Nondisjunction

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Meiosis I Meiosis II Fertilization Zygote The left image at the blue arrow is nondisjunction taking place during meiosis II. The right image at the green arrow is nondisjunction taking place during meiosis I. Nondisjunction is when chromosomes fail to separate normally resulting in a gain or loss of chromosomes. Nondisjunction Diagrams.svg
The left image at the blue arrow is nondisjunction taking place during meiosis II. The right image at the green arrow is nondisjunction taking place during meiosis I. Nondisjunction is when chromosomes fail to separate normally resulting in a gain or loss of chromosomes.

Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division (mitosis/meiosis). There are three forms of nondisjunction: failure of a pair of homologous chromosomes to separate in meiosis I, failure of sister chromatids to separate during meiosis II, and failure of sister chromatids to separate during mitosis. [1] [2] [3] Nondisjunction results in daughter cells with abnormal chromosome numbers (aneuploidy).

Contents

Calvin Bridges and Thomas Hunt Morgan are credited with discovering nondisjunction in Drosophila melanogaster sex chromosomes in the spring of 1910, while working in the Zoological Laboratory of Columbia University. [4]

Types

In general, nondisjunction can occur in any form of cell division that involves ordered distribution of chromosomal material. Higher animals have three distinct forms of such cell divisions: Meiosis I and meiosis II are specialized forms of cell division occurring during generation of gametes (eggs and sperm) for sexual reproduction, mitosis is the form of cell division used by all other cells of the body.

Meiosis II

Ovulated eggs become arrested in metaphase II until fertilization triggers the second meiotic division. [5] Similar to the segregation events of mitosis, the pairs of sister chromatids resulting from the separation of bivalents in meiosis I are further separated in anaphase of meiosis II. In oocytes, one sister chromatid is segregated into the second polar body, while the other stays inside the egg. During spermatogenesis, each meiotic division is symmetric such that each primary spermatocyte gives rise to 2 secondary spermatocytes after meiosis I, and eventually 4 spermatids after meiosis II. Meiosis II-nondisjunction may also result in aneuploidy syndromes, but only to a much smaller extent than do segregation failures in meiosis I. [6]

Nondisjunction of sister chromatids during mitosis: Left: Metaphase of mitosis. Chromosome line up in the middle plane, the mitotic spindle forms and the kinetochores of sister chromatids attach to the microtubules. Right: Anaphase of mitosis, where sister chromatids separate and the microtubules pull them in opposite directions. The chromosome shown in red fails to separate properly, its sister chromatids stick together and get pulled to the same side, resulting in mitotic nondisjunction of this chromosome. Mitotic nondisjunction.png
Nondisjunction of sister chromatids during mitosis:
Left: Metaphase of mitosis. Chromosome line up in the middle plane, the mitotic spindle forms and the kinetochores of sister chromatids attach to the microtubules.
Right: Anaphase of mitosis, where sister chromatids separate and the microtubules pull them in opposite directions.
The chromosome shown in red fails to separate properly, its sister chromatids stick together and get pulled to the same side, resulting in mitotic nondisjunction of this chromosome.

Mitosis

Division of somatic cells through mitosis is preceded by replication of the genetic material in S phase. As a result, each chromosome consists of two sister chromatids held together at the centromere. In the anaphase of mitosis, sister chromatids separate and migrate to opposite cell poles before the cell divides. Nondisjunction during mitosis leads to one daughter receiving both sister chromatids of the affected chromosome while the other gets none. [2] [3] This is known as a chromatin bridge or an anaphase bridge. Mitotic nondisjunction results in somatic mosaicism, since only daughter cells originating from the cell where the nondisjunction event has occurred will have an abnormal number of chromosomes. [3] Nondisjunction during mitosis can contribute to the development of some forms of cancer, e.g., retinoblastoma (see below). [7] Chromosome nondisjunction in mitosis can be attributed to the inactivation of topoisomerase II, condensin, or separase. [8] Meiotic nondisjunction has been well studied in Saccharomyces cerevisiae . This yeast undergoes mitosis similarly to other eukaryotes. Chromosome bridges occur when sister chromatids are held together post replication by DNA-DNA topological entanglement and the cohesion complex. [9] During anaphase, cohesin is cleaved by separase. [10] Topoisomerase II and condensin are responsible for removing catenations. [11]

Molecular mechanisms

Central role of the spindle assembly checkpoint

The spindle assembly checkpoint (SAC) is a molecular safe-guarding mechanism that governs proper chromosome segregation in eukaryotic cells. [12] SAC inhibits progression into anaphase until all homologous chromosomes (bivalents, or tetrads) are properly aligned to the spindle apparatus. Only then, SAC releases its inhibition of the anaphase promoting complex (APC), which in turn irreversibly triggers progression through anaphase.

Sex-specific differences in meiosis

Surveys of cases of human aneuploidy syndromes have shown that most of them are maternally derived. [5] This raises the question: Why is female meiosis more error prone? The most obvious difference between female oogenesis and male spermatogenesis is the prolonged arrest of oocytes in late stages of prophase I for many years up to several decades. Male gametes on the other hand quickly go through all stages of meiosis I and II. Another important difference between male and female meiosis concerns the frequency of recombination between homologous chromosomes: In the male, almost all chromosome pairs are joined by at least one crossover, while more than 10% of human oocytes contain at least one bivalent without any crossover event. Failures of recombination or inappropriately located crossovers have been well documented as contributors to the occurrence of nondisjunction in humans. [5]

Due to the prolonged arrest of human oocytes, weakening of cohesive ties holding together chromosomes and reduced activity of the SAC may contribute to maternal age-related errors in segregation control. [6] [13] The cohesin complex is responsible for keeping together sister chromatids and provides binding sites for spindle attachment. Cohesin is loaded onto newly replicated chromosomes in oogonia during fetal development. Mature oocytes have only limited capacity for reloading cohesin after completion of S phase. The prolonged arrest of human oocytes prior to completion of meiosis I may therefore result in considerable loss of cohesin over time. Loss of cohesin is assumed to contribute to incorrect microtubule-kinetochore attachment and chromosome segregation errors during meiotic divisions. [6]

Consequences

The result of this error is a cell with an imbalance of chromosomes. Such a cell is said to be aneuploid. Loss of a single chromosome (2n-1), in which the daughter cell(s) with the defect will have one chromosome missing from one of its pairs, is referred to as a monosomy. Gaining a single chromosome, in which the daughter cell(s) with the defect will have one chromosome in addition to its pairs is referred to as a trisomy. [3] In the event that an aneuploidic gamete is fertilized, a number of syndromes might result.

Monosomy

The only known survivable monosomy in humans is Turner syndrome, where the affected individual is monosomic for the X chromosome (see below). Other monosomies are usually lethal during early fetal development, and survival is only possible if not all the cells of the body are affected in case of a mosaicism (see below), or if the normal number of chromosomes is restored via duplication of the single monosomic chromosome ("chromosome rescue"). [2]

Turner syndrome (X monosomy) (45, X0)

Karyotype of X monosomy (Turner syndrome) This condition is characterized by the presence of only one X chromosome and no Y chromosome (see bottom right corner). 45,X.jpg
Karyotype of X monosomy (Turner syndrome)
This condition is characterized by the presence of only one X chromosome and no Y chromosome (see bottom right corner).

Complete loss of an entire X chromosome accounts for about half the cases of Turner syndrome. The importance of both X chromosomes during embryonic development is underscored by the observation that the overwhelming majority (>99%) of fetuses with only one X chromosome (karyotype 45, X0) are spontaneously aborted. [14]

Autosomal trisomy

The term autosomal trisomy means that a chromosome other than the sex chromosomes X and Y is present in 3 copies instead of the normal number of 2 in diploid cells.

Down syndrome (trisomy 21)

Karyotype of trisomy 21 (Down syndrome) Note that chromosome 21 is present in 3 copies, while all other chromosomes show the normal diploid state with 2 copies. Most cases of trisomy of chromosome 21 are caused by a nondisjunction event during meiosis I (see text). Down Syndrome Karyotype.png
Karyotype of trisomy 21 (Down syndrome)
Note that chromosome 21 is present in 3 copies, while all other chromosomes show the normal diploid state with 2 copies. Most cases of trisomy of chromosome 21 are caused by a nondisjunction event during meiosis I (see text).

Down syndrome, a trisomy of chromosome 21, is the most common anomaly of chromosome number in humans. [2] The majority of cases result from nondisjunction during maternal meiosis I. [14] Trisomy occurs in at least 0.3% of newborns and in nearly 25% of spontaneous abortions. It is the leading cause of pregnancy wastage and is the most common known cause of intellectual disability. [15] It is well documented that advanced maternal age is associated with greater risk of meiotic nondisjunction leading to Down syndrome. This may be associated with the prolonged meiotic arrest of human oocytes potentially lasting for more than four decades. [13]

Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13)

Human autosomal trisomies compatible with live birth, other than Down syndrome (trisomy 21), are Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13). [1] [2] Complete trisomies of other chromosomes are usually not viable and represent a relatively frequent cause of miscarriage. Only in rare cases of a mosaicism, the presence of a normal cell line, in addition to the trisomic cell line, may support the development of a viable trisomy of the other chromosomes. [2]

Sex chromosome aneuploidy

The term sex chromosome aneuploidy summarizes conditions with an abnormal number of sex chromosomes, i.e., other than XX (female) or XY (male). Formally, X chromosome monosomy (Turner syndrome, see above) can also be classified as a form of sex chromosome aneuploidy.

Klinefelter syndrome (47, XXY)

Klinefelter syndrome is the most common sex chromosome aneuploidy in humans. It represents the most frequent cause of hypogonadism and infertility in men. Most cases are caused by nondisjunction errors in paternal meiosis I. [2] About eighty percent of individuals with this syndrome have one extra X chromosome resulting in the karyotype XXY. The remaining cases have either multiple additional sex chromosomes (48,XXXY; 48,XXYY; 49,XXXXY), mosaicism (46,XY/47,XXY), or structural chromosome abnormalities. [2]

XYY Male (47, XYY)

The incidence of XYY syndrome is approximately 1 in 800–1000 male births. Many cases remain undiagnosed because of their normal appearance and fertility, and the absence of severe symptoms. The extra Y chromosome is usually a result of nondisjunction during paternal meiosis II. [2]

Trisomy X (47,XXX)

Trisomy X is a form of sex chromosome aneuploidy where females have three instead of two X chromosomes. Most patients are only mildly affected by neuropsychological and physical symptoms. Studies examining the origin of the extra X chromosome observed that about 58–63% of cases were caused by nondisjunction in maternal meiosis I, 16–18% by nondisjunction in maternal meiosis II, and the remaining cases by post-zygotic, i.e., mitotic, nondisjunction. [16]

Uniparental disomy

Uniparental disomy denotes the situation where both chromosomes of a chromosome pair are inherited from the same parent and are therefore identical. This phenomenon most likely is the result of a pregnancy that started as a trisomy due to nondisjunction. Since most trisomies are lethal, the fetus only survives because it loses one of the three chromosomes and becomes disomic. Uniparental disomy of chromosome 15 is, for example, seen in some cases of Prader-Willi syndrome and Angelman syndrome. [14]

Mosaicism syndromes

Mosaicism syndromes can be caused by mitotic nondisjunction in early fetal development. As a consequence, the organism evolves as a mixture of cell lines with differing ploidy (number of chromosomes). Mosaicism may be present in some tissues, but not in others. Affected individuals may have a patchy or asymmetric appearance. Examples of mosaicism syndromes include Pallister-Killian syndrome and Hypomelanosis of Ito. [14]

Mosaicism in malignant transformation

Loss of a tumor suppressor gene locus according to the two-hit model: In the first hit, the tumor suppressor gene on one of the two chromosomes is affected by a mutation that makes the gene product non-functional. This mutation may arise spontaneously as a DNA replication error or may be induced by a DNA damaging agent. The second hit removes the remaining wild-type chromosome, for example through a mitotic nondisjunction event. There are several other potential mechanisms for each of the two steps, for example an additional mutation, an unbalanced translocation, or a gene deletion by recombination. As a result of the double lesion, the cell may become malignant because it is no longer able to express the tumor suppressor protein. Two hit malignant transformation with chromosome loss.png
Loss of a tumor suppressor gene locus according to the two-hit model:
In the first hit, the tumor suppressor gene on one of the two chromosomes is affected by a mutation that makes the gene product non-functional. This mutation may arise spontaneously as a DNA replication error or may be induced by a DNA damaging agent. The second hit removes the remaining wild-type chromosome, for example through a mitotic nondisjunction event. There are several other potential mechanisms for each of the two steps, for example an additional mutation, an unbalanced translocation, or a gene deletion by recombination. As a result of the double lesion, the cell may become malignant because it is no longer able to express the tumor suppressor protein.

Development of cancer often involves multiple alterations of the cellular genome (Knudson hypothesis). Human retinoblastoma is a well studied example of a cancer type where mitotic nondisjunction can contribute to malignant transformation: Mutations of the RB1 gene, which is located on chromosome 13 and encodes the tumor suppressor retinoblastoma protein, can be detected by cytogenetic analysis in many cases of retinoblastoma. Mutations of the RB1 locus in one copy of chromosome 13 are sometimes accompanied by loss of the other wild-type chromosome 13 through mitotic nondisjunction. By this combination of lesions, affected cells completely lose expression of functioning tumor suppressor protein. [7]

Diagnosis

Preimplantation genetic diagnosis

Pre-implantation genetic diagnosis (PGD or PIGD) is a technique used to identify genetically normal embryos and is useful for couples who have a family history of genetic disorders. This is an option for people choosing to procreate through IVF. PGD is considered difficult due to it being both time consuming and having success rates only comparable to routine IVF. [17]

Karyotyping

Karyotyping involves performing an amniocentesis in order to study the cells of an unborn fetus during metaphase 1. Light microscopy can be used to visually determine if aneuploidy is an issue. [18]

Polar body diagnosis

Polar body diagnosis (PBD) can be used to detect maternally derived chromosomal aneuploidies as well as translocations in oocytes. The advantage of PBD over PGD is that it can be accomplished in a short amount of time. This is accomplished through zona drilling or laser drilling. [19]

Blastomere biopsy

Blastomere biopsy is a technique in which blastomeres are removed from the zona pellucida. It is commonly used to detect aneuploidy. [20] Genetic analysis is conducted once the procedure is complete. Additional studies are needed to assess the risk associated with the procedure. [21]

Lifestyle/environmental hazards

Exposure of spermatozoa to lifestyle, environmental and/or occupational hazards may increase the risk of aneuploidy. Cigarette smoke is a known aneugen (aneuploidy inducing agent). It is associated with increases in aneuploidy ranging from 1.5 to 3.0-fold. [22] [23] Other studies indicate factors such as alcohol consumption, [24] occupational exposure to benzene, [25] and exposure to the insecticides fenvalerate [26] and carbaryl [27] also increase aneuploidy.

Related Research Articles

<span class="mw-page-title-main">Meiosis</span> Cell division producing haploid gametes

Meiosis is a special type of cell division of germ cells and apicomplexans in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately result in four cells with only one copy of each chromosome (haploid). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilisation, the haploid cells produced by meiosis from a male and a female will fuse to create a cell with two copies of each chromosome again, the zygote.

<span class="mw-page-title-main">Mitosis</span> Process in which chromosomes are replicated and separated into two new identical nuclei

Mitosis is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis is an equational division which gives rise to genetically identical cells in which the total number of chromosomes is maintained. Mitosis is preceded by the S phase of interphase and is followed by telophase and cytokinesis; which divides the cytoplasm, organelles and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis altogether define the mitotic phase of a cell cycle—the division of the mother cell into two daughter cells genetically identical to each other.

<span class="mw-page-title-main">Prophase</span> First phase of cell division in both mitosis and meiosis

Prophase is the first stage of cell division in both mitosis and meiosis. Beginning after interphase, DNA has already been replicated when the cell enters prophase. The main occurrences in prophase are the condensation of the chromatin reticulum and the disappearance of the nucleolus.

<span class="mw-page-title-main">Aneuploidy</span> Presence of an abnormal number of chromosomes in a cell

Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any number of complete chromosome sets is called a euploid cell.

<span class="mw-page-title-main">Homologous chromosome</span> Chromosomes that pair in fertilization

A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci, where they provide points along each chromosome that enable a pair of chromosomes to align correctly with each other before separating during meiosis. This is the basis for Mendelian inheritance, which characterizes inheritance patterns of genetic material from an organism to its offspring parent developmental cell at the given time and area.

<span class="mw-page-title-main">Mosaic (genetics)</span> Condition in multi-cellular organisms

Mosaicism or genetic mosaicism is a condition in which a multicellular organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized egg. Mosaicism is one of several possible causes of chimerism, wherein a single organism is composed of cells with more than one distinct genotype.

<span class="mw-page-title-main">Spindle checkpoint</span> Cell cycle checkpoint

The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during metaphase of mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.

<span class="mw-page-title-main">Monosomy</span> Medical condition

Monosomy is a form of aneuploidy with the presence of only one chromosome from a pair. Partial monosomy occurs when a portion of one chromosome in a pair is missing.

<span class="mw-page-title-main">Cohesin</span> Protein complex that regulates the separation of sister chromatids during cell division

Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3. Cohesin holds sister chromatids together after DNA replication until anaphase when removal of cohesin leads to separation of sister chromatids. The complex forms a ring-like structure and it is believed that sister chromatids are held together by entrapment inside the cohesin ring. Cohesin is a member of the SMC family of protein complexes which includes Condensin, MukBEF and SMC-ScpAB.

<span class="mw-page-title-main">Genetics of Down syndrome</span>

Down syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on chromosome 21, either in whole or part. The effects of the extra copy varies greatly from individual to individual, depending on the extent of the extra copy, genetic background, environmental factors, and random chance. Down syndrome can occur in all human populations, and analogous effects have been found in other species, such as chimpanzees and mice. In 2005, researchers have been able to create transgenic mice with most of human chromosome 21.

A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where there is an atypical number of chromosomes, or as structural abnormalities, where one or more individual chromosomes are altered. Chromosome mutation was formerly used in a strict sense to mean a change in a chromosomal segment, involving more than one gene. Chromosome anomalies usually occur when there is an error in cell division following meiosis or mitosis. Chromosome abnormalities may be detected or confirmed by comparing an individual's karyotype, or full set of chromosomes, to a typical karyotype for the species via genetic testing.

Chromosome segregation is the process in eukaryotes by which two sister chromatids formed as a consequence of DNA replication, or paired homologous chromosomes, separate from each other and migrate to opposite poles of the nucleus. This segregation process occurs during both mitosis and meiosis. Chromosome segregation also occurs in prokaryotes. However, in contrast to eukaryotic chromosome segregation, replication and segregation are not temporally separated. Instead segregation occurs progressively following replication.

Sister chromatid cohesion refers to the process by which sister chromatids are paired and held together during certain phases of the cell cycle. Establishment of sister chromatid cohesion is the process by which chromatin-associated cohesin protein becomes competent to physically bind together the sister chromatids. In general, cohesion is established during S phase as DNA is replicated, and is lost when chromosomes segregate during mitosis and meiosis. Some studies have suggested that cohesion aids in aligning the kinetochores during mitosis by forcing the kinetochores to face opposite cell poles.

<span class="mw-page-title-main">SMC1B</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 1B (SMC-1B) is a protein that in humans is encoded by the SMC1B gene. SMC proteins engage in chromosome organization and can be broken into 3 groups based on function which are cohesins, condensins, and DNA repair. SMC-1B belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis. SMC1B protein appears to participate with other cohesins REC8, STAG3 and SMC3 in sister-chromatid cohesion throughout the whole meiotic process in human oocytes.

<span class="mw-page-title-main">STAG3 (gene)</span> Protein-coding gene in the species Homo sapiens

Stromal antigen 3 is a protein that in humans is encoded by the STAG3 gene. STAG3 protein is a component of a cohesin complex that regulates the separation of sister chromatids specifically during meiosis. STAG3 appears to be paramount in sister-chromatid cohesion throughout the meiotic process in human oocytes and spermatocytes.

Ovum quality is the measure of the ability of an oocyte to achieve successful fertilisation. The quality is determined by the maturity of the oocyte and the cells that it comprises, which are susceptible to various factors which impact quality and thus reproductive success. This is of significance as an embryo's development is more heavily reliant on the oocyte in comparison to the sperm.

<span class="mw-page-title-main">Tetrasomy X</span> Chromosomal disorder with 4 X chromosomes

Tetrasomy X, also known as 48,XXXX, is a chromosomal disorder in which a female has four, rather than two, copies of the X chromosome. It is associated with intellectual disability of varying severity, characteristic "coarse" facial features, heart defects, and skeletal anomalies such as increased height, clinodactyly, and radioulnar synostosis. Tetrasomy X is a rare condition, with few medically recognized cases; it is estimated to occur in approximately 1 in 50,000 females.

<span class="mw-page-title-main">Pentasomy X</span> Chromosomal disorder

Pentasomy X, also known as 49,XXXXX, is a chromosomal disorder in which a female has five, rather than two, copies of the X chromosome. Pentasomy X is associated with short stature, intellectual disability, characteristic facial features, heart defects, skeletal anomalies, and pubertal and reproductive abnormalities. The condition is exceptionally rare, with an estimated prevalence between 1 in 85,000 and 1 in 250,000.

<span class="mw-page-title-main">Trisomy X</span> Chromosome disorder in women

Trisomy X, also known as triple X syndrome and characterized by the karyotype 47,XXX, is a chromosome disorder in which a female has an extra copy of the X chromosome. It is relatively common and occurs in 1 in 1,000 females, but is rarely diagnosed; fewer than 10% of those with the condition know they have it.

Oocytes are immature egg cells that develop to maturity within a follicle in the ovary. Oocyte abnormalities can occur due to several factors, including premature ovarian insufficiency (POI), other maturation abnormalities, maternal ageing, and mitochondrial abnormalities.

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  25. ↑ McHale CM, Smith MT, Zhang L (2014). "Application of toxicogenomic profiling to evaluate effects of benzene and formaldehyde: from yeast to human". Ann. N. Y. Acad. Sci. 1310 (1): 74–83. Bibcode:2014NYASA1310...74M. doi:10.1111/nyas.12382. PMC   3978411 . PMID   24571325.
  26. ↑ Xia Y, Bian Q, Xu L, Cheng S, Song L, Liu J, Wu W, Wang S, Wang X (2004). "Genotoxic effects on human spermatozoa among pesticide factory workers exposed to fenvalerate". Toxicology. 203 (1–3): 49–60. doi:10.1016/j.tox.2004.05.018. PMID   15363581. S2CID   36073841.
  27. ↑ Xia Y, Cheng S, Bian Q, Xu L, Collins MD, Chang HC, Song L, Liu J, Wang S, Wang X (2005). "Genotoxic effects on spermatozoa of carbaryl-exposed workers". Toxicol. Sci. 85 (1): 615–23. doi: 10.1093/toxsci/kfi066 . PMID   15615886.
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