Reproductive evaluations in female rat offspring exposed to metformin during intrauterine and intrauterine/lactational periods

Forcato, Simone; Montagnini, Bruno Garcia; Góes, Maria Luiza Marino de; Novi, Daniella Regina Barrionuevo da Silva; Kiss, Ana Carolina Inhasz; Ceravolo, Graziela Scalianti; Gerardin, Daniela Cristina Ceccatto

doi:10.1016/j.reprotox.2019.04.009

Cited by 8 publications

(3 citation statements)

References 56 publications

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“…Indeed, the histopathological ovarian damages caused by ACR exhibited by the oocyte vacuolization and high number of ovarian apoptotic cells detected by TUNEL assay would not imply that sex steroid hormone levels should be spectacularly increased but decreased since growing follicles, mainly antral, are the primary producers of 17β-estradiol [61]. In agreement with this result, prenatal exposure to metformin increased the plasma estradiol levels in the adult offspring females, and this increase might be related to programming in theca and/or granulosa cells during development [62]. It has been described that high estrogen levels in females are associated with ovarian aging.…”

Section: Discussionmentioning

confidence: 73%

Fetal programming: in utero exposure to acrylamide leads to intergenerational disrupted ovarian function and accelerated ovarian aging

Aldawood

Jalouli

Alrezaki

et al. 2022

Aging

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In this study we investigated the effects of multigenerational exposures to acrylamide (ACR) on ovarian function. Fifty-day-old Wistar albino female rats were divided into the control and ACR-treated groups (2.5, 10, and 20 mg/kg/day) from day 6 of pregnancy until delivery. The obtained females of the first (AF1) and second generation (AF2) were euthanized at 4 weeks of age, and plasma and ovary samples were collected. We found that in utero multigenerational exposure to ACR reduced fertility and ovarian function in AF1 through inducing histopathological changes as evidenced by the appearance of cysts and degenerating follicles, oocyte vacuolization, and pyknosis in granulosa cells. TMR red positive cells confirmed by TUNEL assay were mostly detected in the stroma of the treated groups. Estradiol and IGF-1 concentrations significantly decreased as a result of decreased CYP19 gene and its protein expression. However, ACR exposure in AF2 led to early ovarian aging as evidenced by high estradiol and progesterone levels among all treated groups compared to control group, corresponding to the upregulation of the CYP19 gene and protein expression. The apoptotic cells of the stroma were greatly detected compared to that in the control group, whereas no significant difference was reported in ESR1 and ESR2 gene expression. This study confirms the developmental adverse effects of ACR on ovarian function and fertility in at least two consecutive generations. It emphasizes the need for more effective strategies during pregnancy, such as eating healthy foods and avoiding consumption of ACR-rich products, including fried foods and coffee.

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Section: Discussionmentioning

confidence: 73%

Fetal programming: in utero exposure to acrylamide leads to intergenerational disrupted ovarian function and accelerated ovarian aging

Aldawood

Jalouli

Alrezaki

et al. 2022

Aging

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show abstract

“…In the present study, metformin exposure during the foetal period did not affect testosterone levels and thus there were no modifications of genitals, as attested by the AGD ( 61 ), as well as the testis, ovary and annexe gland morphology and weight. The absence of a metformin effect on sex differentiation has been reported recently ( 62 )…”

Section: Discussionmentioning

confidence: 90%

In Utero Exposure to Metformin Reduces the Fertility of Male Offspring in Adulthood

et al. 2021

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Metformin is a drug used for the treatment of type 2 diabetes and disorders associated with insulin resistance. Metformin is also used in the treatment of pregnancy disorders such as gestational diabetes. However, the consequences of foetal exposure to metformin on the fertility of exposed offspring remain poorly documented. In this study, we investigated the effect of in utero metformin exposure on the fertility of female and male offspring. We observed that metformin is detectable in the blood of the mother and in amniotic fluid and blood of the umbilical cord. Metformin was not measurable in any tissues of the embryo, including the gonads. The effect of metformin exposure on offspring was sex specific. The adult females that had been exposed to metformin in utero presented no clear reduction in fertility. However, the adult males that had been exposed to metformin during foetal life exhibited a 30% reduction in litter size compared with controls. The lower fertility was not due to a change in sperm production or the motility of sperm. Rather, the phenotype was due to lower sperm head quality – significantly increased spermatozoa head abnormality with greater DNA damage – and hypermethylation of the genomic DNA in the spermatozoa associated with lower expression of the ten-eleven translocation methylcytosine dioxygenase 1 (TET1) protein. In conclusion, while foetal metformin exposure did not dramatically alter gonad development, these results suggest that metabolic modification by metformin during the foetal period could change the expression of epigenetic regulators such as Tet1 and perturb the genomic DNA in germ cells, changes that might contribute to a reduced fertility.

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“…Several studies have established its effects on male and female reproductive system [ 33 , 34 , 42 , 43 , 44 , 45 , 46 ]. This study began with the determination of the age of onset of sexual maturation in experimental animals, which is characterized by vaginal opening [ 25 , 26 , 50 , 51 ]. Therefore, this work aimed at assessing the effects of tartrazine on sexual maturation and on folliculogenesis in a model of immature female Wistar rats.…”

Section: Discussionmentioning

confidence: 99%

Effects of Tartrazine on Some Sexual Maturation Parameters in Immature Female Wistar Rats

Mindang

Awounfack

Ndinteh

et al. 2022

IJERPH

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Over the past century, the average age for onset of puberty has declined. Several additives present in our food are thought to contribute significantly to this early puberty which is recognized to also affect people’s health in later life. On this basis, the impact of 40-days unique oral administration of the food dye tartrazine (7.5, 27, and 47 mg/kg BW doses) was evaluated on some sexual maturation parameters on immature female Wistar rats. Vaginal opening was evaluated during the treatment period. At the end of the treatments, animals were sacrificed (estrus phase) and the relative weight of reproductive organs, pituitary gonadotrophin and sexual steroids level, cholesterol level in ovaries and folliculogenesis were evaluated. Compared to the control group, animals receiving tartrazine (47 mg/kg BW) showed significantly high percentage of early vaginal opening from day 45 of age, and an increase in the number of totals, primaries, secondaries, and antral follicles; a significant increase in serum estrogen, LH and in uterine epithelial thickness. Our findings suggest that tartrazine considerably disturbs the normal courses of puberty. These results could validate at least in part the global observations on increasingly precocious puberty in girls feeding increasingly with industrially processed foods.

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Reproductive evaluations in female rat offspring exposed to metformin during intrauterine and intrauterine/lactational periods

Cited by 8 publications

References 56 publications

Fetal programming: in utero exposure to acrylamide leads to intergenerational disrupted ovarian function and accelerated ovarian aging

Fetal programming: in utero exposure to acrylamide leads to intergenerational disrupted ovarian function and accelerated ovarian aging

In Utero Exposure to Metformin Reduces the Fertility of Male Offspring in Adulthood

Effects of Tartrazine on Some Sexual Maturation Parameters in Immature Female Wistar Rats

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