Multi Species Analyses Reveal Testicular T3 Metabolism and Signalling as a Target of Environmental Pesticides

Abstract

Thyroid hormones (THs) regulate many biological processes in vertebrates, including reproduction. Testicular somatic and germ cells are equipped with the arrays of enzymes (deiodinases), transporters, and receptors necessary to locally maintain the optimal level of THs and their signalling, needed for their functions and spermatogenesis. Pesticides, as chlorpyrifos (CPF) and ethylene thiourea (ETU), impair the function of thyroid and testis, affecting male fertility. However, their ability to disarrange testicular T3 (t-T3) metabolism and signalling is poorly considered. Here, a multi-species analysis involving zebrafish and mouse suggests the damage of t-T3 metabolism and signalling as a mechanism of gonadic toxicity of low-doses CPF and ETU. Indeed, the developmental exposure to both compounds reduces Dio2 transcript in both models, as well as in ex-vivo cultures of murine seminiferous tubules, and it is linked to alteration of steroidogenesis and germ cell differentiation. A major impact on spermatogonia was confirmed molecularly by the expression of their markers and morphologically evidenced in zebrafish. The results reveal that in the adopted models, exposure to both pesticides alters the t-T3 metabolism and signalling, affecting the reproductive capability. Our data, together with previous reports suggest zebrafish as an evaluable model in assessing the action of compounds impairing locally T3 signalling.

Pesticides and Male Fertility: A Dangerous Crosstalk

“…Indeed, it was shown that PPARα and PPARβ/δ activation could stimulate the expression of genes involved in fatty acids transport and oxidation in Sertoli cells [74]. Furthermore, exposure to both chlorpyrifos, an organophosphate compound, and ethylene thiourea, the main metabolite of mancozeb, showed to interfere with thyroid hormones that are essential regulators of testis functionality, by reducing testicular T3-metabolism signaling in the exposed mice [75]. In essence, these pesticides can interfere in testicular metabolism through multiple mechanisms.…”

A Cross-Species Analysis Reveals Dysthyroidism of the Ovaries as a Common Trait of Premature Ovarian Aging

“…Currently, epidemiological studies have been focused on its neurotoxicity and carcinogenesis [20,21]. Its ability to affect reproduction and promote follicle atresia has been described in mice and zebrafish [22][23][24]. In both species, CPF exposure has been associated with a decrease in circulating estrogen levels and derangement of other hormones active along the HPG axis.…”

“…Since we already conducted a study aimed to characterize the effect of environmentally relevant exposure to chlorpyrifos (CPF) on the metabolism and signaling of THs in zebrafish, we took advantage of collected samples to characterize ovarian dysthyroidism in females. Their reproductive dysfunctions [24,26] were revealed by investigating the impact of CPF on the reproductive health of the exposed females breeding them with unexposed males as described in the Material and Methods section (M&M, from now on). Briefly, AB wild-type zebrafish embryos were exposed starting from 6 h post fertilization (6 hpf) until adulthood (180 days post-fertilization, dpf) to CPF 30 nM and CPF 300 nM, adding it to fish water (Figure S1a).…”

Thyroid Hormone Signaling and Function: News from Classical and Emerging Models

“…Nittoli et al evaluate the TH disrupting activity of pesticides, in the context of testicular toxicity comparing mouse and zebrafish. In particular, the authors proposed the possibility to use zebrafish as a suitable model to go in depth and dissect such responses [7]. The review from Zekri et al, provides an interesting summary of THs role in controlling adaptive thermogenesis (i.e., high energy expenditure and low body mass index) pointing out the debate of local versus central control of THs activity [8].…”