Chemical-induced retinoid disruption
The report covers an overview of the retinoid system, the role of retinoids in the reproductive organs,
the impact of chemicals on reproduction via the retinoid system, potential adverse outcome pathways,
and an initial scoping effort for the possible role of chemical-induced retinoid disruption of the male
and female reproductive systems. In this report, the term reproduction refers to the formation and
development of reproduction organs and their normal function.
Crosstalk between the retinoid signaling pathway and other endocrine signaling pathways
RXR can heterodimerize with other steroid and nuclear receptors, and functions essentially as a
** master switch between different signaling pathways.** Consequently, the retinoid signaling pathway
can crosstalk with other signaling pathways: in addition to the RARs, the heterodimerization partners
of RXRs include PPARs, TR, and VDR; the vitamin D receptor (Chambon 1996). In addition, crosstalk
with androgenic signaling (Long et al. 2019), as well as with xenobiotica-related receptor pathways,
via e.g. CAR; the constitutive androstane receptor, PXR, and AhR; the aryl hydrocarbon receptor has
been demonstrated. Possible responses to toxic insult include induction of xenobiotica-metabolizing
enzymes (Murphy et al. 2007, Shmarakov et al. 2019).
The Role of Retinoids in Female and Male Reproduction Including a Scoping
Effort to Identify Potential Methods for Regulatory Use
A few thoughts,
Polycystic ovarian syndrome
Polycystic ovary syndrome (PCOS) is a common endocrine condition affecting women of
reproductive age, characterized by hyperandrogenism
Polycystic ovarian syndrome (PCOS) is a heterogenous disorder, characterized both by signs of
** androgen excess and ovarian dysfunction (such as irregular ovulation and/or polycystic ovarian
morphology) (Escobar-Morreale 2018). Increased ovarian androgen production from theca cells,
elevated LH:FSH hormone ratio, and enlarged ovaries containing many antral follicles is often
observed; the associated arrest in follicular growth and anovulation can cause subfertility or
infertility (Jiang et al. 2017).
When comparing the response to RA, 9-cis-RA and retinol in cultured theca cells isolated from
normal-cycling women and women with PCOS, only RA led to increased testosterone production
(possibly via increased Cyp17 expression) in normal theca cells, ile in the theca cells of PCOS
patients, all three (RA, retinol, and 9-cis-RA) variants have the same effect (Wickenheisser et al.
** 2005). Thus, in PCOS, theca cells may be sensitized to retinoid signaling stimulation. Moreover,
** mRNA expression of RA-synthesizing enzymes RoDH2 and ALDH6 was increased in PCOS theca cells**
** (Wood et al. 2003), and PCOS ovaries show enhanced expression of RoDH (Marti et al. 2017). These**
** data suggest an increased rate of RA synthesis in the thecal cells of PCOS women** (Jiang et al. 2017).
Epigenetics and its role in the retinoid system
Epigenetic changes are changes in gene expression that
a) do not involve gene sequence alterations
b) may persist after the initial trigger is long gone
Male reproductive organ development, function and health, and the role of retinoids
Degradation of endogenous RA appears to be critical for normal testis development
Impact on female and male reproduction by chemicals acting via the retinoid system
It should be pointed out that effects of chemicals on retinoid homeostasis can be indirect, since some
metabolic enzymes are used both for detoxification and for retinoid homeostasis, If the end result is altered RA concentrations in fetal or adult reproductive organs, correct development and/or function of these organs could be compromised.
#SolvePFS Working Hypothesis
