Aneuploidy: a common and early evidence-based biomarker for carcinogens and reproductive toxicants

Abstract

Aneuploidy, defined as structural and numerical aberrations of chromosomes, continues to draw attention as an informative effect biomarker for carcinogens and male reproductive toxicants. It has been well documented that aneuploidy is a hallmark of cancer. Aneuploidies in oocytes and spermatozoa contribute to infertility, pregnancy loss and a number of congenital abnormalities, and sperm aneuploidy is associated with testicular cancer. It is striking that several carcinogens induce aneuploidy in somatic cells, and also adversely affect the chromosome compliment of germ cells. In this paper we review 1) the contributions of aneuploidy to cancer, infertility, and developmental abnormalities; 2) techniques for assessing aneuploidy in precancerous and malignant lesions and in sperm; and 3) the utility of aneuploidy as a biomarker for integrated chemical assessments of carcinogenicity, and reproductive and developmental toxicity.

Meiotic nondisjunction and sperm aneuploidy in humans

“…Multiple studies have demonstrated an association between environmental factors and increased sperm aneuploidy frequencies. Associations that have been reported include smoking, air pollution, benzene, chemotherapy, parabens, polychlorinated biphenyl and scrotal heating, amongst others (Robbins et al 2005, Tempest et al 2005, Perry 2008, Xing et al 2010, Ji et al 2012, Mcauliffe et al 2012, Figueroa et al 2015, Governini et al 2015, Radwan et al 2016, Perry et al 2016, Beal et al 2017, Jurewicz et al 2017, Rives et al 2017. It is important to note that such studies in humans are notoriously difficult to design, compare and reproduce, and it is extremely difficult to prove causation given the multitude of confounding factors that exist in such studies.…”

“…Genotoxic and mutagenic studies frequently assess chromosome aberrations in somatic cells to determine whether compounds have carcinogenic potential through multiple techniques, including FISH, comet assay and the micronucleus assay, amongst others. Inclusion of sperm aneuploidy in such studies could also provide valuable information on reproductive toxicants and will ultimately provide a more comprehensive evaluation of carcinogenicity and reproductive toxicity (Mandrioli et al 2016). In addition to investigating chromosome aneuploidy in sperm, other biomarkers should be considered to monitor exposure to environmental hazards, including sperm DNA integrity (DNA fragmentation), chromatin modifications (epigenetics) and nuclear organization amongst others (Anton & Krawetz 2012).…”

Endocrine Disruptors: Very Low Doses with Genuinely High Impacts on Male Reproduction

“…The comparable effect of EDs is known during spermatogenesis: BPA is capable of affecting meiotic division and chromosome segregation, increasing the incidence of aneuploidy-derived disorders [73]. In addition, the molecular mechanism of BPA consists in impacting several signal pathways and results in the change of protein kinase A activity and protein tyrosine phosphorylation, ATP generation, and oxidative stress-related enzymes (i.e., peroxiredoxin-5, glutathione peroxidase 4, succinate dehydrogenase), crucial for sperm motility and ability of oocyte fertilization [26,27,74].…”

Maternal common variant rs2305957 spanning PLK4 is associated with blastocyst formation and early recurrent miscarriage

“…Recently, aneuploid embryos have been discovered to account for >50% of early miscarriages (7,8). Aneuploidy, defined as structural and numeric aberrations of chromosomes, is prevalent in human embryonic development (9). It is considered to be a primary genetic origin of implantation failure, miscarriage, and congenital abnormalities, both naturally and after IVF (9)(10)(11)(12).…”

“…Aneuploidy, defined as structural and numeric aberrations of chromosomes, is prevalent in human embryonic development (9). It is considered to be a primary genetic origin of implantation failure, miscarriage, and congenital abnormalities, both naturally and after IVF (9)(10)(11)(12). Despite extensive investigation, little is known about the complex origins and mechanisms underlying aneuploidy.…”