Actions of Bisphenol A and Bisphenol S on the Reproductive Neuroendocrine System During Early Development in Zebrafish

Abstract

Bisphenol A (BPA) is a well-known environmental, endocrine-disrupting chemical, and bisphenol S (BPS) has been considered a safer alternative for BPA-free products. The present study aims to evaluate the impact of BPA and BPS on the reproductive neuroendocrine system during zebrafish embryonic and larval development and to explore potential mechanisms of action associated with estrogen receptor (ER), thyroid hormone receptor (THR), and enzyme aromatase (AROM) pathways. Environmentally relevant, low levels of BPA exposure during development led to advanced hatching time, increased numbers of GnRH3 neurons in both terminal nerve and hypothalamus, increased expression of reproduction-related genes (kiss1, kiss1r, gnrh3, lhβ, fshβ, and erα), and a marker for synaptic transmission (sv2). Low levels of BPS exposure led to similar effects: increased numbers of hypothalamic GnRH3 neurons and increased expression of kiss1, gnrh3, and erα. Antagonists of ER, THRs, and AROM blocked many of the effects of BPA and BPS on reproduction-related gene expression, providing evidence that those three pathways mediate the actions of BPA and BPS on the reproductive neuroendocrine system. This study demonstrates that alternatives to BPA used in the manufacture of BPA-free products are not necessarily safer. Furthermore, this is the first study to describe the impact of low-level BPA and BPS exposure on the Kiss/Kiss receptor system during development. It is also the first report of multiple cellular pathways (ERα, THRs, and AROM) mediating the effects of BPA and BPS during embryonic development in any species.

Neuroendocrine disruption in animal models due to exposure to bisphenol A analogues

“…Exposure to BPS (100 μg/L) for the same embryonic time period resulted in increased number of GnRH3 neurons and upregulated expression of kiss1 , gnrh3 , and esr1 . In contrast to the above study that indicated the neural effects of BPS were independent of ESR1 [99], the findings from this other study showed that antagonists to ESRs, THRs, and aromatase inhibitor blocked most of the gene expression changes induced by BPA or BPS (at the 100 μg/L exposure dose) [100]. Exposure of 4 or 7 days post-fertilization (dpf) larvae to BPS, BPF, or BPAF (1 μM concentration) activated the expression of aromatase B (cyp19a1b) in the hypothalamus of developing zebrafish, and competitive ligand binding assays revealed this effect was mediated through zFER [28].…”

“…Another study that compared the neuroendocrine changes induced by developmental exposure to BPA or BPS also found that both chemicals resulted in similar alterations [100]. Low levels of BPA exposure (0.1 to 1000 μg/L) from 2 hpf until either 25 or 120 hpf led to advanced hatching time, increased numbers of gonadotrophin releasing hormone 3 (GnRH3) neurons in the terminal nerve region and hypothalamus (at the 100 μg/L dose).…”

“…Such changes include morphological and gene expression changes in the hypothalamus [99; 100; 101]. Conflicting results have been reported as to whether such BPA and BPA-analogue effects on the hypothalamus are mediated by ESRs.…”

“…Developmental or adult exposure of animal models to BPA-substitutes leads to several behavioral disruptions, including an increase in anxiogenic and hyperactive behaviors, compromised social interactions and parental care ability, and delayed habituation responses [62; 63; 64; 99; 107]. The collective data to date suggests that these chemicals can affect gene expression in the prefrontal cortex, hypothalamus, MPOA region, and likely other brain areas [28; 64; 65; 100; 103; 105]. These other bisphenols also induce hormonal imbalances in E2 synthesis and circulating concentrations, T levels, and thyroid hormone production [28; 66; 101; 102; 103; 104; 105].…”

Bisphenol S instead of bisphenol A: a story of reproductive disruption by regretable substitution - a review

“…The study of Qiu and colleagues evaluated the impact of BPA and BPS on the reproductive neuroendocrine system during zebrafish embryonic development, and explored potential mechanisms of action associated with ER, thyroid hormone receptor, and enzyme aromatase pathways. All of these pathways were necessary to observe the full effects of BPS on the changes in gene expression in the reproductive neuroendocrine axis (Qiu et al 2016). These data were substantiated by a decrease in egg production and hatchability and an increasing number of embryo malformations (Ji et al 2013).…”