The present study aims to analyze the effects of developmental exposure to phthalates at environmentally relevant doses on the neural control of male and female reproduction. For this purpose, C57Bl/6J mice were exposed to di-(2-ethylexyl) phthalate (DEHP) alone (5 or 50 μg/kg/d), or DEHP (5 μg/kg/d) in a phthalate mixture. Exposure through diet started 6 weeks before the first mating and lasted until weaning of litters from the second gestation (multiparous dams). Analyses of offspring born from multiparous dams exposed to DEHP alone or in a phthalate mixture showed that females experienced a delayed pubertal onset, and as adults they had prolonged estrous cyclicity and reduced Kiss1 expression in the preoptic area and mediobasal hypothalamus. Male littermates showed a reduced anogenital distance and delayed pubertal onset compared with controls. However, in adulthood the weight of androgen-sensitive organs and hypothalamic Kiss1 expression were unaffected, suggesting normal functioning of the male gonadotropic axis. Developmental exposure to DEHP alone or in a phthalate mixture reduced the ability of intact males and ovariectomized and hormonally primed females to attract a sexual partner and to express copulatory behaviors. In addition, females were unable to discriminate between male and female stimuli in the olfactory preference test. Social interaction was also impaired in females, while locomotor activity and anxiety-like behavior in both sexes were unaffected by the treatment. The sexual deficiencies were associated with reduced expression of the androgen receptor in the preoptic area and progesterone receptor in the mediobasal hypothalamus, the key regions involved in male and female sexual behavior, respectively. Thus, the neural structures controlling reproduction are vulnerable to developmental exposure to phthalates at environmentally relevant doses in male and female mice. Adult females had an impaired gonadotropic axis and showed more affected behaviors than adult males.

Anxiety disorders are one of the most prevalent mood disorders that can lead to impaired quality of life. Current treatment of anxiety disorders has various adverse effects, safety concerns, or restricted efficacy; therefore, novel therapeutic targets need to be studied. Sex steroid hormones (SSHs) play a crucial role in the formation of brain structures, including regions of the limbic system and prefrontal cortex during perinatal development. In the brain, SSHs have activational and organizational effects mediated by either intracellular or transmembrane G-protein coupled receptors. During perinatal developmental periods, the physiological concentrations of SSHs lead to the normal development of the brain; however, the early hormonal dysregulation could result in various anxiety diorders later in life. Sex differences in the prevalence of anxiety disorders suggest that SSHs might be implicated in their development. In this review, we discuss preclinical and clinical studies regarding the role of dysregulated SSHs signaling during early brain development that modifies the risk for anxiety disorders in a sex-specific manner in adulthood. Moreover, our aim is to summarize potential molecular mechanisms by which the SSHs may affect anxiety disorders in preclinical research. Finally, the potential effects of SSHs in the treatment of anxiety disorders are discussed.

暂无摘要。

Japanese quail (Coturnix japonica) is an avian model used to evaluate the reproductive and developmental toxicity of chemicals. The National Institute for Environmental Studies (NIES) of Japan established a strain of Japanese quail, NIES-L, which may be a better model because of its highly inbred characteristics. To understand sexual differentiation of the reproductive organs and the value of using NIES-L quails for avian toxicity assessment, we profiled estradiol and androgen plasma levels by enzyme-linked immunosorbent assay; the mRNA levels of estrogen receptor-α (ERα), ERβ, and androgen receptor (AR) in the gonads, Müllerian ducts, Wolffian ducts; and the mRNA levels of steroidogenic enzymes, cholesterol side chain cleavage enzyme (P450scc), 17α-hydroxylase/C17-20 lyase (P45017α, lyase), 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD), and aromatase (P450arom), anti-Müllerian hormone (AMH), and AMH receptor type 2 (AMHR2) in the gonads of NIES-L Japanese quails on embryonic days 9, 12, and 15 using a real-time quantitative PCR method. The plasma estradiol concentration was higher in females than males on these embryonic days, but no sex difference was found in the plasma androgens. The mRNA levels of all examined steroidogenic enzymes were significantly higher in female than male embryos. In particular, the P450arom mRNA levels showed a striking sex difference: P450arom was expressed in female but not male gonads. In contrast, the AMH and AMHR2 mRNA levels in the gonads were higher in males than females. The ERα, ERβ, and AR mRNA levels increased in the left female gonad and peaked on embryonic day 15, but not in the left and right male gonads; therefore, there was a female-biased sex difference. The ERα, ERβ, and AR mRNA levels in the left Müllerian duct, but not in the right Müllerian duct, of females increased and peaked on embryonic day 15, which resulted in asymmetric mRNA levels. The Wolffian ducts expressed ERα, ERβ, and AR in both sexes, and no sex difference or asymmetry of mRNA levels was found. The information obtained from this study helps elucidate the molecular endocrinological basis of sexual dimorphism formation of reproductive organs and clarify the value of NIES-L quails for toxicity assessment.

Sex-steroid receptors (SSRs) are essential mediators of estrogen, progestin, and androgen signaling that are critical in vast aspects of human development and multi-organ homeostasis. Dysregulation of SSR function has been implicated in numerous pathologies including cancers, obesity, Type II diabetes mellitus, neuroendocrine disorders, cardiovascular disease, hyperlipidemia, male and female infertility, and other reproductive disorders. Endocrine disrupting chemicals (EDCs) modulate SSR function in a wide variety of cell and tissues. There exists strong experimental, clinical, and epidemiological evidence that engagement of EDCs with SSRs may disrupt endogenous hormone signaling leading to physiological abnormalities that may manifest in disease. In this chapter, we discuss the molecular mechanisms by which EDCs interact with estrogen, progestin, and androgen receptors and alter SSR functions in target cells. In addition, the pathological consequences of disruption of SSR action in reproductive and other organs by EDCs is described with an emphasis on underlying mechanisms of receptors dysfunction.

In a large part of the population inefficient ingestion of proteins, whether for cultural, aesthetic or economic reasons, is a global concern. Low-protein diets can cause severe functional complications, mainly during the development and maturation of organs and systems, including the female reproductive system. The present study investigated the effect of nutritional protein restriction during puberty on the oestrous cycle and expression of sex steroid receptors (AR, ERα e ERβ) in ovarian and uterine tissues of adult rats. Protein restriction promoted lower body weight gain, feed efficiency and higher caloric intake. There was an increase in the oestrus phase arrest without changing the total length of the oestrous cycle. The consumption of low-protein diet also reduced the thickness of the uterine endometrium (uterine epithelium and endometrial stroma) in addition to increasing the number of primary and atretic follicles in the ovaries. Furthermore, the low-protein diet reduced the levels of androgen receptor (AR) and increased the oestrogen receptor β (ERβ) in the ovary, while no significant changes were observed in the uterus. Our study reinforces the importance of adequate protein intake during puberty, since physiological changes in this developmental period interfere with the histomorphometry of the ovaries and uteri, possibly resulting in impaired folliculogenesis and fertility in the reproductive period.

Breast cancer (BC) is the most common cancer among women, and current available therapies often have high success rates. Nevertheless, BC might acquire drug resistance and sometimes relapse. Current knowledge about the most aggressive forms of BC points to the role of specific cells with stem properties located within BC, the so-called \"BC stem cells\" (BCSCs). The role of BCSCs in cancer formation, growth, invasiveness, therapy resistance and tumor recurrence is becoming increasingly clear. The growth and metastatic properties of BCSCs are regulated by different pathways, which are only partially known. Sex steroid receptors (SSRs), which are involved in BC etiology and progression, promote BCSC proliferation, dedifferentiation and migration. However, in the literature, there is incomplete information about their roles. Particularly, there are contrasting conclusions about the expression and role of the classical BC hormonal biomarkers, such as estrogen receptor alpha (ERα), together with scant, albeit promising information concerning ER beta (ERβ) and androgen receptor (AR) properties that control different transduction pathways in BCSCs. In this review, we will discuss the role that SRs expressed in BCSCs play to BC progression and recurrence and how these findings have opened new therapeutic possibilities.

Despite recent development in targeted therapies, lung cancer still remains the leading cause of cancer death. Therefore, a better understanding of its pathogenesis and progression could contribute to improving the eventual clinical outcome of the patients. Results of recently published several in vitro and clinical studies indicated the possible involvement of sex steroids in both development and progression of non-small cell lung carcinoma (NSCLC). Therefore we summarized the reported clinical relevant information of the sex steroids, their receptors and steroid metabolizing enzymes related to NSCLC in this mini-review. In addition, we also reviewed the potential \"endocrine therapy\", targeting sex steroid actions and/or metabolism in NSCLC patients.

It has long been known that the incidence of thyroid cancer in women is significantly higher than that in men. The objective of this article is to review gender differences in thyroid cancer, as well as epidemiological, clinical and experimental research on the role of sex hormones, their receptors and other molecular factors in this well-established thyroid cancer gender discrepancy. Although more common in women, thyroid cancer typically presents at a more advanced stage and with a worse disease prognosis in men. Clinical evidence on the impact of estrogen and other sex hormones on thyroid cancer has remained inconclusive, although numerous experimental studies have suggested that these hormones and their receptors may play a role in tumorigenesis and tumor progression. Studies of thyroid cancer cell lines suggest that an imbalance between the two estrogen receptor (ER) isoforms, α and β, may be responsible for the cell proliferation seen with estrogen treatment. Expression studies on thyroid tumors indicate that they express ER and possibly progesterone receptors and androgen receptors, but there is conflicting evidence as to whether or not there is a difference in receptor status between thyroid cancers, benign thyroid lesions and normal thyroid tissue. There have been few studies evaluating the ERα/ERβ profiles in thyroid tumors and normal thyroid tissue. Our understanding of the underlying basis for sex differences in thyroid cancer has improved over the last few decades, but the relationship between gender and thyroid cancer risk has remained elusive. Areas for future research include ERα/ERβ profiling of normal and neoplastic thyroid tissue, association between ER status and tumor dedifferentiation, and evaluation of the signaling pathways by which estrogen and other sex steroids exert their effects on thyroid cancer cells. Sex steroid receptors, and then downstream signaling pathways, represent promising future therapeutic targets for thyroid cancer treatment, and further study is required.

Nandrolone decanoate (ND) is a synthetic steroid, which promotes adverse effects on the ovarian tissue, and melatonin (MLT) exhibits a number of beneficial properties in the reproductive system. This study evaluated the general features of the ovarian tissue and the immunoexpression of sex steroid receptors in ND-treated rats that were submitted to short-term melatonin treatment. Adult rats received mineral oil (control group) and ND at doses of 7.5 mg/kg for 15 days (ND-treated group). The treatment with MLT (10mg/kg for 7 days) was given alone, before or in combination with ND. All ND-treated animals showed persistent dioestrus. In the androgenized groups that received MLT, ovarian morphology and size, and the number/area of corpora lutea were recovered. The number of healthy and atretic follicles was recovered when MLT was administered prior to ND; this was similar to the ovaries of control and MLT groups. There was a decrease in estrogen receptors immunostaining in the follicles of androgenized rats that were treated with MLT, and pretreatment with MLT reduced the expression of androgen receptor in atretic follicles and corpora lutea, when compared with ND-treated group. We conclude that MLT treatment recovered the histopathological aspects of the androgenized ovaries, and MLT pretreatment was the most effective.