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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 8  |  Issue : 2  |  Page : 71-77

Effect of advancing maternal age on some histomorphological characteristics and other parameters of the offspring of wistar rats


1 Department of Anatomy, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria
2 Department of Human Anatomy, College of Medicine, Kaduna State University, Kaduna, Nigeria
3 Department of Human Physiology, College of Medicine, Kaduna State University, Kaduna, Nigeria

Date of Submission08-May-2020
Date of Decision21-Jun-2020
Date of Acceptance29-Jun-2020
Date of Web Publication11-Feb-2021

Correspondence Address:
Dr. Timothy Danboyi
Department of Human Physiology, College of Medicine, Kaduna State University, Kaduna
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njecp.njecp_12_20

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  Abstract 


Background: The average age of mothers at the time of first childbirth has been increasing over the past decades. Delayed motherhood comes with several adverse outcomes. Objective: We investigated the effect of advancing maternal age on some histomorphological parameters in the litters of female Wistar rats. Materials and Methods: Twenty-seven female rats (11–40 weeks old) were divided into three groups (young-, mid-, and old aged) of 9 rats each and mated with 12 male rats. The morphological parameters of the litters were obtained and a classic maze task was performed. Data were analyzed using the Statistical Package for the Social Sciences version 23 and values at P < 0.05 were considered significant. Results: The litters of young-age mothers were significantly fewer (5.0 ± 0.4) compared to litters of mid- (8.0 ± 0.3) and old-aged (11.6 ± 0.8) mothers. Sex ratio significantly increased as the maternal age increases. Litters of young-aged mothers committed more errors (3.4 ± 0.5) and took longer to complete the maze task (147.0 ± 24.9s) compared to litters of the other groups. However, the biomarkers of oxidative stress (OS) in the brain homogenate were worse with advancing maternal age. Histologically, there was a significant decrease in the external pyramidal layer width with advancing maternal age (8.18 ± 0.23 mm in young aged; 4.16 ± 0.09 mm in the old aged). Conclusion: Advancing maternal age has an enhancing effect on the litters' size, sex ratio, and cognitive abilities but a negative effect on OS and cortical width.

Keywords: AJdvancing, age, litter, maternal, ratio, sex


How to cite this article:
Kusemiju TO, Yama OE, Olabiyi O O, Aladejare A A, Danboyi T, Teru Goj AD, Avidime OM. Effect of advancing maternal age on some histomorphological characteristics and other parameters of the offspring of wistar rats. Niger J Exp Clin Biosci 2020;8:71-7

How to cite this URL:
Kusemiju TO, Yama OE, Olabiyi O O, Aladejare A A, Danboyi T, Teru Goj AD, Avidime OM. Effect of advancing maternal age on some histomorphological characteristics and other parameters of the offspring of wistar rats. Niger J Exp Clin Biosci [serial online] 2020 [cited 2021 Feb 25];8:71-7. Available from: https://www.njecbonline.org/text.asp?2020/8/2/71/309163




  Introduction Top


Gender selection refers to the use of reproductive techniques/technologies such as in vitro fertilization for the deliberate and unnatural selection of one's offspring, either pre- or postconception.[1],[2] The main reasons for sex selection include medical, such as preventing the birth of children affected or at risk of X-linked disorders, family balancing, and gender preference, stemming from the sociocultural and economic bias often in favor of male children.[2] The natural sex ratio, which is often distorted by sex-selection practices,[2] has been explained by several theories such as the Trivers and Willard's theory,[3] a sex ratio biased toward sons, and the local resource competition theory,[4] biased toward daughters. Sex ratio which had been biased toward sons has been declining over the past three decades now due to harsh industrial chemicals against the male androgens, particularly testosterone, stress, harsh socioeconomic condition, and natural and man-made horrors.[5]

With an increase in age, there is a decline in physiological functions, called senescence, in which cellular processes are halted or even arrested.[6] The concept of female “biological clock” and advancing maternal age constitutes a source of concern for many women.[7] The average age of mothers at the time of first childbirth has been increasing over the past decades.[7],[8] This may be due to the societal trend in which couples delay child bearing for career or socioeconomic reasons.[7] However, this increase had been associated with several adverse outcomes such as infertility, miscarriages, trisomy 21, low birth weights, cancers, and hypertension.[7],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18] Could there also be positive effects of advancing maternal age on the offspring? This study aimed to find out the effect of advancing maternal age on sex ratio, litters' intelligence, and other histomorphological parameters in the offspring of Wistar rats.


  Materials and Methods Top


Experimental animals and laboratory conditions

Thirty-nine apparently healthy adult rats (Rattus norvegicus) of both sexes (27 females and 12 males) were housed in plastic cages (three rats per cage), measuring 30 cm × 20 cm × 13 cm, with soft wooden shavings as beddings. They were fed with rat chow and water ad libitum. They were kept under standardized animal house conditions (temperature: 28°C–-31°C; light: approximately 12 h natural light per day; and humidity: 50%–55%) and allowed 2 weeks of acclimatization to these conditions before the commencement of the study.

General protocol

All procedures conformed to the National Academy of Sciences' Guide for the Care and Use of Laboratory Animals.[19]

Animal grouping

Twenty-seven female rats were divided into three groups of nine rats each, based on their ages: those within 11–20 weeks old were placed in the young-aged group, those within 21–30 weeks old, mid-aged group, and those 31–40 weeks old, old-aged group. The 12 mid-aged male rats (within 21–30 weeks old) were used to mate the females. After grouping, blood samples were collected for analysis of biomarkers for oxidative stress (OS).

Determining stage of estrous cycle and mating

Representative photographs and micrographs for each stage of the estrous cycle were obtained following the steps described by Byers et al.,[20] via assessment of the vaginal opening and vaginal cytology. The male Wistar rats were introduced overnight to the female Wistar rats during the estrus phase. A vaginal smear was carried out the following morning to confirm mating. If sperm plugs were seen under the microscope, that day was termed “day 1” of pregnancy.

Animal sacrifice

After parturition, the gross morphology of the litters was carried out, then subdivided into subgroups A and B before humanely sacrificing them. The brains of subgroup A were harvested for homogenate preparation but those from subgroup B for histology.

Tissue processing

The cerebral tissues were cut to 5 mm size by a sharp sterilized blade. The tissue processing was carried out according to the method described by Akpantah et al.[21]

Homogenate preparation

After harvesting the cerebral tissues from the litters, the tissues were preserved immediately in a freezing chamber. Five gram was cut from the frontal cerebral lobe and homogenized with 0.4 M phosphate buffer and later centrifuged for 10 min at 3000 rpm. Biomarkers for OS analyzed include superoxide (SOD) according to the method described by Kakkar et al.;[22] reduced glutathione (GSH), according to the method described by Ellman;[23] catalase (CAT), based on the method of Sinha,[24] and malondialdehyde (MDA) according to the method described by Okhawa et al.[25]

The classic maze task

The classic maze task was performed according to the method described by Hanson.[26] It consists of a branching pathway with six closed (false) routes, a “Start” point (to place the rat) and an “End” point (where it's feed is placed). To train the rats, oil from a fried meat was used to trace the open (true) route from the “Start” to the “End” of the maze. The rat is expected to trace the aroma of the meat through to the “End.” This was done three times daily (9 am, 12 pm, and 3 pm) for the first 7 days. On the 8th day, the classic maze was cleaned and dried in the sun to clear away the aroma of the fried meat. The rat was introduced and expected to go through the only true route from the “Start” to the “End” of the maze with minimal errors. The time taken for each rat in each group to complete the tour round the maze was recorded. The number of entries into the false routes was counted as an error and recorded.

Statistical analysis

Data were expressed as mean ± standard deviation and were analyzed using the Statistical Package for the Social Sciences (SPSS) software version 23 (Armonk, NY:IBM Corp, 2017). One-way analysis of variance was employed for multiple comparisons between groups, followed by the Student–Newman–Keuls test. The difference between the groups was considered statistically significant at P < 0.05.


  Results Top


There was a significant increase in the number of litter size (5.0 ± 0.4 in the young-aged; 8.0 ± 0.3 in the mid-aged, and 11.6 ± 0.8 in the old-aged mothers) and in the sex ratio (0.42 in the young-aged; 0.90 in the mid-aged and 2.41, in the old-aged mothers), with advancing maternal age [Table 1].
Table 1: Sex ratio and number of litters across the maternal age groups

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The litters' weight and other morphological parameters (umbilical cord, crown-rump, and tail lengths) significantly decrease with increasing maternal age [Table 2].
Table 2: Morphological characteristics of the litters across the maternal age groups

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Acclimatization of the maze was fastest among the litters born to young-aged mothers (31.6 ± 6.5s), but with advancing maternal age, the number of errors as well as the total time to complete the task decreases (87.0 ± 8.1s in mid-aged and 82.0 ± 9.8s in the old-aged mothers) [Table 3].
Table 3: Litters intelligence in the classic maze across the maternal age groups

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The cell count in the external pyramidal layer remains relatively the same across the age group, but the width of the same layer decreases as the maternal age increases (from 8.18 ± 0.23 cm in young-aged mothers to 4.16 ± 0.09 cm in the old-aged mothers) [Table 4].
Table 4: Average cell count (per grid) of the external pyramidal layer and width of the litters' cerebral frontal lobe

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The MDA concentration, GSH, and CAT levels were significantly higher (12.61 ± 0.04 umol/g, 38.85 ± 0.54 μmol/mgpr and 4.01 ± 0.05 μmol/mg respectively), while the SOD level was lower (2.17 ± 0.01 μmol/mg) in litters born to old-aged mothers than those seen in the other age groups [Table 5] and this corresponds with the parameters of the maternal sera [Table 6].
Table 5: Stress markers activities in the frontal cerebral tissue of the litter across the groups

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Table 6: Stress markers activities in maternal serum across the groups

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  Discussion Top


The effects of maternal age on sex ratio can be variable.[27] While a decline in the male-to-female ratio with advancing maternal age was reported in some studies,[28],[29] no association was found in another study,[30] but we found a significant increase in the male-to-female sex ratio of the litters as the maternal age increased [Table 1]. Our finding is in line with that of some studies,[31] which showed an increase in the sex ratio among older dams compared to the younger ones, and they predicted the ratio to be increased when young dams give birth to big litters and old dams give birth to small litters and vice versa. This is absolutely a true reflection of our findings. This may be due to a combination of both maternal and paternal factors,[31] but it, however, deviates from the Trivers-Willard hypothesis[3] discussed above.

It had been established[32] that litter size is often affected by maternal age. Although the young-aged mothers in the present study gave birth to much fewer litters compared to the mid- and old-aged mothers, the morphologic characteristics of their litters were surprisingly significantly higher [Table 2]. Hence, the litters' size (in terms of their number) is inversely related to their weights as the pups of young-age mothers were significantly weightier than the pups of the old-aged mothers but fewer in number. This is contrary to the findings of Sampino et al.,[33] who found that young-age mice mothers gave birth to significantly more pups compared to old-aged mice mothers.

Litters of young-age mothers are expected to have smaller weights and other morphologic characteristics since the mothers are also growing and competition for available nutrient during gestation will most likely exist between their (the mothers) bodies and their fetuses. This was demonstrated in some human studies.[34],[35] The increase in fetal characteristics in such studies was notably significant only in the first trimester, and the birth weights and other parameters were higher among babies born to the optimum (or mid) age and advanced (or old) mothers compared to the young-aged mothers.

The increase in number of litters born to the mid- and old-aged mothers may be probably due to an increase in the number of ova shed during estrus, increase in sizes of their pregnancies, parity as well as body surface areas or mass.[36] Since the mid- and old-aged mothers had more fetuses, fetal competition for nutrient in utero might have accounted for the smaller litter's weights and other parameters compared to the young-aged mothers. This was explained by some studies[37],[38] who found that advanced maternal age is associated with fetal growth restriction caused by aberrant or dysregulated methylation and gene expression in oocytes and reproductive tissues of maternally aged mice,[37] but younger maternal age was also associated with low birth weight study.[38] However, the prevalence of small for gestational age outcome was highest among babies those to advanced age mothers owing to placental aging.[35]

Furthermore, older mothers are more likely to have longer body length and heavier weight than the younger-age mothers. A study by Polzlberger et al.[39] revealed a significantly positive association between maternal height and crown-rump length in the first trimester and other fetal characteristics in the second and third trimesters. Their study also demonstrated that prepregnancy maternal weight status is significantly and positively associated with all fetal parameters in the third trimester. It is, therefore, not surprising Polzlberger et al.[39] found the maternal height and prepregnancy weight to be significantly and positively associated with newborn size. Hence, irrespective of the maternal age, the pregestation height and weight determine the fetal morphological characteristics as well as litters' weights and this also explains the increase in litters' weights and fetal morphological parameters observed among the young aged mothers in the present study.

Litters' intelligence appeared to increase with increasing maternal age [Table 3]. The litters from the old-aged mothers ran through the maze in the shortest time and made the least number of errors, even though their adaptation to the experimental procedure was delayed. This shows that they have a superior spatial learning ability and better working memory compare to litters of both young- and mid-aged mothers. The delay in adapting to the procedure may be due to persistent olfactory cues from litters of the other groups, who were first to perform the procedure each day despite the pretest wiping with alcohol wet cotton wool. However, litters from the young-aged mothers had the quickest adaptation to the experimental procedure.

Saha et al.[40] and Myrskyla et al.[41] demonstrated that increasing maternal age was associated with better performance in some cognitive tasks. This may be due to age-related alterations in fetal neurodevelopment in utero,[33],[42] including alterations in hippocampal gene expression which play a role in anxiety-related behaviors and synaptic plasticity,[33] but it is still controversial as recent studies showed poorer performances in some cognitive tasks.[43],[44],[45] While “early” advanced maternal age (35–40 years) was significantly and positively associated with cognitive and behavioral outcomes, such association ceases to exist after the age of 40 years according to a study.[46] Moreover, no association was found between advanced maternal age and neurodevelopmental impairment among very low birth weight preterm babies born to advanced-aged mothers.[47] In fact, it is believed that advanced maternal age is protective on offspring's behavioral and cognitive outcomes.[48]

It is possible that as the maternal age increases, the cerebral cortical layers shrink, resulting in compaction of the neural cells in each layer [Figure 1]a,[Figure 1]b,[Figure 1]c. Stereologically, neural cell count was relatively the same across the age groups [Table 4]. Hence, the neural cells are most dense in the most shrunk cerebral frontal lobe of litters of old-aged mothers. This in line with the finding of Cabeza et al.,[49] who demonstrated that brain shrinkage is differential, i.e., the rate of shrinkage varies spatially (across regions, structures, and compartment) and temporarily, along the age continuum.[49]
Figure 1: Histology of cerebral frontal lobe tissue: Photomicrograph sections of litters of young.aged (a), mid.aged (b), and old aged (c) Wistar rats showing the cytoarchitecture of the cerebral frontal lobes (M: Molecular, EG: External granular, EP: External pyramidal, IG: Internal granular, IP: Internal pyramidal, F layers: Fusiform) using hematoxylin and eosin stain, ×100

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The observed increase in biomarkers for OS in the cerebral frontal lobe of the litters with advancing maternal age [Table 5] corresponded with that in the maternal sera [Table 6], showing the effect of aging on OS,[50] which, in turn, contributes to the aging process[51] through the uncontrolled production of reactive oxygen species by aging mitochondria and decreases ability of the body to produce antioxidants.[50] In some human studies and reviews, OS had been associated with an increase in ovulation.[52],[53],[54] This may explain our earlier assertion that there might have been increase in the number of ova shed by the older-aged mothers in this study. Hence, the more the OS, the more ova are shed (ovulation), and the more the litters' size.


  Conclusion Top


The findings of this study show enhancing effects of advancing maternal age on the litter's intelligence, male-to-female sex ratio and litter size, and deleterious effects on the cerebral frontal lobe histo-architecture, OS, and other morphological parameters such as litters' weight, and umbilical, crown-rump and tail lengths.

There have been concerns about the negative outcomes of delayed motherhood, but these might have been exaggerated as it has been established to have so many advantages,[55],[56] some of which had been demonstrated in this study. As rightly pointed out by Cardin,[57] a complete or balanced information outlining both the “risks” and benefits (which outweighs the risks) of delayed motherhood should be provided for all intending mothers so that no woman should be under pressure to conceive too early or too late.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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   Abstract
  Introduction
   Materials and Me...
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