Retraction: Sustained Exposure to the Widely Used Herbicide Atrazine: Altered Function and Loss of Neurons in Brain Monoamine Systems

Atrazine (ATR; 2-chloro-4-ethylamino-6-isopropylamino-s-triazine), a chlorinated member of the family of s-substituted triazines, is one of the most widely employed herbicides in the world, with an estimated 76.4 million pounds used annually in the United States alone. It acts to suppress photosynthesis by inhibiting electron transfer at the reducing site of chloroplast complex II (Eldridge et al. 1999). Although it has limited solubility in water, ATR is frequently detected in ground and surface waters in agricultural regions (Colborn and Short 1999). Studies also reveal that ATR can be transported into the home, presumably tracked by soil (Lioy et al. 2000). Human exposure has been confirmed (Adgate et al. 2001; Clayton et al. 2003), and, in fact, approximately 60% of the U.S. population is exposed to ATR (Birnbaum and Fenton 2003). Recent reports indicate that acute dietary exposures range from 0.234 to 0.857 μg/kg/day, and corresponding figures for chronic dietary exposure are 0.046 to 0.286 μg/kg/day, considering all commodities with U.S. Environmental Protection Agency (EPA) tolerances and drinking water (Gammon et al. 2005). Occupational exposure to ATR, as measured in mixer-loadertender applicators, was reported to be approximately 2.8 mg ATR/day of work, with an absorbed dose of 1.8–6.1 μg/kg/day based on a 5.6% dermal absorption rate (Gammon et al. 2005). An earlier study of manufacturing workers reported a total ATR exposure of 10–700 μmol (~ 2.157–151.004 mg) per work shift (Catenacci et al. 1993). The understanding of the potential of ATR to serve as a contributing factor to human disease and dysfunction is currently extremely limited. Epidemiologic studies have linked environmental and/or occupational ATR exposure to increased mortality (Sathiakumar et al. 1996), and to nonHodgkin’s lymphoma (MacLennan et al. 2003; Sathiakumar and Delzell 1997). In experimental models, however, a growing experimental literature documents deleterious hormonal and reproductive system effects of ATR. In rodents, reported effects include reductions in testosterone levels; increases in triiodothyronine (Friedmann 2002; Stoker et al. 2000, 2002); suppression of immune function (Rooney et al. 2003), of luteinizing hormone (LH), and of prolactin surges (Cooper et al. 2000); the appearance of mammary gland tumors; a disruption of regular ovarian cycles; and the induction of pseudopregnancies (Cooper et al. 1996; Laws et al. 2000). The effects of ATR on ovarian function in female rats have been ascribed to changes in function of catecholamines in the hypothalamus, specifically decreases in norepinephrine (NE) and increases in dopamine (DA) in this region (Cooper et al. 1998). In correspondence with this observation, in vitro studies in PC12 cells show concentration-dependent decreases in intracellular DA after exposure to 12.5–200 μM ATR for 6, 12, 18, and 24 hr and decreases in NE release and intracellular NE concentrations after exposures to 100 and 200 μM ATR for 12, 18, and 24 hr (Das et al. 2000, 2003). In addition, reductions in the expression of DA β-hydroxylase [but not of tyrosine hydroxylase (TH)] were observed. The inhibitory effects of ATR on intracellular NE content and NE release, but not on DA intracellular content, were reversed when PC12 cells were co-incubated with ATR and agents known to enhance transcription, phosphorylation, or activity of TH and DA β-hydroxylase, such as 8-bromo-cAMP, forskolin, or dexamethasone (Das et al. 2003). These findings suggest that ATR could disrupt catecholamine metabolism by altering its biosynthetic enzymes. The fact that ATR can adversely affect hypothalamic catecholamine systems has notable implications because such effects would be unlikely to be restricted to this particular region, but could affect brain catecholamine systems more generally and thus affect pathways critical to the control of movement (nigrostriatal dopaminergic systems) and of complex cognitive functions (mesocorticolimbic dopaminergic systems). If so, then ATR exposures may also serve as a risk factor for neurodegenerative diseases and/or dysfunctions associated with these systems, which include Parkinson’s disease, schizophrenia, and attention deficit disorder, among others (Crossman 2000; Epstein et al. 1999; Viggiano et al. 2003). Indeed, epidemiologic studies have linked pesticides to an increased odds ratio for Parkinson’s disease (Breysse et al. 2002), and various pesticides that affect catecholaminergic