Maternal administration of flutamide during late gestation affects the brain and reproductive organs development in the rat male offspring

Pallarés, María Eugenia; Adrover, Ezequiela; Imsen, Mercedes; González, Diego; Fabre, Bibiana; Mesch, Viviana; Baier, Carlos Javier; Antonelli, Marta C.

doi:10.1016/j.neuroscience.2014.07.074

Cited by 8 publications

(4 citation statements)

References 48 publications

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“…Studies have shown that the levels and mRNA expression of proteins implicated in androgen synthesis were reduced following exposure to DEHP in early life ( Gray et al, 2000 ; Parks et al, 2000 ; Borch et al, 2006 ; Lin et al, 2008 ). Furthermore, the low levels of prenatal androgens caused by the androgen receptor antagonist, flutamide, decreased the expression of MAP2 and induced reductions of dendritic branches in hippocampal neurons ( Pallares et al, 2014 ). However, high-androgen pups exhibited hippocampal neurons with longer dendrites and a larger number of dendritic branches in early life and also performed better in a Morris water maze test ( Isgor and Sengelaub, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

Exposure to Di-(2-ethylhexyl) Phthalate During Perinatal Period Gender-Specifically Impairs the Dendritic Growth of Pyramidal Neurons in Rat Offspring

You

Dong

et al. 2018

Front. Neurosci.

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Di-(2-ethylhexyl) phthalate (DEHP), as a prevalent xenoestrogen endocrine disrupter, is omnipresent in the environment and commonly used in polyethylene plastic products. Although DEHP has potential adverse effects on multisystem organs, damage to the central nervous system is more significant. However, the consequences and mechanisms of DEHP exposure remain to be explored. The aim of this study was to investigate the effects and related mechanisms of maternal DEHP exposure on dendritic development of hippocampal pyramidal neurons in a rat model. Pregnant Wistar rats were intragastrically administrated either vehicle or DEHP (30, 300, and 750 mg/kg/d) from gestation day 0 to postnatal day (PN) 21. The dendritic length and complexity of dendritic arbors’ pattern in pyramidal neurons of the hippocampus were measured using Golgi–Cox staining and Sholl analysis. The expression of dendritic development-related proteins was detected using western blot and immunofluorescence staining. DEHP-treated male but not female pups showed an obvious decrease in the total length and branching numbers of basal dendrites on PN7, PN14, and PN21. The phosphorylation of MAP2c, stathmin, and JNK1 in the male pup hippocampus was significantly decreased in DEHP treatment groups compared to controls. However, protein expression alteration in the hippocampus of female offspring was not observed. In summary, our study indicated that DEHP has a gender-specific negative impact on the dendritic growth of CA1 pyramidal neurons in male offspring of a rat model of DEHP exposure. The adverse impact may be related to the dysregulation of phosphorylated and total MAP2c and stathmin mediated by JNK1.

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Section: Discussionmentioning

confidence: 99%

Exposure to Di-(2-ethylhexyl) Phthalate During Perinatal Period Gender-Specifically Impairs the Dendritic Growth of Pyramidal Neurons in Rat Offspring

You

Dong

et al. 2018

Front. Neurosci.

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“…Pre-and postnatal testosterone exposure promotes a larger field size in CA1 and CA3 regions in males, compared to females, driven by increased dendritic arborization. This appears to be an androgen-specific effect, as dendritic arborization is promoted in females by neonatal administration of DHT, but not estradiol, and is blocked by androgen receptor antagonism in neonatal males [67,72,79,80]. The density of dendritic spine synapses on pyramidal neurons in these regions is also promoted by perinatal androgen receptor signaling, which remains in juvenile animals [79].…”

Section: Changes In Hippocampal Cytoarchitecturementioning

confidence: 96%

Androgens and the developing hippocampus

Kight

McCarthy

2020

Biol Sex Differ

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The hippocampus is central to spatial learning and stress responsiveness, both of which differ in form and function in males versus females, yet precisely how the hippocampus contributes to these sex differences is largely unknown. In reproductively mature individuals, sex differences in the steroid hormone milieu undergirds many sex differences in hippocampal-related endpoints. However, there is also evidence for developmental programming of adult hippocampal function, with a central role for androgens as well as their aromatized byproduct, estrogens. These include sex differences in cell genesis, synapse formation, dendritic arborization, and excitatory/inhibitory balance. Enduring effects of steroid hormone modulation occur during two developmental epochs, the first being the classic perinatal critical period of sexual differentiation of the brain and the other being adolescence and the associated hormonal changes of puberty. The cellular mechanisms by which steroid hormones enduringly modify hippocampal form and function are poorly understood, but we here review what is known and highlight where attention should be focused.

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“…It is known that in mammals, antiandrogens principally affect all androgen-dependent functions and organ systems. In rats, AR antagonists such as flutamide, p,p’- DDE and CPA are known to be potent inhibitors of androgen dependent reproductive organs ( Neri & Peets, 1975 ) resulting in reduced anogenital distance ( Fussell et al, 2015 ; Pallares et al, 2014 ), hypospadias ( Sinclair et al, 2017 ), atrophy of seminal vesicles ( Pallares et al, 2014 ), nipple retention ( Fussell et al, 2015 ), delayed onset of puberty and reduced ventral prostate weight in male rats ( Kelce et al, 1995 ). In fish, flutamide adversely affects male and female sex differentiation.…”

Section: Discussionmentioning

confidence: 99%

No effects of the antiandrogens cyproterone acetate (CPA), flutamide and p,p’-DDE on early sexual differentiation but CPA-induced retardation of embryonic development in the domestic fowl (Gallus gallus domesticus)

Jessl,

Oehlmann

2023

PeerJ

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Because a wide range of environmental contaminants are known to cause endocrine disorders in humans and animals, in vivo tests are needed to identify such endocrine disrupting chemicals (EDCs) and to assess their biological effects. Despite the lack of a standardized guideline, the avian embryo has been shown to be a promising model system which responds sensitively to EDCs. After previous studies on the effects of estrogenic, antiestrogenic and androgenic substances, the present work focuses on the effects of in ovo exposure to p,p’-DDE, flutamide and cyproterone acetate (CPA) as antiandrogenic model compounds regarding gonadal sex differentiation and embryonic development of the domestic fowl (Gallus gallus domesticus). The substances were injected into the yolk of fertilized eggs on embryonic day one. On embryonic day 19 sex genotype and phenotype were determined, followed by gross morphological and histological examination of the gonads. Treatment with flutamide (0.5, 5, 50 µg/g egg), p,p’-DDE (0.5, 5, 50 µg/g egg) or CPA (0.2, 2, 20 µg/g egg) did not affect male or female gonad development, assessed by gonad surface area and cortex thickness in both sexes and by the percentage of seminiferous tubules in males as endpoints. This leads to the conclusion that antiandrogens do not affect sexual differentiation during embryonic development of G. gallus domesticus, reflecting that gonads are not target organs for androgens in birds. In ovo exposure to 2 and 20 µg CPA/g egg, however, resulted in significantly smaller embryos as displayed by shortened lengths of skull, ulna and tarsometatarsus. Although gonadal endpoints were not affected by antiandrogens, the embryo of G. gallus domesticus is shown to be a suitable test system for the identification of substance-related mortality and developmental delays.

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Maternal administration of flutamide during late gestation affects the brain and reproductive organs development in the rat male offspring

Cited by 8 publications

References 48 publications

Exposure to Di-(2-ethylhexyl) Phthalate During Perinatal Period Gender-Specifically Impairs the Dendritic Growth of Pyramidal Neurons in Rat Offspring

Exposure to Di-(2-ethylhexyl) Phthalate During Perinatal Period Gender-Specifically Impairs the Dendritic Growth of Pyramidal Neurons in Rat Offspring

Androgens and the developing hippocampus

No effects of the antiandrogens cyproterone acetate (CPA), flutamide and p,p’-DDE on early sexual differentiation but CPA-induced retardation of embryonic development in the domestic fowl (Gallus gallus domesticus)

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