Atrazine Exposure and Reproductive Dysfunction through the Hypothalamus-Pituitary-Gonadal (HPG) Axis

Abstract

Endocrine disrupting chemicals (EDC) are exogenous agents that alter endogenous hormone signaling pathways. These chemicals target the neuroendocrine system which is composed of organs throughout the body that work alongside the central nervous system to regulate biological processes. Of primary importance is the hypothalamic-pituitary-gonadal (HPG) axis which is vital for maintaining proper reproductive function. Atrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine) is a pre-emergent herbicide used to prevent the growth of weeds on various crops. This herbicide is reported to widely contaminate potable water supplies everywhere it is applied. As such, the European Union banned the use of atrazine in 2004. Currently the United States Environmental Protection Agency regulates atrazine at 3 parts per billion (ppb; μg/L) in drinking water, while the World Health Organization recently changed their drinking water guideline to 100 ppb. Atrazine is implicated to be an EDC that alters reproductive dysfunction by targeting the HPG axis. However, questions remain as to the human health risks associated with atrazine exposure with studies reporting mixed results on the ability of atrazine to alter the HPG axis. In this review, the current findings for atrazine's effects on the HPG axis are examined in mammalian, anuran, and fish models and in epidemiological studies.

Keywords: atrazine; endocrine disrupting chemical; hormones; hypothalamus-pituitary-gonadal axis; reproductive dysfunction.

Figure 1

Working conceptual model of steroidogenesis and upstream regulators associated with atrazine exposure. This diagram represents the upstream cellular mechanisms (upstream regulators are in blue) and steroidogenic genes (in red) that are reported to be altered by atrazine exposure. All genes are included above as their human homologs.

Figure 2

Working conceptual model of atrazine toxicity on the hypothalamus-pituitary-gonadal (HPG) axis across mammalian, anuran, and fish species. This diagram summarizes the main common alterations observed with atrazine exposure on the HPG axis based upon studies across multiple species and exposure paradigms. Atrazine exposure elicits an increase in Kiss1 mRNA and a decrease in gonadotropin releasing hormone (GnRH) release leading to a downstream reduction in luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary. This reduction in gonadotropins elicits alterations in testosterone, estrogen, and progesterone. In addition, histological and morphological alterations in the ovaries and testes are observed and are ultimately dependent on time of exposure and dose. (Green indicates increases, pink indicates reductions, and grey indicates that both increases and reductions are reported. Histological and morphological effects in males are indicated in purple, while alterations in females are in red; VO: vaginal opening).