There is evidence from longitudinal studies that being light at birth and weaning is associated with subsequent rapid weight gain in infants. This is referred to as "centile crossing", which can lead to increased risk of lifetime obesity, glucose dysregulation and type 2 diabetes. Here, pregnant CD-1 mice were hemi-ovariectomized so that the entire litter was contained in one uterine horn to increase variability in fetal growth rate. Pregnant females were implanted on gestation day (GD) 9 with a Silastic capsule containing 6, 60 or 600 μg bisphenol A (BPA). On GD 18 the mean fetal serum unconjugated BPA concentrations were 17, 177 and 1858 pg/ml, respectively. Capsules were not removed, to avoid maternal stress, and were predicted to release BPA for at least 3 weeks. Body weight at weaning was strongly negatively correlated with post-weaning weight gain in both control and BPA-treated male mice, consistent with human data; female offspring were excluded, avoiding complications associated with postpubertal estrogens. Within each treatment group, male offspring were sorted into tertiles based on relative weight gain during the two weeks after weaning, designated as having Rapid (R), Medium (M) or Slow (S) growth rate. BPA exposure was associated with altered growth rate between weaning and postnatal week 12 (young adulthood), when a low-dose (20 mg/kg, i.p.) glucose tolerance test (GTT) was performed. We found altered glucose regulation in response to all doses of BPA. However, glucose tolerance was only significantly impaired (blood glucose levels were elevated) compared to controls in males in the rapid post-weaning growth group exposed perinatally to BPA. We conclude that male mice that are light at weaning, but then experience rapid catch-up growth immediately after weaning, represent a sensitive sub-population that is vulnerable to the metabolic disrupting effects of very low pg/ml fetal serum concentrations of BPA.

Evaluating the biological significance of human-relevant exposures to environmental estrogens involves assessing the individual and total estrogenicity of endogenous and exogenous estrogens found in serum, for example from biomonitoring studies. We developed a method for this assessment by integrating approaches for (i) measuring total hormone concentrations by mass spectrometry (Fleck et al., 2017), (ii) calculating hormone bioavailable concentrations in serum and, (iii) solving multiple equilibria between estrogenic ligands and receptors, and (iv) quantitatively describing key elements of estrogen potency. The approach was applied to endogenous (E1, E2, E3, E4), environmental (BPA), and dietary (Genistein (GEN), Daidzein (DDZ) estrogens measured in the serum of thirty pregnant women. Fractional receptor occupancy (FRO) based estrogenicity was dominated by E1, E2 and E3 (ER-α, 94.4-99.2% (median: 97.3%), ER-β, 82.7-97.7% (median: 92.8%), as was the total response (TR), which included ligand specific differences in recruitment of co-activator proteins (RCA). The median FRO for BPA was at least five orders of magnitude lower than E1, E2 and E3, and three orders of magnitude lower than the fetal derived E4 and GEN and DDZ. BPA contributed less than 1/1000th of the normal daily variability in total serum estrogenicity in this cohort of pregnant women.

In breast cancer cells, some topologically associating domains (TADs) behave as hormonal gene regulation units, within which gene transcription is coordinately regulated in response to steroid hormones. Here we further describe that responsive TADs contain 20- to 100-kb-long clusters of intermingled estrogen receptor (ESR1) and progesterone receptor (PGR) binding sites, hereafter called hormone-control regions (HCRs). In T47D cells, we identified more than 200 HCRs, which are frequently bound by unliganded ESR1 and PGR. These HCRs establish steady long-distance inter-TAD interactions between them and organize characteristic looping structures with promoters in their TADs even in the absence of hormones in ESR1+-PGR+ cells. This organization is dependent on the expression of the receptors and is further dynamically modulated in response to steroid hormones. HCRs function as platforms that integrate different signals, resulting in some cases in opposite transcriptional responses to estrogens or progestins. Altogether, these results suggest that steroid hormone receptors act not only as hormone-regulated sequence-specific transcription factors but also as local and global genome organizers.

Epidemiological studies demonstrate disparities between men and women in cardiovascular disease prevalence, clinical symptoms, treatments, and outcomes. Enrollment of women in clinical trials is lower than men, and experimental studies investigating molecular mechanisms and efficacy of certain therapeutics in cardiovascular disease have been primarily conducted in male animals. These practices bias data interpretation and limit the implication of research findings in female clinical populations. This review will focus on the biological origins of sex differences in cardiovascular physiology, health, and disease, with an emphasis on the sex hormones, estrogen and testosterone. First, we will briefly discuss epidemiological evidence of sex disparities in cardiovascular disease prevalence and clinical manifestation. Second, we will describe studies suggesting sexual dimorphism in normal cardiovascular function from fetal life to older age. Third, we will summarize and critically discuss the current literature regarding the molecular mechanisms underlying the effects of estrogens and androgens on cardiac and vascular physiology and the contribution of these hormones to sex differences in cardiovascular disease. Fourth, we will present cardiovascular disease risk factors that are positively associated with the female sex, and thus, contributing to increased cardiovascular risk in women. We conclude that inclusion of both men and women in the investigation of the role of estrogens and androgens in cardiovascular physiology will advance our understanding of the mechanisms underlying sex differences in cardiovascular disease. In addition, investigating the role of sex-specific factors in the development of cardiovascular disease will reduce sex and gender disparities in the treatment and diagnosis of cardiovascular disease. © 2019 American Physiological Society. Compr Physiol 9:375-411, 2019.

Estrogens generated within endocrine organs and the reproductive system act as ligands for at least three types of estrogen receptors. Estrogen receptors α (ERα) and β (ERβ) belong to the so-called classical family of estrogen receptors, whereas the G protein-coupled receptor GPR30, also known as GPER-1, has been described as a novel estrogen receptor sited in the cell membrane of target cells. Furthermore, these receptors are under stimulation of a family of exogenous estrogens, known as phytoestrogens, which are a diverse group of non-steroidal plant compounds derived from plant food consumed by humans and animals. Because phytoestrogens are omnipresent in our daily diet, they are becoming increasingly important in both human health and disease. Recent evidence indicates that in addition to classical estrogen receptors, phytoestrogens also activate GPER-1 a relevant observation since GPER-1 is involved in several physiopathological disorders and especially in estrogen-dependent diseases such as breast cancer.The first estrogen receptors discovered were the classical ERα and ERβ, but from an evolutionary point of view G protein-coupled receptors trace their origins in history to over a billion years ago suggesting that estrogen receptors like GPER-1 may have been the targets of choice for ancient phytoestrogens and/or estrogens.This review provides a comprehensive and systematic literature search on phytoestrogens and its relationship with classical estrogen receptors and GPER-1 including its role in breast cancer, an issue still under discussion.

The widespread use of the synthetic estrogen 17 α-ethinylestradiol (EE2) has resulted in elevated levels in aquatic environments, where it is known to act as an endocrine disrupting chemical affecting fish and other aquatic organisms. Examining changes in the structure of the fish' gonads and liver has proven to be an effective approach for assessing these impacts. While changes have been reported for various fish species, it is not clear whether impacts are equally severe in live-bearing fishes. The present study looked at gonadal and liver development in EE2-exposed least killifish (Heterandria formosa), a live-bearing Poeciliid. Exposures to 0, 5, or 25 ng/L EE2 began within six days of birth and continued until fish became sexually mature 12-23 weeks later. Exposure to 5 ng/L EE2 resulted in severe intersex in fish with external male characteristics, a slowdown of spermatogenesis in these intersex fish and a slowdown of oogenesis in the female fish. Moreover, these fish had a variety of liver injuries. Fish exposed to 25 ng/L EE2 exhibited intersex but at a lower frequency than occurred at 5 ng/L. In contrast, liver damage and slowdown of both oogenesis and spermatogenesis exhibited the typical dose-dependence. These findings illustrate the importance of including histological analyses when assessing endocrine disruption in fish, demonstrate that the live-bearing mode of reproduction appears to provide limited protection from the effects of waterborne EE2, and provide further evidence that EE2 has multiple impacts on fish health and reproduction that are severe enough to potentially affect fish populations.

Co-existence of cyanobacterial harmful algal blooms (CyanoHABs) and steroid estrogens (SEs) has been an increasing concern in eutrophic waters. The cellular responses and biodegradation of 17β-estradiol (E2) in cyanobacterium Microcystis aeruginosa were investigated at different nitrogen levels. During the 10-d experiment, the growth of M. aeruginosa was stimulated by 10-100 μg L-1 of E2 at the lowest nitrogen level of 0.5 mg L-1, whereas the presence of E2 inhibited the cyanobacterial growth at 5 mg L-1 of nitrogen. With nitrogen concentration increased to 50 mg L-1, the impact of E2 on levels of growth rate and chlorophyll a (Chla) alleviated. Exposure to E2 also promoted the superoxide dismutase activity of M. aeruginosa, coupled with cellular oxidative damage as indicated by the increasing malondialdehyde content. A sufficient nitrogen supply mitigated the oxidative stress of E2 through enhancing the synthesis of detoxification-related enzymes. Simultaneously, the secretion of tryptophan-like substances in loosely- and tightly-bound extracellular polymeric substances was triggered for adapting to an E2 addition in the short term. Moreover, significant biodegradation of E2 was observed, and the process followed a first-order kinetic reaction. The obtained half-lives decreased with nitrogen levels and ranged from 2.47 to 2.81 and 3.39-5.04 d, respectively, at 10 and 100 μg L-1 of E2. These results provide a better understanding of the potential effects of SEs on CyanoHABs formation, as well as the important role of CyanoHABs on SEs removal in aquatic ecosystems, which should be fully considered in the control of combined pollution.

Breast and thyroid cancers are two malignancies with highest incidence in women. These cancers often occur metachronously. Women with thyroid cancer are at increased risk for subsequent breast cancer; women with breast cancer have an increased incidence of later development of thyroid cancer suggesting a common etiology. This bidirectional relationship is reported worldwide, however the underlying reasons for this co-occurrence is unknown. In this review, we summarize the current epidemiological evidence and putative mechanisms of these metachronous or synchronous cancers. Key potential causative factors are chemotherapy and radiotherapy of the primary tumor, genetic variants linking the two diseases, hormonal signaling both from the thyroid gland and from estrogens, lifestyle and environmental factors. There is a critical need for additional epidemiological studies focused on gender and regional incidence together with molecular investigations on common tumorigenic pathways in these endocrine cancers. Understanding the putative mechanisms will aid in the diagnosis and clinical management of both diseases.

The reasons for the higher severity of type 2 diabetes (T2DM)-associated cardiomyopathy in women, despite their inherent estrogen (E2)-dependent cardioprotection, remain unknown. We hypothesized that the reliance of the healthy females' hearts on augmented adiponectin (APN)-connexin43 (Cx43) signaling becomes paradoxically detrimental when disrupted by T2DM in an E2-dependent manner. We tested this hypothesis in high fat-low dose streptozotocin diabetic rats and their controls with the following designations: (a) sham operated (SO); (b) ovariectomized (OVX); (c) ovariectomized with E2 supplementation (OVX+E2); and (d) male. E2-replete (SO or OVX+E2) diabetic rats exhibited higher mortality and greater increases in left ventricular (LV) mass, and reduced LV developed pressure, LV contractility and fractional shortening, but preserved ejection fraction. Further, compared to respective nondiabetic counterparts, the hearts of these E2-replete diabetic rats exhibited greater upregulation of cardiac estrogen receptor α (ERα) and reductions in Cx43 expression and in the phosphorylation levels of the survival molecules pERK1/2 and pAKT. While serum APN was reduced independent of sex and ovarian hormone status in all DM, cardiac APN was most drastically reduced in DM SO rats. The present translational findings are the first to implicate ovarian hormones/E2 in the exacerbated myocardial dysfunction in diabetic females, and to suggest a pivotal role for malfunctioning cardiac APN-Cx43 signaling in this sex/E2-specific clinical problem.