Alterations in male rats following in utero exposure to betamethasone suggests changes in reproductive programming

Borges, Cibele dos Santos; Dias, Ana Flávia M.G.; Rosa, Josiane Lima; Silva, Patricia V.; Silva, Raquel F.; Barros, Aline Lima de; Sanabria, Marciana; Guerra, Marina Trevizan; Gregory, Mary; Cyr, Daniel G.; Kempinas, Wilma De Grava

doi:10.1016/j.reprotox.2016.05.021

Cited by 16 publications

(40 citation statements)

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“…This work is part of a comprehensive study we are performing concerning the effects of prenatal BM exposure on the female and male offspring of rats. In males, we reported delay in puberty onset, testicular dysfunction and altered sperm quality and fertility, and part of these injuries were seen in the next generation (Borges et al ., , ). In females, as shown in the present work, the main findings were delayed sexual maturation, alteration in estrous cycle and LH levels, deleterious effects on fertility and uterus morphology and physiology.…”

Section: Discussionmentioning

confidence: 97%

“…Pregnant female rats were randomly assigned to two experimental groups (n = 11-13/group): control, treated with saline (vehicle) alone and treated (0.1 mg kg À1 ; betamethasone 21-phosphate disodium diluted in vehicle; Sigma-Aldrich, St. Louis, MO, USA). The dosing paradigm used in the present work has been previously adopted (Borges et al, 2016(Borges et al, , 2017Piffer et al, 2009a, b;Souza et al, 2001) and takes into account the beginning of the critical window of rat reproductive tract development (Crain et al, 2008;Davis et al, 1996;McIntyre et al, 2002;Wilson et al, 2004) and fetus brain sexual differentiation (Pereira & Piffer, 2005;Pereira et al, 2003;Piffer et al, 2009a, b). Rats received an intramuscular injection of vehicle or BM on days 12, 13, 18 and 19 of pregnancy.…”

Section: Experimental Groupsmentioning

confidence: 99%

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Reproductive disorders in female rats after prenatal exposure to betamethasone

Borges

Pacheco

Guerra

et al. 2017

J of Applied Toxicology

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Betamethasone is the drug of choice for antenatal treatment, promoting fetal lung maturation and decreasing mortality. Previous studies in rats reported male programming and alteration in sperm parameters and sexual behavior following intrauterine betamethasone exposure. The impact on the female reproductive development is not known. In this study, rat female offspring was assessed for sexual development, morphophysiology of the reproductive tract and fertility after maternal exposure to 0.1 mg kg of betamethasone or vehicle on gestational days 12, 13, 18 and 19. The treatment promoted reduction of litter weight on postnatal day 1, morphological masculinization in females, delay in the age of puberty onset, reduction in estrus number, increase in estrous cycle length and increase in luteinizing hormone serum levels and uterus weight. The females from the betamethasone group showed an increase of myometrial uterine area and decrease in endometrial uterine area. These animals also performed less lordosis during the sexual behavior test and showed impaired reproductive performance. The uterus showed higher contraction in the treated group as shown by a pharmacological assay. In conclusion, prenatal betamethasone exposure in rats promoted female masculinization, altered sexual development and reproductive parameters. Copyright © 2017 John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 97%

Section: Experimental Groupsmentioning

confidence: 99%

Reproductive disorders in female rats after prenatal exposure to betamethasone

Borges

Pacheco

Guerra

et al. 2017

J of Applied Toxicology

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“…Following the period of cellular differentiation, Cx43 becomes localized between basal and principal cells, suggesting a role in basal cell functions (Cyr et al ., ; Dufresne et al ., ) and also in myoid cells of the epididymis, reported to be androgen‐dependent (Cyr et al ., ). We previously showed that BM gestational administration promoted fetal reproductive reprogramming, resulting in decreased testosterone levels and alterations in both Cx43 and PCNA immunostaining in the testis (Borges et al ., ). Another key regulator of basal cells is the transcription factor tumor protein 63 (TP63) (Hayashi et al ., ; Murashima et al ., ; Mandon et al ., ).…”

Section: Introductionmentioning

confidence: 97%

“…In recent studies, we showed that prenatal BM exposure promoted fetal reproductive reprogramming of male rat offspring, as characterized by reduction of anogenital distance, altered testicular and epididymal development, testicular morphology, impaired sperm quality, and fertility of treated animals (Borges et al ., , 2017a,b; Barros et al ., ).…”

Section: Introductionmentioning

confidence: 99%

“…Studies on the toxicology of the epididymis are scarce (De Grava Kempinas & Klinefelter, ; Cyr et al ., ). As BM exposure during intrauterine life reduces fetal testosterone and directly impacts reproductive organ development (Borges et al ., ), the present work aims to investigate long‐term effects of BM exposure on the morphology and physiology of the epididymis in F1 and F2 male offspring from female rats treated with BM during gestation.…”

Section: Introductionmentioning

confidence: 99%

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Prenatal exposure to betamethasone causes intergenerational impairment of epididymal development in the rat

et al. 2019

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Background: Studies on epididymal toxicology are scarce. Betamethasone (BM) is a glucocorticoid used in clinical practice for antenatal therapy. We previously reported changes to testicular morphology, altered sperm quality, and fertility in adult rats following intrauterine administration of BM. Objectives: Given that high levels of corticosteroids during gestation lead to fetal androgen depletion, and the essential role of testosterone during epididymal development, here we investigated epididymal morphology and physiology in the F1 and F2 male offspring of female rats treated with BM during gestation. Materials and methods: Pregnant rats were randomly divided into two experimental groups: control (saline vehicle, n = 11) and BM-treated group (0.1 mg/kg betamethasone 21-phosphate disodium, n = 13). Rats received an intramuscular injection of vehicle or BM on gestational days 12, 13, 18, and 19. This encompasses the beginning of the critical window of male rat reproductive tract development. A subset of three males from each litter (n = 5 litters/group) was used: One rat per litter was euthanized at puberty, one was euthanized at adulthood, while the others were mated with a non-treated female to obtain the F2 generation. The same protocol described for the F1 was applied for F2, except for the mating protocol. Results: In both F1 and F2 generations, prenatal BM exposure resulted in delayed differentiation of the cauda epididymal epithelium, characterized by increased cribriform appearance on PND 45, and displayed weaker or non-detectable Cx43 immunostaining. Furthermore, in the F1 generation only, immunostaining of TP63, a transcription factor expressed in basal cells, appeared more intense with a greater number of TP63-positive cells observed in the cauda epididymis. In adults, the epithelial area was reduced in the F1 BM rats. The contractile activity of isolated epididymal ducts was comparable between groups. Discussion and Conclusion: Prenatal BM exposure leads to intergenerational impairment in the development and structure of the rat epididymis.

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Effects of social environments on male primate HPG and HPA axis developmental programming

Brown,

Gettler,

Rosenbaum

2024

Developmental Psychobiology

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Developmental plasticity is particularly important for humans and other primates because of our extended period of growth and maturation, during which our phenotypes adaptively respond to environmental cues. The hypothalamus–pituitary–gonadal (HPG) and hypothalamus–pituitary–adrenal (HPA) axes are likely to be principal targets of developmental “programming” given their roles in coordinating fitness‐relevant aspects of the phenotype, including sexual development, adult reproductive and social strategies, and internal responses to the external environment. In social animals, including humans, the social environment is believed to be an important source of cues to which these axes may adaptively respond. The effects of early social environments on the HPA axis have been widely studied in humans, and to some extent, in other primates, but there are still major gaps in knowledge specifically relating to males. There has also been relatively little research examining the role that social environments play in developmental programming of the HPG axis or the HPA/HPG interface, and what does exist disproportionately focuses on females. These topics are likely understudied in males in part due to the difficulty of identifying developmental milestones in males relative to females and the general quiescence of the HPG axis prior to maturation. However, there are clear indicators that early life social environments matter for both sexes. In this review, we examine what is known about the impact of social environments on HPG and HPA axis programming during male development in humans and nonhuman primates, including the role that epigenetic mechanisms may play in this programming. We conclude by highlighting important next steps in this research area.

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Alterations in male rats following in utero exposure to betamethasone suggests changes in reproductive programming

Cited by 16 publications

References 53 publications

Reproductive disorders in female rats after prenatal exposure to betamethasone

Reproductive disorders in female rats after prenatal exposure to betamethasone

Prenatal exposure to betamethasone causes intergenerational impairment of epididymal development in the rat

Effects of social environments on male primate HPG and HPA axis developmental programming

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