Effect of environmental and pharmaceutical exposures on fetal testis development and function: a systematic review of human experimental data

Abstract

BACKGROUND Overall, the incidence of male reproductive disorders has increased in recent decades. Testicular development during fetal life is crucial for subsequent male reproductive function. Non-genomic factors such as environmental chemicals, pharmaceuticals and lifestyle have been proposed to impact on human fetal testicular development resulting in subsequent effects on male reproductive health. Whilst experimental studies using animal models have provided support for this hypothesis, more recently a number of experimental studies using human tissues and cells have begun to translate these findings to determine direct human relevance. OBJECTIVE AND RATIONALE The objective of this systematic review was to provide a comprehensive description of the evidence for effects of prenatal exposure(s) on human fetal testis development and function. We present the effects of environmental, pharmaceutical and lifestyle factors in experimental systems involving exposure of human fetal testis tissues and cells. Comparison is made with existing epidemiological data primarily derived from a recent meta-analysis. SEARCH METHODS For identification of experimental studies, PubMed and EMBASE were searched for articles published in English between 01/01/1966 and 13/07/2018 using search terms including ‘endocrine disruptor’, ‘human’, ‘fetal’, ‘testis’, ‘germ cells’, ‘testosterone’ and related search terms. Abstracts were screened for selection of full-text articles for further interrogation. Epidemiological studies involving exposure to the same agents were extracted from a recent systematic review and meta-analysis. Additional studies were identified through screening of bibliographies of full-texts of articles identified through the initial searches. OUTCOMES A total of 25 experimental studies and 44 epidemiological studies were included. Consistent effects of analgesic and phthalate exposure on human fetal germ cell development are demonstrated in experimental models, correlating with evidence from epidemiological studies and animal models. Furthermore, analgesic-induced reduction in fetal testosterone production, which predisposes to the development of male reproductive disorders, has been reported in studies involving human tissues, which also supports data from animal and epidemiological studies. However, whilst reduced testosterone production has been demonstrated in animal studies following exposure(s) to a variety of environmental chemicals including phthalates and bisphenol A, these effects are not reproduced in experimental approaches using human fetal testis tissues. WIDER IMPLICATIONS Direct experimental evidence for effects of prenatal exposure(s) on human fetal testis development and function exists. However, for many exposures the data is limited. The increasing use of human-relevant models systems in which to determine the effects of environmental exposure(s) (including mixed exposures) on development and function of human tissues should form an important part of the process for assessment of such exposures by regulatory bodies to take account of animal–human differences in susceptibility.

Oestrogenic Endocrine Disruptors in the Placenta and the Fetus

“…Phthalates can cross the placental barrier as a result of continuous exposure during pregnancy, with profoundly negative consequences for the future health of infants, by increasing the risk of developing defects such as low birth weight, cardiovascular diseases, cryptorchidism, and cancer later in life [111,112]. The metabolites of DEHP have been detected by mass spectrometry in amniotic fluid.…”

<p>Fetal Programming of Semen Quality (FEPOS) Cohort – A DNBC Male-Offspring Cohort</p>

“…18 This was supported by Sharpe and Skakkebaek,19 who subsequently proposed that hypospadias, cryptorchidism, poor semen quality, and testicular cancer are symptoms of one underlying entity with a common fetal origin. 20,21 Although an increasing number of studies of maternal lifestyle and health during pregnancy, such as maternal diet, alcohol consumption, smoking, medication use, and obesity support this fetal programming hypothesis, [22][23][24][25][26][27] large-scale epidemiological evidence is still lackingespecially regarding maternal exposure to endocrine disrupting chemicals at home and at work. 28 The limited body of evidence is likely explained by the complex logistics and high costs of establishing long-term longitudinal populationbased studies of male reproductive function, with information on exposures during early life, such as the need for detailed maternal information and bio-specimens stored for decades before follow-up.…”

Regional difference in semen quality of young men: a review on the implication of environmental and lifestyle factors during fetal life and adulthood

“…As far as experimental studies are concerned, the majority of them are based on rodent experiments despite the significant differences between humans and rodents in testicular development and reprotoxic effects. These inter-species differences forced the scientific community to develop more relevant in vitro approaches utilizing human tissues [158]. In the past few years, we have seen the emergence of new model systems such as in vitro or xenograft approaches using human fetal testis at human-relevant doses that can bridge the gap between direct evidence from animal experimental models and indirect evidence based on epidemiological data.…”