The developmental neuroendocrinology of reproduction and adaptation: lessons from animal research
Presented the results of animal research in the field of developmental neuroendocrinology of reproduction and adaptation in early ontogenesis. The sex differentiation of the brain and developmental programming of hypothalamic-pituitary-adrenal axis.
| Рубрика | Медицина |
| Вид | статья |
| Язык | английский |
| Дата добавления | 16.06.2022 |
| Размер файла | 500,3 K |
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One of the approaches to pharmacological blockade of maternal stress is stimulation of the brain's stress-limiting system. Prenatal use of the GABA agonist, phenibut (100 mg/kg, per os), according to the same scheme as dexamethasone, prevented the development of early postnatal changes in AA in the POA of males and significantly improved the timing of puberty. Prenatal phenibut completely normalized male sexual performance in male offspring, reduced by a third the number of lordosis reactions, restored the HPA axis response to an acute stress, but did not affect its noradrenergic sensitivity.
According to the literature [63], sexual dysfunction in PS male rats can be prevented by administering to pregnant mothers tyrosine, the precursor of catecholamine synthesis. The preventive effect of tyrosine is associated with the restoration of noradrenaline content in the hypothalamus, which reduced due to stress. These findings are consistent with the concept of the involvement of noradrenaline in SDB as its important determinant.
In order to clarify the role of maternal noradrenergic activation as a part of stress in association with SDB disorders, we used methyldopa as sympatholytic agent (400 mg/kg, per os, 30 min before immobilizing procedure).
Prenatal methyldopa contributed to the partial normalization of AA in the POA of males at PND 10, some indices of male sexual behavior, but did not prevent lordosis reactions and did not affect the PS-induced modification of the HPA axis stress reactivity.
Opioids are an important component of the stress-limiting system of the brain. Stress in pregnant rats is accompanied by an increase in the content of opioids, in particular, p-endorphin, in the hypothalamus and adenohypophysis of the mother and fetus [64]. Signs of the failure of the SDB in adult male rats are expressed after the introduction of p-endorphin at a dose of 33 mcg three times a day to their mothers in late pregnancy [65]. In our laboratory, it was shown that the introduction of p-endorphin in a similar scheme reproduces the effect of PS on AA in the POA [61]. Opioids have been suggested to be responsible for inhibiting testosterone secretion by fetal testicles during stress due to a decrease in hypothalamic LH-RH secretion and, consequently, for demasculinization of the brain. It has previously been found out that the use of naltrexone, an opioid antagonist, which mainly binds to mu-receptors, during stress in pregnant dams, prevents impairment of sexual behavior in male offspring [66]. However, the neurochemical basis of this effect remained unstudied.
In our research, naltrexone pre-treatment of stressed dams (10 mg/kg, s/c, daily, 30 min before one-hour immobilizing during the last week of pregnancy) prevented modifying the effect of PS on AA, noradrenaline content, and protein pattern in the POA of 10-day-old males. In adulthood, they demonstrated normal sexual behavior and HPA axis function including corticosterone and hypothalamic noradrenaline response to an acute stress and baclofen, as well as HPA axis noradrenergic sensitivity. These findings indicate that endogenic opioids mediate detrimental effect of PS on neurochemical determinants of the SDB that may underlie demasculinization of the male sexual behavior.
Calcium is one of the most important ions required for brain development and function including interneuronal signaling, synapse formation, transmission and plasticity, and apoptosis and necrosis. The role of calcium signaling in the pathogenesis of PS syndrome was studied by stressing pregnant rats on the background of nimodipine, which was introduced orally at a dose of 20 mg/kg 30 min before immobilization. At this dose, nimodipine blocks L-type channels in brain cells [48]. Sexual dimorphism of AA and 66 kDa protein content in the POA of 10-day-old PS rats disappeared due to their drop in males.
Prenatal nimodipine did not affect PS- induced delayed puberty in males and females. At the end of the 6-month follow-up period in females, changes in estrus cycles were less pronounced, instead, they maintained normal female behavior.
Prenatal nimodipine normalized absolutely all studied indicators of male sexual behavior in PS males and prevented modification of HPA axis stress-responses in males and females. Given together, these data indicate an important role of calcium signaling in the pathogenesis of PS syndrome.
Endocrine disrupting chemicals and SDB
The impact of endocrine disrupting chemicals (EDC) as environmental pollutants on the developing brain organization has been in the circle of scientific interest of G. Dorner and his colleagues [67]. Today, the impact of EDC on human health and especially on pregnant mothers and fetuses are the focus of research around the world [68, 69]. A distinctive feature of EDC is the lack of dependence of the pathogenic effect on the dose of exposure, which complicates the establishment of threshold toxic doses and the predictability of the consequences. EDC interferes with one or simultaneously with several biological processes involved in hormonal regulation [70]. Agonistic or antagonistic effect on natural hormonal ligands is realized through interaction with estrogen, androgen, progesterone receptors, which leads to disorders of intracellular signaling mechanisms and functioning of genome. In addition, they are capable of causing oxidative stress.
The reproductive system is the most vulnerable to EDC [71-73]. The action of such substances on the pregnant woman causes a cascade of neurohormonal changes in the mother and fetus, which, with the involvement of imprinting mechanisms, program disorders of the neuroendocrine control of many physiological functions, including behavior, reproduction processes, and adaptation to changing environment. Moreover, under certain conditions, they cause teratogenic effects, such as cryptorchidism and gonadal dysgenesis.
Dibutyl phthalate. One of the most common endocrine disruptors are phthalic acid esters (phthalates). They are used mainly in manufacturing polyvinyl chloride products, for example, flooring and roofing, packaging for beverages, coating drugs and children's toys. Due to their inherent anti-androgenic activity, phthalates disrupt the normal development of the male reproductive tract. This effect is caused by inhibition of testosterone synthesis in fetal testicles and disorganization of the histo- architectural structure of Leydig cells.
The long-term effects of pre- and perinatal administration of phthalates, especially dibutyl phthalate (DBP), on the fetus in terms of functional teratology are poorly studied. Published sources reported diminution of sexual behavior in male rat offspring. Unlike most of the published papers, in which the effects of DBP have been studied after its administration during embryo-, fetogenesis, and lactation, we have selectively investigated the epigenetic reprogramming of developing neuroendocrine system and the behavior that occurs at SDB window.
The minimum daily dose that did not cause any visible anatomical defects in male offspring of rats (NOAEL) when DBP was given to mothers during 12-20 days of pregnancy was set at 66 mg/kg/day [74]. We studied early and long-term consequences of prenatal low dose DBP (100 mg/kg/day by gavage for gestational days 15 21) on sexual maturation and behavior of Wistar male rat progeny [75]. At PND 2, the anogenital distance slightly reduced relative to the control, which is a marker of the antiandrogenic activity of DBP. Nevertheless, on the 7th day, this difference disappeared due to the completion of the crotch fusion. There were no other anatomical abnormalities in the newborns.
Surprising findings were that exposure of pregnant dams to low dose DBP during the critical period of the fetus SDB leads in male offspring to premature puberty, hyperandrogenism, and hyperactive male sexual behavior in reproductive age. The descent of the testes into the scrotum, which is an indicator of puberty, occurred in DBP group earlier compared to the control group. In six-month-old males, the level of testosterone in the blood plasma doubled (7.53 ± 1.45 x 10-9 g/ml vs. 3.76 ± 0.85 x 10-9 g/ ml in the control group, P < 0.05). It is likely that premature puberty is due to the hyperandrogenic condition of the animals.
Histological examination of the gonads revealed no changes in the spermatogenic layer of seminal tubules. Numerous Leydig cells were enlarged and in the active synthesis phase, which explains the increase in plasma testosterone levels. The sperm concentration in the flushes of the epididymis increased slightly.
Testing of male sexual behavior in experimental animals at 6 and 10 months of age revealed hypersexual male activity toward receptive females. The latency of the first mounting, the first intromission, the first ejaculation, and the duration of the post-ejaculation refractory period significantly reduced. The number of intromissions and ejaculations increased. We call this phenomenon “prenatal dibutyl phthalate syndrome”. If this phenomenon is reproduced in men in real life, it might be a pathogenetic basis of so-called criminal hypersexuality, which is usually associated with excessively high levels of testosterone in the blood.
In 18-month-old DBP-exposed rats, premature involution of testes and accessory sexual glands as well as exhausting of male sexual potency occur. Testosterone levels in the blood plasma decreased by an average of two and a half time against corresponding aging controls (1.04 ± 0.17 x 10-9 g/ml vs 2.48 ± 0.71 x 10-9 g/ml). The sperm concentration in the flushing of the epididymis decreased from 53.2 ± 2.9 x 106/ml to 38.3 ± 4.6 x 106/ml. The difference between the latency of the first mounting in the experimental and control groups disappeared, the number of intromissions reduced tenfold, and ejaculations were absent at all.
The hypersexual behavior of young males is probably due to excessive brain masculiniza- tion and high plasma testosterone levels. The hyperactivity of the neuroendocrine center of male sexual behavior is evidenced by the morphological signs of enhanced functional activity of neurocytes of the hypothalamic MPN. Presumably, the cause of excessive masculinization of the developing brain is increased synthesis of testosterone in the fetus testicles. The basis for this hypothesis is the information about the direct stimulating effect of low concentrations of DBP and its metabolite, monobutyl phthalate, on testosterone synthesis in mouse Leydig cell (MLTC-1) culture [76]. Instead, at high concentrations, both compounds inhibited steroidogenesis [77]. Our hypothesis relies on the data on the kinetics of testosterone secretion by fetal testicles resulting from feeding female rats at a daily dose of 100 mg/kg for gestation days 12-19 [78]. Within 24 h after inhibition of testosterone synthesis, plasma testosterone level restores and then grows above initial level due to rebound effect. A transient burst of testosterone secretion in the SDB window could be the cause of the brain hypermasculinization.
One of the consequences of prenatal low dose DBP was enhanced feminization of the male brain, which, in conditions of estrogen- progestin loading, manifested by an increase in the frequency of lordosis responses to the presence of a normal sexually active male. Both ten-month-old and aging males, castrated and hormone-primed, demonstrated a homosexual type of behavior. Unexpected activation of female sexual behavior might be caused by impaired defeminization of neuroendocrine structures, for example, because of DBP-induced oxidative stress.
In adult female offspring, we found quasi- copulatory behavior in the form of mounts on receptive females, although their lordosis behavior did not alter.
Bisphenol A. Bisphenol A (BPA) acts on the endocrine system as an estrogen receptor agonist. In our study, it was introduced into the stomach to pregnant Wistar rats during the last gestation week at a daily dose of 25 mcg/kg, which did not cause teratogenic effects in the descendants. Sexual behavior was examined in male descendants at the age of 10 months. Almost complete inhibition of copulatory components of male sexual behavior was observed against the background of normal testosterone levels and the absence of morphological changes of the gonads and prostate. According to histological and karyometric examination of the MPN, neurocyte activity was attenuated, correlating with inhibition of male sexual behavior.
One of the effects of prenatal BPA was the appearance of lordosis in ovaryectomized and primed with estradiol and progesterone males in the presence of a normal male, that is, conservation of the sensitivity of the neuroendocrine centers of reproduction to stimulation by female sex hormones in adult male offspring, indicating a severe violation of androgen-dependent SDB. Probably, the violation of androgen-dependent SDM is due to the antagonistic action of BPA against testicular testosterone of the fetus because of the estrogenlike activity of the disruptor.
Finally, it should be noted that disorders of early programming of neuroendocrine functions and behavior are polyetiological and polypathogenetic in nature and require further study.
CONCLUSIONS
Man is a part of the world of mammals, and the laws of human ontogenesis are largely common to other animal species. Therefore, there is a high probability that the results of animal studies could be extrapolated to human beings. The findings of experimental studies obtained in the last decades as well as clinical observations on the etiology and pathogenesis of psychological, neuroendocrine, and other functional disorders caused by numerous perinatal factors created a basis for the practical implementation of prevention of these disorders. Early-life programming of sexual behavior might explain the way of formation of gender self-identification. Epigenetic mechanisms of developmental modifications of neuroendocrine and behavioral individual phenotype need to be investigated in the future. Preclinical studies of new drugs intended for use in pregnant women should be complemented by an exploration of the long-term effects on fetal health. Psychological, somatic, and social aspects of early brain programming should be studied in the age aspect on an interdisciplinary basis. This will contribute to a deeper understanding of the biological and social nature of man, as well as the preservation of his health and quality of life.
The authors of this study confirm that the research and publication of the results were not associated with any conflicts regarding commercial or financial relations, relations with organizations and/or individuals who may have been related to the study.
О.Г. Резніков
ДУ «Інститут ендокринології та обміну речовин ім. В.П. Комісаренка НАМН України», Київ
ФОРМУВАННЯ НЕЙРОЕНДОКРИННОЇ РЕГУЛЯЦІЇ РЕПРОДУКЦІЇ ТА АДАПТАЦІЇ: УРОКИ ДОСЛІДЖЕНЬ НА ТВАРИНАХ
З нагоди 30-ї річниці створення Відділу ендокринології репродукції та адаптації Інституту ендокринології та обміну речовин ім. В.П. Комісаренка НАМН України в огляді розглядаються результати експериментальних досліджень у галузі формування нейроендокринної регуляції репродукції та адаптації в ранньому онтогенезі. Особлива увага приділяється статевій диференціації мозку та програмуванню розвитку системи гіпоталамус-гіпофіз- надниркові залози. Представлені перепрограмувальні перинатальні ефекти стероїдів, стресу, деяких ліків та хімічних ендокринних дисрапторів на мозок, що розвивається. Обговорюються феноменологія та ней- рохімічні механізми, що лежать в основі гормон- нейромедіаторного імпринтингу морфології гіпоталамуса, статевої поведінки, репродуктивних та ендокринних функцій та стрес-реактивності. Результати досліджень можуть сприяти пренатальній профілактиці нейроендокринних та поведінкових розладів.
Ключові слова: мозок; статева диференціація; андрогени; естрогени; глюкокортикоїди; нейромедіатори; пренатальний стрес; статева поведінка; стрес-реактивність; ендокринні дисраптори; щури
А.Г. Резников
ГУ «Институт эндокринологии и обмена веществ им. В.П. Комиссаренко НАМН Украины», Киев
ФОРМИРОВАНИЕ НЕЙРОЭНДОКРИННОЙ РЕГУЛЯЦИИ РЕПРОДУКЦИИ И АДАПТАЦИИ: УРОКИ ИССЛЕДОВАНИЙ НА ЖИВОТНЫХ
В связи с 30-летием создания Отдела эндокринологии репродукции и адаптации Института эндокринологии и обмена веществ им. В.П. Комиссаренко НАМН Украины в обзоре рассматриваются результаты экспериментальных исследований в области формирования нейроэндокринной регуляции репродукции и адаптации в раннем онтогенезе. Особое внимание уделяется половой дифференциации мозга и программированию развития системы гипотала- мус-гипофиз-надпочечники. Представлены перепрограм- мирующие перинатальные эффекты стероидов, стресса, некоторых лекарств и химических эндокринных дисрап- торов на развивающийся мозг. Обсуждаются феноменология и нейрохимические механизмы, лежащие в основе гормон-нейромедиаторного импринтинга морфологии гипоталамуса, полового поведения, репродуктивных и эндокринных функций и стресс-реактивности. Результаты исследований могут способствовать пренатальной профилактике нейроэндокринных и поведенческих расстройств. Ключевые слова: мозг; половая дифференциация; андрогены; эстрогены; глюкокортикоиды, нейромедиаторы; пренатальный стресс; половое поведение; стресс-реактивность; эндокринные дисрапторы; крысы
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