RESUMO
Infertility is becoming a major public health problem, with increasing frequency due to medical, environmental and societal causes. The increasingly late age of childbearing, growing exposure to endocrine disruptors and other reprotoxic products, and increasing number of medical reproductive dysfunctions (endometriosis, polycystic ovary syndrome, etc.) are among the most common causes. Fertility relies on fine-tuned control of both neuroendocrine function and reproductive behaviors, those are critically regulated by sex steroid hormones. Testosterone and estradiol exert organizational and activational effects throughout life to establish and activate the neural circuits underlying reproductive function. This regulation is mediated through estrogen receptors (ERs) and androgen receptor (AR). Estradiol acts mainly via nuclear estrogen receptors ERα and ERß. The aim of this review is to summarize the genetic studies that have been undertaken to comprehend the specific contribution of ERα and ERß in the neural circuits underlying the regulation of the hypothalamic-pituitary-gonadal axis and the expression of reproductive behaviors, including sexual and parental behavior. Particular emphasis will be placed on the neural role of these receptors and the underlying sex differences.
Assuntos
Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Reprodução , Humanos , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Animais , Reprodução/fisiologia , Feminino , Comportamento Reprodutivo/fisiologia , MasculinoRESUMO
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.