Experimental Evidence of 2,3,7,8-Tetrachlordibenzo-p-Dioxin (TCDD) Transgenerational Effects on Reproductive Health

Abstract

Previous studies have demonstrated that endocrine disruptors (EDs) can promote the transgenerational inheritance of disease susceptibility. Among the many existing EDs, 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) affects reproductive health, including in humans, following direct occupational exposure or environmental disasters, for instance the Agent Orange sprayed during the Vietnam War. Conversely, few studies have focused on TCDD multigenerational and transgenerational effects on human reproductive health, despite the high amount of evidence in animal models of such effects on male and female reproductive health that mimic human reproductive system disorders. Importantly, these studies show that paternal ancestral TCDD exposure substantially contributes to pregnancy outcome and fetal health, although pregnancy outcome is considered tightly related to the woman’s health. In this work, we conducted a systematic review of the literature and a knowledge synthesis in order (i) to describe the findings obtained in rodent models concerning TCDD transgenerational effects on reproductive health and (ii) to discuss the epigenetic molecular alterations that might be involved in this process. As ancestral toxicant exposure cannot be changed in humans, identifying the crucial reproductive functions that are negatively affected by such exposure may help clinicians to preserve male and female fertility and to avoid adverse pregnancy outcomes.

Impact of Endocrine Disruptors upon Non-Genetic Inheritance

“…Exposure to dioxin induces transgenerational effects on both female and male reproductive health. It decreases sex ratio (male/female), alters the onset of puberty and impairs both male and female fertility [ 50 ]. In males, TCDD exposure alters the steroidogenic gene expression in fetal and neonatal testes by reducing pituitary LH production, and reduces the expression of the cholesterol biosynthesis pathway genes in fetal testis, followed by decreased testosterone production [ 50 ].…”

“…In females, TCDD exposure in utero affects estradiol, FSH, and AMH levels. It impairs follicular development and leads to premature ovarian failure by involving mRNA expression, leading to the downregulation of the imprinted genes insulin-like growth factor 2 (Igf2) and H19, and the upregulation of Amh and Amhr2 [ 50 ]. The ancestral exposure of a gestating female to dioxin promotes an altered fetal gonadal development and epigenetic reprogramming of the germline that then transmits the altered epigenome to subsequent generations to contribute to the development of these ovarian diseases transgenerationally.…”

Effects of dioxins on animal spermatogenesis: A state-of-the-art review

“…There are several lines of evidence confirming that the effects of TCDD exposure on animals and humans can persist into the next generation (166,167). This was shown in humans exposed to TCDD as a result of the 1976 chemical explosion in Seveso, Italy, where a reduced motility and a low count of sperm of their male offspring during puberty was reported (122,168).…”

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces multigenerational alterations in the expression of microRNA in the thymus through epigenetic modifications

“…While the impact of toxic chemicals such as TCDD during gestation on fetal health can be explained because such chemicals can cross the placenta and can directly affect the fetus, as in the case of induction of thymic atrophy ( 21 , 22 ), any effect on subsequent generations such as F3 and beyond can be explained primarily by the ability of the chemicals to induce epigenetic changes in the germ-line. This phenomenon is called transgenerational epigenetic inheritance, a process that involves the transmission of an altered epigenome and its impact on the phenotype across generations through the germline even when the chemical is not present to directly cause the toxicity [reviewed in ( 23 )]. The pathways through which transgenerational epigenetic inheritance is mediated include primarily DNA methylation, histone modifications, and noncoding RNAs, including microRNA (miR) ( 23 ).…”

“…This phenomenon is called transgenerational epigenetic inheritance, a process that involves the transmission of an altered epigenome and its impact on the phenotype across generations through the germline even when the chemical is not present to directly cause the toxicity [reviewed in ( 23 )]. The pathways through which transgenerational epigenetic inheritance is mediated include primarily DNA methylation, histone modifications, and noncoding RNAs, including microRNA (miR) ( 23 ).…”