Xenotransplantation Models to Study the Effects of Toxicants on Human Fetal Tissues

Abstract

Many diseases that manifest throughout the lifetime are influenced by factors affecting fetal development. Fetal exposure to xenobiotics, in particular, may influence the development of adult diseases. Established animal models provide systems for characterizing both developmental biology and developmental toxicology. However, animal model systems do not allow researchers to assess the mechanistic effects of toxicants on developing human tissue. Human fetal tissue xenotransplantation models have recently been implemented to provide human-relevant mechanistic data on the many tissue-level functions that may be affected by fetal exposure to toxicants. This review describes the development of human fetal tissue xenotransplant models for testis, prostate, lung, liver, and adipose tissue, aimed at studying the effects of xenobiotics on tissue development, including implications for testicular dysgenesis, prostate disease, lung disease, and metabolic syndrome. The mechanistic data obtained from these models can complement data from epidemiology, traditional animal models, and in vitro studies to quantify the risks of toxicant exposures during human development.

Decellularization of tumours: A new frontier in tissue engineering

“…In these models, human cells, tissues or organs can be implanted into an immunodeficient animal host, which provides the environment for the human tissue to function and grow normally. 71 These models have been studied for organ transplantation or toxicity studies, 71 , 72 and have emerged as a powerful research tool in the fight against cancer. 53 , 54 With these models, it is possible to grow an unlimited number of patient-specific tumours that can then be harvested for experimentation, including decellularization studies.…”

A xenotransplantation mouse model to study physiology of the mammary gland from large mammals

“…Historically, xenotransplantation models have served as valuable tools to understand cancer biology [12][13][14], assess stem/progenitor cell repopulation potential [15,16], and resolve critical developmental mechanisms [17]. Furthermore, drug responses in xenotransplanted tissues, both healthy and malignant, often align with clinical responses [14,[18][19][20], indicating their value in modeling drug pharmacokinetics. Regarding the generation of mammary xenografts, one approach relies on the murine mammary fat pad de-epithelializing (clearing) method, in which the postnatally-developing endogenous mammary epithelium is excised during puberty, at about 3-4 weeks of age, followed by xenotransplantation of typically freshly obtained mammary tissues or sorted stem/ progenitor cells from other mammals into the residual stroma [21], as has been described for rat [22], cow [15,[23][24][25][26][27], and human [28][29][30].…”

Environmental Toxicant Induced Epigenetic Transgenerational Inheritance of Prostate Pathology and Stromal-Epithelial Cell Epigenome and Transcriptome Alterations: Ancestral Origins of Prostate Disease

“…Although a variety of environmental toxicants following direct exposure have been associated with prostate pathology and disease 13,14 , few studies have investigated transgenerational effects in later generations not exposed in utero or neonatally. Initial studies of the ability of environmental toxicants to promote the epigenetic transgenerational inheritance of prostate pathology and disease showed that ancestral exposure to the agricultural fungicide vinclozolin increased rates of prostatic epithelial atrophy, cystic hyperplasia and prostatitis in the transgenerational F3 and F4 generations 15,16 .…”