinary creatinine levels, the odds ratio of general obesity comparing the highest with lowest quartile of urinary bisphenol levels was 1.74 (95% confidence interval [CI], 0.92 to 3.31) for BPA, 1.54 (95% CI, 1.02 to 2.32) for BPF, and 1.36 (95% CI, 0.53 to 3.51) for BPS. Moreover, the associations were stronger in boys than in girls for BPA and BPF. Similar results were observed for abdominal obesity. CONCLUSION: This study for the first time showed that exposure to BPF, a commonly used substitute for BPA, was positively associated with higher risk of obesity in children and adolescents. The association of BPA and BPF with general and abdominal obesity was primarily observed in boys, suggesting a possible sex difference. Further investigations on the underlying mechanisms are needed.

MECHANISMS IN ENDOCRINOLOGY: Estrogens in consumer milk: is there a risk to human reproductive health?

Possible effects of xenoestrogens on human health, in particular on male reproductive health, have attracted considerable attention in recent years. Cow's milk was suggested in numerous publications as one of possible sources of xenoestrogens that could affect human health. Although milk has undoubtedly many beneficial health effects and could even have a role in reducing incidence of some cancers, concerns were raised about presumably high levels of estrogens in cow's milk. In intensive farming, concentrations of estrogens in milk are higher due to long milking periods that today extend long into the pregnancy, when concentrations of estrogens in the cow's body rise. Numerous studies examined potential effects of milk on reproductive health and endocrine-related cancers in both experimental studies with laboratory animals, and in human epidemiological studies. In the present review article, we compiled a review of recently published literature about the content of estrogens in cow's milk and potential health effects, in particular on reproductive system, in humans. Although results of published studies are not unequivocal, it seems that there is stronger evidence suggesting that amounts of estrogens in cow's milk are too low to cause health effects in humans.

Bisphenol A exposure and type 2 diabetes mellitus risk: a meta-analysis.

BACKGROUND: This meta-analytic study explored the relationship between the risk of type 2 diabetes mellitus (T2DM) and bisphenol A concentrations. METHODS: The Embase and Medline (PubMed) databases were searched, using relevant keywords, for studies published between 1980 and 2018. A total of 16 studies, twelve cross-sectional, two case-control and one prospective, were included in the meta-analysis. The odds ratio (OR) and its 95% confidence interval (CI) were determined across the sixteen studies. The OR and its 95% CI of diabetes associated with bisphenol A were estimated using both fixed-effects and random-effects models. RESULTS: A total of 41,320 subjects were included. Fourteen of the sixteen studies included in the analysis provided measurements of urine bisphenol A levels and two study provided serum bisphenol A levels. Bisphenol A concentrations in human bio-specimens showed positive associations with T2DM risk (OR 1.28, 95% CI 1.14, 1.44). A sensitivity analysis indicated that urine bisphenol A concentrations were positively associated with T2DM risk (OR 1.20, 95% CI 1.09, 1.31). CONCLUSIONS: This meta-analysis indicated that Bisphenol A exposure is positively associated with T2DM risk in humans.