Abstract
Disrupted ovarian development induced by chemical exposure may impair fertility later in life. Since androgens are essential for early ovarian development, we speculated that perinatal exposure to a binary mixture of the known anti-androgens DEHP and procymidone could alter steroid synthesis, disrupt ovarian follicle recruitment and ultimately maturation in female rat offspring. Wistar rat dams were exposed by oral gavage from gestation day 7 to postnatatal day 22 to two mixture doses known to alter reproductive development in male offspring (low: 10 mg/kg bw/day of procymidone and 30 mg/kg bw/day of DEHP; high: 20 mg/kg bw/day of procymidone and 60 mg/kg bw/day of DEHP). The Effects on plasma steroid hormones, ovarian follicle distribution and expression of markers related to steroid synthesis were examined in female offspring. In prepubertal offspring, we observed an increased number of newly recruited (primary) follicles in exposed animals compared to controls, and the plasma steroid hormone profile was altered by exposure: levels of progesterone, corticosterone and estrone were dose dependently elevated, whereas androgen levels were unaffected. In adulthood, a trend towards a smaller number of early-stage follicles may point to accelerated loss of follicle reserves, which is disconcerting. The changes in follicle distribution in exposed ovaries may reflect the combined influence of androgen receptor antagonism and altered ovarian steroid synthesis. This study adds to a growing body of evidence showing altered ovarian development following exposure to human relevant chemicals with possible severe consequences for female fertility.
Highlights
Fertility problems in women have increased in recent decades
Androgens are essential for early ovarian development, as they induce the expres sion of follicle stimulating hormone receptor (FSHR), which supports follicle stimulating hormone (FSH)-driven follicular growth and matu ration (Dewailly et al, 2016; Lebbe and Woodruff, 2013)
In male offspring exposed to the same mixture, we see clear effects on male reproductive development that are likely related to an anti-androgenic influence (Christiansen et al, 2020), and we speculate that other modes of action may be prominent in females, as discussed below
Summary
Fertility problems in women have increased in recent decades. The causes are not well known, but exposure to endocrine disrupting chemicals (EDCs) is proposed to contribute to the disease burden (Buck Louis et al, 2011; Johansson et al, 2017). EDCs can disrupt the endo crine system and lead to a wide range of health problems that may contribute to reproductive disorders later in life (Schug et al, 2011; Isling et al, 2014; Gore et al, 2015), including altered ovarian follicle development and recruitment (Karavan and Pepling, 2012; Moyer and Hixon, 2012; Johansson et al, 2017) This is of great concern since girls are presumed to be born with a set number of oocytes, a reserve that is meant to last throughout their reproductive lifespan. Androgens are essential for early ovarian development, as they induce the expres sion of follicle stimulating hormone receptor (FSHR), which supports follicle stimulating hormone (FSH)-driven follicular growth and matu ration (Dewailly et al, 2016; Lebbe and Woodruff, 2013)
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