Insulin-like factor 3 as a monitor of endocrine disruption

Anand‐Ivell, Ravinder; Ivell, Richard

doi:10.1530/rep-13-0486

Cited by 33 publications

(36 citation statements)

References 48 publications

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“…The inguinal canal remains wide in the adult rat, allowing the male rat to lift its testicle into the abdomen (Wensing, ). Intrauterine exposure to phthalates in rats causes reduced INSL3 production by fetal Leydig cells and leads to cryptorchidism (Anand‐Ivell and Ivell, ).…”

Section: Testicular Descentmentioning

confidence: 99%

Comparative Aspects of Pre‐ and Postnatal Development of the Male Reproductive System

Picut

Ziejewski

Stanislaus

2017

Birth Defects Research

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This review describes pre- and postnatal development of the male reproductive system in humans and laboratory animals, and highlights species differences in the timing and control of hormonal and morphologic events. Major differences are that the fetal testis is dependent on gonadotropins in humans, but is independent of such in rats; humans have an extended postnatal quiescent period, whereas rats exhibit no quiescence; and events such as secretion by the prostate and seminal vesicles, testicular descent, and the appearance of spermatogonia are all prenatal events in humans, but are postnatal events in rats. Major differences in the timing of the developmental sequence between rats and humans include: gonocyte transformation period (rat: postnatal day 0-9; human: includes gestational week 22 to 9 months of age); masculinization programming window (rat: gestational day 15.5-17.5; human: gestational week 9-14); and mini-puberty (rat: 0-6 hr after birth; human: 3-6 months of age). Endocrine disruptors can cause unique lesions in the prenatal and early postnatal testis; therefore, it is important to consider the differences in the timing of the developmental sequence when designing preclinical studies as identification of windows of sensitivity for endocrine disruption or toxicants will aid in interpretation of results and provide clues to a mode of action. Birth Defects Research 110:190-227, 2018. © 2017 Wiley Periodicals, Inc.

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Section: Testicular Descentmentioning

confidence: 99%

Comparative Aspects of Pre‐ and Postnatal Development of the Male Reproductive System

Picut

Ziejewski

Stanislaus

2017

Birth Defects Research

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“…In addition, androgens and insulin-like factor 3 from FLCs also play a role in the regulation of transabdominal and inguinoscrotal testicular decent [2,3,37]. Androgen and insulin-like factor 3 deficiency during embryonic development lead to the retainment of testes in the body cavity, causing cryptorchidism (for a review, see [38]). Cryptorchidism leads to infertility later in adult life since the higher temperature of the body cavity at 37 °C is detrimental to spermatogenesis which requires an optimal temperature of 35 °C by residing in the scrotum.…”

Section: Flc Cytogenesismentioning

confidence: 99%

Development, function and fate of fetal Leydig cells

Wen

Cheng

Liu

2016

Seminars in Cell & Developmental Biology

103

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During fetal testis development, fetal Leydig cells (FLCs) are found to be originated from multiple progenitor cells. FLC specification and function are under tight regulation of specific genes and signaling proteins. Furthermore, Sertoli cells play a crucial role to regulate FLC differentiation during fetal testis development. FLC progenitor- and FLC-produced biomolecules are also involved in the differentiation and activity of rodent FLCs. The main function of FLCs is to produce androgens to masculinize XY embryos. However, FLCs are capable of producing androstenedione but not testosterone due to the lack of 17β-HSD (17β-hydroxysteroid dehydrogenase), but fetal Sertoli cells express 17β-HSD which thus transforms androstenedione to testosterone in the fetal testis. On the other hand, FLCs produce activin A to regulate Sertoli cell proliferation, and Sertoli cells in turn modulate testis cord expansion. It is now generally accepted that adult Leydig cells (ALCs) gradually replace FLCs during postnatal development to produce testosterone to support spermatogenesis as FLCs undergo degeneration in neonatal and pre-pubertal testes. However, based on studies using genetic tracing mouse models, FLCs are found to persist in adult testes, making up ~20% of total Leydig cells. In this review, we evaluate the latest findings regarding the development, function and fate of FLCs during fetal and adult testis development.

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“…This hormone induces the transabdominal descent of foetal testes from their initial mesonephrotic position to the entrance of the inguinal duct, whereas the inguino-scrotal descent is androgen-dependent [72]. Exposure to some phthalates also reduces Insl-3 expression in the rat foetal testis [73, 74].…”

Section: Reviewmentioning

confidence: 99%

Man is not a big rat: concerns with traditional human risk assessment of phthalates based on their anti-androgenic effects observed in the rat foetus

Habert

Livera

Rouiller-Fabre

2014

Basic Clin. Androl.

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Phthalates provide one of the most documented example evidencing how much we must be cautious when using the traditional paradigm based on extrapolation of experimental data from rodent studies for human health risk assessment of endocrine disruptors (EDs). Since foetal testis is known as one of the most sensitive targets of EDs, phthalate risk assessment is routinely based on the capacity of such compounds to decrease testosterone production by the testis or to impair masculinization in the rat during foetal life. In this paper, the well-established inhibiting effects of phthalates of the foetal Leydig cells function in the rat are briefly reviewed. Then, data obtained in humans and other species are carefully analysed. Already in January 2009, using the organotypic culture system named Fetal Testis Assay (FeTA) that we developed, we reported that phthalates might not affect testosterone production in human foetal testes. Several recent experimental studies using xenografts confirm the absence of detectable anti-androgenic effect of phthalates in the human foetal testes. Epidemiological studies led to contradictory results. Altogether, these findings suggest that phthalates effects on foetal Leydig cells are largely species-specific. Consequently, the phthalate threshold doses that disturb foetal steroidogenesis in rat testes and that are presently used to define the acceptable daily intake levels for human health protection must be questioned. This does not mean that phthalates are safe because these compounds have many deleterious effects upon germ cell development that may be common to the different studied species including human. More generally, the identification of common molecular, cellular or/and phenotypic targets in rat and human testes should precede the choice of the toxicological endpoint in rat to accurately assess the safety threshold of any ED in humans.

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Insulin-like factor 3 as a monitor of endocrine disruption

Cited by 33 publications

References 48 publications

Comparative Aspects of Pre‐ and Postnatal Development of the Male Reproductive System

Comparative Aspects of Pre‐ and Postnatal Development of the Male Reproductive System

Development, function and fate of fetal Leydig cells

Man is not a big rat: concerns with traditional human risk assessment of phthalates based on their anti-androgenic effects observed in the rat foetus

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